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# QUESTIONS Diagnosis/Staging What benefit to clinical management does positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) contribute to the diagnosis or staging of head and neck cancer? What benefit to clinical management does PET or PET/CT contribute to the assessment of treatment response for head and neck cancer? What benefit to clinical management does PET or PET/CT contribute when recurrence of head and neck cancer is suspected but not proven? What benefit to clinical management does PET or PET/CT contribute to restaging at the time of documented recurrence for head and neck cancer? What is the role of PET when a solitary metastasis is identified at the time of recurrence and a metastectomy is being contemplated? # TARGET POPULATION Patients with head and neck cancer are the target population for this recommendation report. # INTENDED PURPOSE This recommendation report is intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality U.K. Health Technology Assessment (HTA) systematic review (1) that included systematic review and primary study literature for the period from 2000 to August 2005, an update of this systematic review undertaken to retrieve the same level of evidence for the period from August 2005 to June 2008, and a subsequent literature search was conducted to retrieve literature from June 2008 to July 2011. PET is recommended in the M and bilateral nodal staging of all patients with head and neck squamous cell carcinoma where conventional imaging is equivocal, or where treatment may be significantly modified. HTA review 2007 (1): One systematic review of four primary studies and one additional primary study showed PET was sensitive and specific and useful where doubt exists (CT/MRI gave different and less optimal results). PET changed stage and treatment planning. 32) and Guido et al (33) indicated that the addition of PET improved primary tumour delineation and nodal staging and subsequently changed the clinical management of several patients in each study. PET is recommended in all patients after conventional imaging and in addition to, or prior to, diagnostic panendoscopy where the primary site is unknown. HTA review 2007 (1): Two systematic reviews (each with eight primary studies) and two additional primary studies showed that PET can detect primary unknown tumours in patients with cervical lymph node metastases. PET detects 30% of primary tumours, including those missed by conventional imaging. 2005-2008 update: One primary study showed that PET is better than conventional imaging in detecting site of primary tumour (Chen et al. 2008 2011 update: One primary study indicated that patients with cervical metastasis and an unknown primary site after undergoing conventional imaging or clinical examination benefit from PET/CT prior to panendoscopy (Rudmik et al PET is recommended for staging and assessment of recurrence of patients with nasopharyngeal carcinoma if conventional imaging is equivocal. HTA review 2007 (1): This topic was not addressed in the HTA review. # Qualifying Statements This report makes no distinction between studies examining PET and those examining PET/CT. Conventional imaging refers to CT and/or magnetic resonance imaging (MRI) unless otherwise specified. Retrospective design studies were excluded from this review, but several exist favouring the use of PET for head and neck cancer. With respect to primary site (T): - PET appears to be more accurate for the diagnosis of primary tumours, especially in cases where CT/MRI results are equivocal (2008-2011 update: Guido et al Wang et al. o PET can identify the primary site in 30% of cases when undetected by clinical assessment and conventional imaging. - PET can detect some synchronous primaries that may be missed by other modalities. With respect to regional nodes (N): In the clinically N-0 neck, PET does not appear to be better than conventional imaging, because of an unacceptably high false-negative rate. There is little evidence that PET leads to change in patient management (2005-2008 update: Hafidh et al Ng et al Schoder et al Wensing et al Kim et al ; 2008-2011 update: Moeller et al and Kyzas et al Liao et al. There was moderate evidence that PET scanning changed nodal staging status and/or radiation treatment planning. However, in many cases there was no pathologic confirmation of PET versus conventional imaging discrepancy. Exceptions were cases where distant metastatic disease was identified by PET and changed treatment (2005-2008 update: Connell et al. # With respect to distant disease (M): - There is strong evidence that PET imaging is valuable in detecting distant metastatic disease and is better than conventional imaging. The advantage of PET is overwhelming for patients at high risk for distant disease, which includes locally advanced disease and nasopharyngeal carcinoma. The substantial incidence of falsepositive rates of PET may mitigate the advantages for low-risk patients (2008-2011 update: Kim et al Law et al Lonneux et al Martin et al Ng et al Senft et al Yamazaki et al Wang et al. # Qualifying Statements With respect to recurrence and tumour surveillance after treatment, the evidence suggests that sites of disease that are clinically accessible for assessment did not benefit from PET imaging. However, for disease sites that were either not clinically accessible or difficult to examine, PET imaging showed significant advantages over conventional evaluation. - Larynx: moderate evidence that PET is beneficial/better than conventional imaging in detecting recurrent disease. PET also reduced the need for debilitating laryngeal biopsies (2005-2008 update: Gordin et al Brouwer et al. . With respect to the role of PET in assessing status of neck lymphadenopathy following radiation or chemoradiation, moderate evidence suggests that PET-directed management of the neck after therapy, appropriately spares neck dissections in patients with PETnegative residual CT abnormalities (2008-2011 update: Porceddu et al. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# GUIDELINE OBJECTIVES To update clinical guidance on the use of multigene profiling assays in individuals with earlystage invasive breast cancer. # TARGET POPULATION Individuals diagnosed with early-stage invasive breast cancer for whom further information is needed for prognosis and treatment decision making. In this guideline, early-stage invasive breast cancer is defined as stage I to III breast cancers that are surgically operable and do not have evidence of inflammatory, locally recurrent or distant metastatic disease with pT1-T3, pN0-N1a based on surgical pathologic staging. # INTENDED USERS This guideline is targeted for clinicians and policy makers involved in the diagnosis and treatment of breast cancer. The purpose of this guideline is to determine the clinical utility of multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index), not to identify which assay is better. No prospective studies have compared these head-to-head. Given that the assays use different scoring systems and classification systems, please refer to Table 1-1 for a summary of each of the assays. Further, this guideline does not cover the utility of multigene profiling assays in helping to guide clinical treatment decisions regarding the use of either neoadjuvant chemotherapy or radiation. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION Recommendation 1 In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy. # Qualifying Statements for Recommendation 1 - There is currently insufficient evidence to use multigene profiling assays among patients with either HER2-positive or triple negative breast cancers. - Multigene profiling assays are recommended for use in patients with lymph nodenegative or lymph node-positive (1-3 lymph nodes) disease who are under consideration for adjuvant chemotherapy if the use is supported by other clinical, pathological, or patient-related factors. Clinical and pathological features include patient age, tumour grade, tumour size and nodal status. - One multigene profiling assay should be requested per patient to guide a specific treatment decision. Requesting multiple tests with different multigene profiling assays on an individual tumour specimen to guide a single treatment decision is discouraged. Additional testing may be considered for patients with either repeat metachronous breast cancer diagnoses or synchronous breast cancer diagnoses where tumour specimens display varying morphologies, grade or hormone receptor status. - Multigene profiling assays should be interpreted cautiously in premenopausal patients where a significant benefit from adjuvant chemotherapy may still exist despite a lowrisk score. - It is uncertain whether at least some of the benefit of chemotherapy among premenopausal patients may be due to chemotherapy induced amenorrhea versus the cytotoxic effects of treatment. - The Prosigna, EndoPredict/EPclin, and Breast Cancer Index assays can identify low-risk node-positive patients whose prognostic outcomes are favourable; however, these assays have not demonstrated predictive evidence to support withholding adjuvant chemotherapy among higher risk, node-positive, ER-positive, HER2-negative breast cancer patients. # Recommendation 5 The evidence to support the use of molecular profiling to select the duration of endocrine therapy is evolving. In patients with ER-positive disease, clinicians may consider using a Breast Cancer Index (BCI) (H/I) high assay result to support a decision to extend adjuvant endocrine therapy if the decision is supported by other clinical, pathological, or patientrelated factors. # Qualifying Statements for Recommendation 5 - While a number of studies have demonstrated clinical utility of BCI for extending adjuvant endocrine therapy, the preliminary results of the NSABP B42 trial are negative leading to some uncertainty. Treatment decisions should be based on all available clinical and pathological information for each patient, rather than depending only on multigene profiling tests. - MammaPrint, Oncotype DX, Prosigna, and EndoPredict currently have insufficient evidence to guide extension of adjuvant endocrine therapy; however, these molecular assays may prognosticate a very low rate of disease recurrence that might not justify an extension of endocrine therapy.

# GUIDELINE OBJECTIVES To make recommendations with respect to the use of T2-weighted magnetic resonance imaging (MRI) ± functional sequences in the pre-treatment local staging of patients with newly diagnosed prostate cancer. - MRI refers to T2-weighted MRI. - Functional sequences include dynamic contrast-enhanced imaging (DCE), diffusionweighted imaging (DWI), and proton magnetic resonance spectroscopic imaging (MRS). - In this guideline, the terminology of MRI ± functional sequences is used interchangeably with MRI ± DCE, DWI, and MRS (See Glossary of Terms, Appendix 1). # TARGET POPULATION Men with newly diagnosed biopsy-confirmed prostate cancer who are under consideration for radical treatment. # INTENDED USERS Clinicians who are involved in the staging and treatment of prostate cancer patients. # RECOMMENDATIONS Recommendation 1 Multiparametric MRI (mpMRI) use for pre-treatment local staging of prostate cancer is a reasonable option for assessment of extraprostatic extension (EPE) in intermediate-and highrisk patients being considered for radical therapy if knowledge of EPE will alter management. # Qualifying Statements for Recommendation 1 - mpMRI is the addition of two or more functional sequences to

Evidence-Based Series 4-5 is CURRENT as of November 2022. In June 2016 a literature search and review determined that the recommendations were still valid and not causing harm but all relevant aspects of the topic were not covered by the original guideline. This document was identified for an UPDATE but it is anticipated that key evidence will be published in the next few years and a new guideline will be undertaken at that time.# New evidence found by update searches since completion of the original guideline is consistent with the original recommendations. # Guideline Question For women with cervical cancer in whom radiotherapy is considered appropriate, does the addition of concurrent platinum-based chemotherapy improve survival and quality of life with acceptable toxicity? # Target Population These recommendations apply to women with cervical cancer for whom primary treatment with radiotherapy is being considered: -those with locally advanced cervical cancer, -those with bulky clinical stage IB (>4 cm) cervical cancer, who are treated with radiotherapy, -those with high-risk early-stage cervical cancer (node-positive or margin-positive), who will be treated with radiotherapy following hysterectomy. - Women with cervical cancer for whom treatment with radiotherapy is being considered (described above) should be offered concurrent cisplatin with their course of radiotherapy. There are no direct comparisons of different cisplatin regimens. Based on the review of the available toxicity data from the randomized controlled trials, the Disease Site Group felt that cisplatinum should be given weekly (40 mg/m 2. # Qualifying Statements - Despite this recommendation, other schedules and doses have been used; thus, there is no conclusive evidence that one dose and schedule is better than the other. There is insufficient evidence available to make recommendations on the addition of 5fluorouracil to cisplatin during radiotherapy Entries to MEDLINE (1966through June 2004, EMBASE (1980EMBASE ( through week 25, 2004, CANCERLIT (1975through October 2002, and Cochrane Library (2004, Issue 2) databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology from 1999 to 2004 were systematically searched for evidence relevant to this practice guideline report. Evidence was selected and reviewed by members of the Practice Guidelines Initiative's Gynecology Cancer Disease Site Group and methodologists. This practice guideline report has been reviewed and approved by the Gynecology Cancer Disease Site Group, comprised of medical oncologists, radiation oncologists, a pathologist, an oncology nurse and patient representatives. External review by Ontario practitioners is obtained for all practice guideline reports through a mailed survey. Final approval of the practice guideline report is obtained from the Practice Guidelines Coordinating Committee. The Practice Guidelines Initiative has a formal standardized process to ensure the currency of each guideline report. This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Key Evidence - Eight randomized controlled trials were eligible for the evidence review: six compared cisplatin-based chemotherapy plus radiotherapy to radiotherapy alone (in one of those trials, para-aortic radiotherapy was added to pelvic radiotherapy in the control arm) and two compared cisplatin-based chemotherapy plus radiotherapy to radiotherapy plus hydroxyurea. - The guideline authors pooled survival data from published reports. Pooled survival rates detected a statistically significant effect in favour of cisplatin-based chemotherapy plus radiotherapy compared with radiotherapy alone or with hydroxyurea (relative risk of death, 0.74; 95% confidence interval, 0.64 to 0.86). - The pooled relative risk of death among the six trials that enrolled only women with locally advanced cervical cancer was 0.78 (95% confidence interval, 0.67 to 0.90) in favour of cisplatin-based chemotherapy and radiotherapy. - The pooled relative risk for the two trials in high-risk early-stage disease also demonstrated a significant benefit for the addition of cisplatin-based chemotherapy to radiotherapy (relative risk, 0.56; 95% confidence interval, 0.41 to 0.77). - Rates of serious hematologic, gastrointestinal and genitourinary acute adverse effects are higher with cisplatin-based chemotherapy plus radiotherapy than with radiotherapy alone. For further information about this practice guideline, please contact the authors through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca The Practice Guidelines Initiative is sponsored by: Cancer Care Ontario & the Ontario Ministry of Health and Long-term Care. Visit for all additional Practice Guidelines Initiative reports.

# GUIDELINE OBJECTIVES To make recommendations with respect to the role of adjuvant systemic chemotherapy in stage II and III colon cancer patients who have undergone complete resection with curative intent. # TARGET POPULATION The target population consists of adult patients with stage II and III colon cancer who have undergone complete resection with curative intent as primary therapy. # INTENDED USERS Intended users of this guidance document are clinicians involved in the delivery of adjuvant systemic chemotherapy for stage II and III colon cancer patients. # Stage II Colon Cancer Recommendation 1 The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, adjuvant therapy is a reasonable option for the subset of patients with high-risk stage II disease. While there is controversy about which tumour features denote high risk in stage II patients, this subset includes patients with inadequately sampled nodes, T4 lesions, perforation at the site of the tumour, or poorly differentiated histology in the absence of microsatellite instability (MSI) or mismatch repair deficiency (dMMR). # Qualifying Statements for Recommendation 1 - The clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity, the presence of high-risk prognostic features on individual prognosis, and patient preferences. - The enrolment of resected stage II patients in clinical trials is encouraged. Additional trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer. # Recommendation 2 When treated with adjuvant therapy, high-risk stage II patients should receive a fluoropyrimidine. There are insufficient data in support of oxaliplatin providing additional benefit to all high-risk individuals. The 2015 guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making. Please see Section 6: Document Assessment and Review for a summary of updated evidence published between 2015 and 2018, and for details on how this guideline was ENDORSED. # Qualifying Statements for Recommendation 2 - It would be reasonable to consider FOLFOX for high-risk patients as part of an informed discussion between patients and their medical oncologists regarding treatment options. # Added to the 2019 Endorsement - Additional evidence is expected that will inform decisions on duration of treatment with oxaliplatin-based treatment in patients with stage II disease. The following data are from a recent abstract (Iveson, ASCO, 2019), and thus should be considered with caution. The IDEA collaboration evaluated 3 vs 6 months of therapy in a randomized, pre-planned, pooled analysis of 4 RCTs focusing on high-risk stage II patients. The decision to use CAPOX or FOLFOX was left to the treating physician. Noninferiority was not met for DFS comparing 3 vs 6 months (HR 1.18, 95% CI 1.05 to 1.31; noninferiority margin was 1.2). Five-year DFS was 80.7% vs 84.0% for 3 and 6 months, respectively. There was a significant reduction in grade 3 to 5 toxicity with 3 months of therapy (irrespective of regimen). See Section 6 for details. Most patients suitable for oxaliplatin-based combination chemotherapy should discuss the differences between CAPOX and FOLFOX with their oncologist and choose a balance between efficacy and toxicity: - The IDEA results suggest that 3 months of CAPOX results in very similar efficacy to 6 months, whereas it appears that 3 months of FOLFOX resulted in slightly lower DFS (but the interaction test for duration and regimen was not statistically significant). - The duration of 5-FU monotherapy was not addressed in IDEA, and should remain 6 months. # Recommendation 3 Adjuvant chemotherapy with a fluoropyrimidine monotherapy regimen following surgery in patients who have MSI/dMMR is not recommended. MSI/dMMR testing should be performed for all stage II patients for whom adjuvant chemotherapy is being considered. In stage II (in the absence of high-risk features) where a patient does not require adjuvant chemotherapy, MSI/dMMR testing is not recommended as it will not influence that decision. # Qualifying Statements for Recommendation 3 - In patients with high-risk stage II colon cancer (e.g., T4) and high MSI/dMMR status (a low risk factor), the choice of treatment is between observation and FOLFOX, but data are lacking to guide this decision. # Stage III Colon Cancer # Qualifying Statements for Recommendation 4 - 5-FU may be given intravenously in combination with LV and oxaliplatin in the regimens known as FOLFOX or FLOX, or capecitabine may be given orally in combination with intravenous oxaliplatin in the regimen known as XELOX. These oxaliplatin-containing regimens have demonstrated superior overall survival when compared with 5-FU plus LV and are the recommended regimens. Oxaliplatin administration is associated with a 12.5% risk of severe neuropathy which is permanent in approximately 1% of patients. This needs to be considered in conjunction with the expected benefits of therapy. - Owing to the toxicity profile of FLOX, it is used less frequently than FOLFOX. - Some patients would not be considered appropriate for oxaliplatin-containing regimens. Examples include patients with underlying neurological conditions or at increased risk of neuropathy, patients at increased risk for infections, and patients likely to poorly tolerate infections as a result of chemotherapy. For these patients the treatment options are: o oral capecitabine which has equivalent efficacy to intravenous bolus 5-FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more hand-foot syndrome when compared with bolus 5-FU/LV. o 5-FU in combination with LV - Suitable patients should be offered entry into clinical trials testing new adjuvant treatments for resected stage III colon cancer. - Patients have begun their adjuvant treatment within four to nine weeks of surgery in the adjuvant randomized controlled trials of resected colon cancer. # Added to the 2019 Endorsement - The IDEA collaboration evaluated 3 vs 6 months of therapy in a randomized, pre-planned, pooled analysis of 6 individual trials focusing on stage III patients. The treatment choice of CAPOX or FOLFOX was left to the treating physician. Overall, noninferiority was not met for 3 vs 6 months (3-year DFS HR 1.07, 95% CI 1.0 to1.15; noninferiority margin was 1.12). Pre-planned sub-group analysis revealed superiority for 6 months of FOLFOX, whereas 3 months of CAPOX was found to be noninferior to 6 months. 3 months of treatment was associated with lower rates of adverse events independent of chemotherapy regimen (Grothey et al, NEJM, 2018). An unplanned analysis was devised sub-dividing patients into "low" and "high" risk stage III disease, and is the basis for our statements below. See Section 6 for details. - Low-risk stage III (T1-3 N1): 3 months of CAPOX is preferred over FOLFOX. Although the overall trial was negative for the primary endpoint, the shorter duration of treatment strikes a reasonable balance between efficacy and neurotoxicity of oxaliplatin (3 months noninferior to 6 months: HR 1.01, 95% CI 0.90 to 1.12). The pros and cons of 3 vs 6 months should be discussed with patients. Alternatively, 5-FU/capecitabine monotherapy for 6 months' duration remains an option, especially for patients with contraindications to oxaliplatin or preferences for oral chemotherapy. - High-risk stage III (T4 +/-N2): 6 months of oxaliplatin-based chemotherapy (CAPOX or FOLFOX). Although the overall trial was negative for the primary endpoint, the shorter duration of treatment resulted in lower DFS (6 months superior to 3 months: HR 1.12, 95% CI 1.03 to 1.23). The longer duration of therapy is associated with higher rates of neurotoxicity. The pros and cons of CAPOX vs FOLFOX need to be discussed with patients. # Recommendation 5 Although post hoc analyses of studies have not shown a clear benefit of adjuvant fluoropyrimidine plus oxaliplatin regimens in patients older than 70 years of age, it is reasonable to consider FOLFOX for patients older than 70 years as part of an informed discussion between patients and their medical oncologists regarding treatment options.

# Section 1: Recommendations Section 2: Recommendations and Key Evidence Section 3: Guideline Methods Overview Section 4: Systematic Review Section 5: Internal and External Review For information about this document, please contact Alex Sun, the lead author, through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # PEBC Report Citation (Vancouver

These guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making.# GUIDELINE OBJECTIVE How should patients presenting to family physicians and other primary care providers (PCPs) with signs and/or symptoms of prostate cancer, including incidental prostate specific antigen (PSA) test results, be managed? The following questions are the factors considered in answering the overall question: RESEARCH QUESTIONS 1. What signs, symptoms, and other clinical features that present in primary care are predictive of prostate cancer? 2. What is the diagnostic accuracy of investigations commonly considered for patients presenting with signs and/or symptoms of prostate cancer? 3. What major, known risk factors increase the likelihood of prostate cancer in patients presenting with signs and/or symptoms of prostate cancer? 4. Which factors are associated with delayed referral? Which delay factors can be attributed to patients, and which factors can be attributed to providers or system-related factors? Does a delay in the time to consultation affect patient outcome? # TARGET POPULATION Adult male patients presenting in primary care settings with signs, including incidental PSA results (defined as results not ordered by the attending FP or other primary care provider, or symptoms suggestive of prostate cancer comprise the target population. This guideline does not provide recommendations for screening healthy patients or opportunistic PSA testing. # INTENDED USERS This guideline is targeted to family physicians (FPs), general practitioners (GPs), emergency room physicians, other PCPs (nurse practitioners, registered nurses, and physician assistants), and urologists. For the purposes of this document, we have referred to FPs, GPs, emergency room physicians, and other PCPs as "FPs and other PCPs". The guidelines are also intended for policymakers to help ensure that resources are in place so that target wait times are achieved. They are intended to coincide with the introduction of prostate cancer Diagnostic Assessment Programs (DAPS) in Ontario. DAPs provide a single point of referral, coordination of care using a clinical navigator, fast tracking of diagnostic tests, and a multidisciplinary team approach. They are an Ontario-wide strategic priority designed to improve patient access and outcomes, as outlined in the Ontario Cancer Plan, 2005-2011 and 2011-2014 (1). Added in December 2019: Formal Cancer Care Ontario DAPs no longer exist in Ontario, but many hospitals provide ongoing multidisciplinary team approaches to diagnosing prostate cancer. The following recommendations were adapted from the New Zealand Guidelines Group (NZGG) guideline "Suspected Cancer in Primary Care: Guidelines for Investigation, Referral and Reducing Ethnic Disparities" and the National Institute for Health and Clinical Excellence (NICE 2005), "Referral Guidelines for Suspected Cancer" (2,3).The recommendations below reflect the integration of the NZGG 2009 and NICE 2005 recommendations, an updated systematic review of the research evidence since the NZGG 2009 and the NICE 2005 guidelines, and consensus by the PEBC Prostate Cancer Referral Working Group (see Section 2: Appendix 1 for a list of members) (2,3). The recommended wait times for referral were based on consensus as opposed to strong evidence from well-conducted studies. During the review process for this document in December 2016 when Version 2 of this guideline was ENDORSED, the Expert Panel noted that these wait time targets should be the goal, but may not always be possible. The recommended wait times for referral were based on consensus rather than strong evidence from well-designed studies. These targets are the goal, but may not always be possible. # KEY EVIDENCE AND JUSTIFICATION All recommended wait times were based on consensus of the Working Group. The Canadian Association of Radiation Oncology recommended a wait time from referral to consultation with a radiation oncologist of no longer than 10 working days (6). This was taken into consideration when developing the wait times in this guideline. The primary care literature evidence examining the diagnostic accuracy of tests for prostate cancer was very weak. Two studies suggested that DREs performed by FPs may be useful in identifying patients who should be referred (7,8), and four studies suggested that PSA values were good predictors of prostate cancer with PPVs ranging from 34.3% to 47% (7,(9)(10)(11). The working group chose to endorse the recommendations from NICE 2005 and NZGG 2009 to recommend a DRE and PSA test for all patients with symptoms of metastatic prostate cancer (2,3). NICE 2005 recommended performing a DRE and PSA test for all men with LUTS and NZGG 2009 recommended these tests only for older men with LUTS (2,3). The working group chose to recommend a DRE for all men with LUTS and a PSA test for selected patients with LUTS, following discussion and treatment. The limited evidence from the systematic review suggested that men with LUTS may not be at any higher risk for prostate cancer or have a poorer prognosis than asymptomatic men would be (9,12). The Canadian Urological Association's benign prostatic hyperplasia guideline for men presenting with LUTS recommended a DRE for all men and a PSA test for selected patients (13). The working group chose to be consistent with this guideline. # Recommendation 1. Actions for Patients with Symptoms of Metastatic Prostate Cancer The NZGG 2009 guideline recommendation that patients with symptoms of metastatic prostate cancer should have a DRE and PSA was endorsed (3). An age threshold of 40 years was included at the suggestion of the Expert Panel and due to the few cases of prostate cancer in men under 40 years in Canada (14). The working group did not think it necessary for a man with erectile dysfunction to undergo a DRE and PSA test and therefore excluded it as a symptom of metastatic prostate cancer. This is consistent with the NZGG 2009 guideline but in contrast to the NICE 2005 guideline (2,3). The working group also excluded unexplained hematuria as a symptom of metastatic prostate cancer because although it can be associated with advanced prostate cancer, the Working Group believed the vast majority of men with gross hematuria usually have a different underlying cause such as benign prostate hyperplasia, bladder or renal cancer, stones or infections. The working group believed hematuria requires urologic assessment but is not part of a prostate cancer care algorithm. a-c. The cut-off values of 10 and 20 ng/ml were taken from the D'Amico classification system for categorizing patients at low risk (cT1-cT2a, Gleason 20 ng/ml or Gleason >7) for prostate cancer (15,16). Although this was not developed in the primary care population, the working group chose to include this classification system because it is widely used to classify risk of prostate cancer and using these thresholds provides guidance for family physicians in determining their course of action. # Recommendation 2. Actions for Patients with Lower Urinary Tract Symptoms (LUTS) The recommendation that a man with LUTS should have a DRE and a discussion about PSA testing was consistent with the Canadian Urological Association's guideline for benign prostatic hyperplasia (13). The working group referred to the individual risk assessment developed by the Canadian Partnership Against Cancer as a guide to who should be given a PSA test (4). This document describes the benefits and harms of PSA testing. The working group also endorsed the recommendations to exclude urinary infection before PSA testing and to postpone PSA testing for at least one month after treatment from the NICE 2005 and NZGG 2009 guidelines (2,3). a. This recommendation was endorsed from the NICE 2005 guideline (2). b. The age-based PSA values were endorsed from the NZGG 2009 guidelines (3). c-e. Please refer to a-c in the previous section under Recommendation 1: Actions for Patients with Symptoms of Metastatic Prostate Cancer. f. i. A cut-off risk value of 5% was chosen because in Ontario, Canada, the hospital admission rate for urological complications within 30 days of TRUS-guided biopsy was found to be 4.1% in 2005 (17). The working group decided to use 5% as a cut-off to separate patients into a higher risk category because for these patients the risk of high-grade prostate cancer would be higher than the risk of complications from TRUSguided biopsy. ii-iii. The prostate risk calculator developed at Sunnybrook Hospital, Toronto, Ontario, Canada, showed a net benefit (the relative value of false-positive versus falsenegative results) when a risk of 15% for aggressive prostate cancer was chosen as a threshold to agree to a biopsy (18). Based on the consensus of the working group a conservative cut-off risk value of 20% was chosen. # Recommendation 3. Actions for Patients with Incidental PSA Although this guideline excludes patients in a screening program, the working group thought that FPs and other PCPs need guidance on how to manage patients with incidental PSA test results, a frequently encountered occurrence in practice. Opportunistic screening has been excluded because it is beyond the scope of this guideline. The working group believed that if an incidental PSA test was abnormal, then standard practise would be to perform a DRE. A hard or irregular prostate on DRE may increase the urgency of referral. Cases with enlarged, smooth prostates were excluded because it was beyond the scope of this guideline since it was not considered to be a sign of prostate cancer. Also, although a rising PSA level could be considered a sign of prostate cancer, the working group believed the guideline was sufficiently thorough to include most possible scenarios for prostate cancer using the absolute PSA values. Furthermore, there were no studies examining the factors associated with delayed referral that could directly inform these recommendations. # FUTURE RESEARCH Further studies are required that specifically investigate the diagnostic performance of signs, symptoms, or tests for prostate cancer in the primary care setting. # GLOSSARY Age-based PSA Age-based PSA values (upper limit of normal): 40-50 years: 2.5 ng/ml 50-60 years: 3.5 ng/ml 60-70 years: 4.5 ng/ml 70 years and over: 6.5 ng/ml Note: This is an example of an age-based range cited in the NZGG resource: Testing for prostate cancer: a consultation resource, 2008 (19). Differences in PSA assay can lead to differences in age-based ranges reported by laboratories. Prostate Risk Calculator developed by Nam et al 2011 is available here: (5). The prostate risk calculator includes the free:total PSA ratio, which is the ratio of free PSA, unbound to serum proteins, to total PSA. This ratio is decreased in men with prostate cancer (20). The free:total PSA ratio in some cases may be charged a laboratory fee to the patient. If this ratio is not determined, then a value of 0.1 can be entered into the risk calculator. # Symptoms of metastatic prostate cancer A healthy 70 year old vigorous gentleman, on no medications, who ran marathons yearly in the spring presented to a FP. He lived in Florida in the winter and usually was seen only once yearly in the spring. He came home to Canada earlier than usual as he had urinary retention in Florida, was catheterized but was having tremendous lower back pain. This thin, muscular man had never complained about lower back pain before. On examination, a firm fixed pelvic mass was noted. DRE noted a firm, irregular, fixed, and enlarged prostate. The urologist saw him within two days. A presumptive diagnosis of prostate cancer with bone metastasis was made. The PSA was 20ng/ml. Although diagnosis of prostate cancer was likely, the patient refused a biopsy and further diagnostic tests. His pain was quite severe and he was admitted to a palliative care unit for pain control and died within three weeks. A healthy 72 year old man with some symptoms of urinary retention and urgency presented to a FP. His older brother was diagnosed with prostate cancer at age 76. Urine analysis was negative and DRE found a smooth, normal prostate. The FP and patient discussed having a PSA test but the patient refused and asked to see a urologist to discuss the LUTS and his family history and was seen two months later. After a discussion with the urologist, the patient agreed to have a PSA and the result was 4.9ng/ml. The urologist explained to the patient that the result was within normal limits for his age. The patient elected to be followed with serial PSAs and DREs by his family physician. No treatments were initiated for the patient's symptoms of some urinary retention and urgency which seemed to resolve spontaneously. Since the first visit with the urologist, the PSA has been monitored every three months and has not increased beyond 6.8ng/ml in two years. # Incidental PSA A healthy 49 year old banker had a PSA test as part of a comprehensive medical examination offered through his insurance company. The physical examination was normal but the PSA was elevated for his age. He presented to his family doctor with a PSA of 3.5ng/ml and no other symptoms. The family doctor on DRE found a smooth, normal prostate. The family doctor evaluated the patient's risk for prostate cancer at 10-20% using the Prostate Risk Cancer nomogram and the patient elected to repeat the PSA and DRE in a few months. However, after further consideration at home, the patient called and asked to be referred to a urologist for a consultation. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

To jointly update the Cancer Care Ontario guideline on brachytherapy for patients with prostate cancer to account for new evidence.An Update Panel conducted a targeted systematic literature review and identified more recent randomized controlled trials comparing dose-escalated external beam radiation therapy (EBRT) with brachytherapy in men with prostate cancer.Five randomized controlled trials provided the evidence for this update.For patients with low-risk prostate cancer who require or choose active treatment, low-dose rate brachytherapy (LDR) alone, EBRT alone, and/or radical prostatectomy (RP) should be offered to eligible patients. For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen-deprivation therapy, brachytherapy boost (LDR or high-dose rate should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL), LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and androgen-deprivation therapy, brachytherapy boost (LDR or HDR) should be offered to eligible patients. Iodine-125 and palladium-103 are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using cesium-131 or HDR monotherapy. Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease. Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/ guidelineswiki.# INTRODUCTION The goal of this update is to provide oncologists, other health care practitioners, patients, and caregivers with recommendations regarding the use of brachytherapy for patients with prostate cancer that includes the most recent evidence. Prostate cancer is the most commonly diagnosed cancer in men. In 2016, it is estimated that there will be 180,890 new cases, along with an estimated 26,120 deaths. 1 For this reason, there is great interest in finding optimum treatment strategies to reduce the burden of disease in this patient population. The Cancer Care Ontario systematic review 2 and clinical practice guideline 3 on low-dose rate (LDR) brachytherapy for patients with low-or intermediate-risk prostate cancer were both published in 2013, and since then randomized evidence has been made available that might alter the original recommendations. The goal of this joint update is to consider this new evidence and determine if the original recommendations remain valid or if updates are warranted. The scope of this guideline covers brachytherapy boost and monotherapy. Currently, the American Society for Radiation Oncology, ASCO, and the American Urologic Association THE BOTTOM LINE Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update Guideline Questions 1. In patients with newly diagnosed prostate cancer, what is the efficacy of brachytherapy alone for clinical outcomes compared with external beam radiation therapy (EBRT) alone or radical prostatectomy (RP) alone? 2. In patients with newly diagnosed prostate cancer, what is the efficacy of brachytherapy combined with EBRT for clinical outcomes compared with brachytherapy alone, EBRT alone, or RP alone? 3. Among the isotopes used for low-dose rate (LDR) brachytherapy (eg, iodine-125 palladium-103 and cesium-131, which isotope maximizes clinical outcomes when used in patients with newly diagnosed prostate cancer? # Target Population Patients with newly diagnosed prostate cancer who require or choose active treatment and are not considering, or are not suitable for, active surveillance. # Target Audience Radiation oncologists, urological surgeons, and other clinicians who provide care for patients defined by the target population. A systematic review of the literature was performed and relevant evidence was evaluated for inclusion into this updated clinical practice guideline using the signals approach. # Updated Recommendations - For patients with low-risk prostate cancer who require or choose active treatment, LDR alone, EBRT alone, or RP should be offered to eligible patients - For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen-deprivation therapy (ADT), brachytherapy boost (LDR or high-dose rate should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL) LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and ADT, brachytherapy boost (LDR or HDR) should be offered to eligible patients. - 125 I and 103 Pd are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using 131 Cs or HDR monotherapy. - Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease. # Qualifying Statements - Patients should be counseled about all their management options (surgery, EBRT, active surveillance, as applicable) in a balanced, objective manner, preferably from multiple disciplines. - Recommendation for low-risk patients is unchanged from initial guideline, because no new randomized data informing this question have been presented or published since. - Patients ineligible for brachytherapy may include: moderate to severe baseline urinary symptoms, large prostate volume, medically unfit, prior transurethral resection of the prostate, and contraindications to radiation treatment. - ADT may be given in neoadjuvant, concurrent, and/or adjuvant settings at physician discretion. It is noted that neoadjuvant ADT may cytoreduce the prostate volume sufficiently to allow brachytherapy - There may be increased genitourinary toxicity compared with EBRT alone. - Brachytherapy should be performed at a center following strict quality-assurance standards. - It cannot be determined whether there is an overall or cause-specific survival advantage for brachytherapy compared with EBRT alone, because none of the trials were designed or powered to detect a meaningful difference in survival outcomes. (continued on following page) are performing a joint review of hypofractionated radiotherapy (including stereotactic ablative body radiotherapy. 10 Where reported, these classifications are summarized. Androgen-deprivation therapy (ADT) is a standard for patients with high-risk prostate cancer treated with radiotherapy and can be considered for those with intermediate-risk disease. 11 Where reported, use and duration of ADT was also summarized. Evidence was also collected through a systematic review of the medical literature. Publications were included if they were phase III randomized clinical trials of brachytherapy compared with either EBRT or RP in men with prostate cancer. These publications were identified by rerunning the original strategy in MEDLINE, EMBASE, and the Cochrane database of systematic reviews, for the period from the original search in 2011 through to the end of August 2015. A final search for important papers was made in December 2016. Of the 32 publications identified, six 5,6,12-15 publications (addressing five RCTs) met the eligibility criteria and form the evidence base for this update. The Update Committee contributed to the development of the guideline, provided critical review, and finalized the guideline recommendations. All ASCO guidelines are reviewed and approved by the ASCO Clinical Practice Guidelines Committee. # Guideline Disclaimers The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions. This is the most recent information as of the publication date. For the most recent information, and to submit new evidence, please visit www.asco.org/Brachytherapy-guideline and the ASCO Guidelines Wiki (www.asco.org/guidelineswiki). # THE BOTTOM LINE (CONTINUED) Additional Resources Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/guidelineswiki. Patient information is available at www.cancer.net. ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate jco.org of a qualified clinician. CCO makes no representations or guarantees of any kind whatsoever regarding the report content or its use or application and disclaims any responsibility for its use or application in any way. # Guideline and Conflicts of Interest The Update Panel (Appendix Table A1, online only) was assembled in accordance with ASCO's Conflict of Interest Management Procedures for Clinical Practice Guidelines ("Procedures," summarized at . asco.org/rwc). Members of the Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Procedures, the majority of the members of the Panel did not disclose any such relationships. Five 5,6,12-15 RCT reports were obtained for this targeted update. All five of these trials were randomized; three were available in fully published form, one 6 was available as both a fully published paper that reported on efficacy outcomes and an abstract 5 that reported on the toxicity outcomes, and one 15 was available in abstract form only. Four 5,12,13,15 of these trials were phase III, and the trial reported by Morton et al 14 was described as being a phase II trial. All efficacy outcomes for the four trials 5,12,13,15 that compared EBRT with brachytherapy are reported in Table 1; adverse effects are reported in Table 2. The earliest trial, the fully published phase III trial reported by Sathya et al 13 in 2005, randomly assigned 104 patients with T2 to 3 nonmetastatic prostate cancer to either EBRT (four-field box radiation to the prostate and seminal vesicles with a 2-cm margin at 66 Gy total dose given in 33 fractions over 6.5 weeks; n 5 53) or brachytherapy boost (iridium implant, 35 Gy over 48 hours) with EBRT (40 Gy, 20 fractions over 4 weeks; n 5 51). Use of concurrent ADT was not reported. Patients were stratified by age, prostate-specific antigen (PSA) levels, Gleason score, tumor stage (T2 v T3), and risk status (intermediate v high). The primary outcome for this trial was biochemical or clinical failure (which was defined as biochemical failure, clinical failure, or death resulting from prostate cancer), and a statistically significant benefit in favor of the EBRT with brachytherapy arm was detected (hazard ratio 0.42; P 5.0024) after a median reported follow-up of 98 months. 16 While the authors report that the treatment effect was greater in the intermediate-risk group compared with the high-risk group, the difference between the HR for biochemical or clinical failure was not significant; however, when adjusted for age, baseline PSA, Gleason score, and tumor stage, the treatment effect (brachytherapy boost v EBRT alone) was more pronounced (HR, 0.31; 95% CI, 0.17 to 0.58; P 5.0002). No differences in the toxicity profile between the two arms were detected. The second trial, the fully published phase III trial first reported by Hoskin et al 12 in 2007, randomly assigned 220 patients with histologically confirmed T1 to 3 prostate cancer, no evidence of metastases, PSA 50, no previous transurethral resection of the prostate, and fitness for general anesthesia to either EBRT (given as either three-field without shaped blocks or threedimensional volumetric planning and conformal three-field plans at 55 Gy given in 20 fractions; n 5 111) or EBRT (35.75 Gy, 13 fractions) with high-dose rate brachytherapy boost (HDR-B; iridium implant delivering a total of 17 Gy in two fractions over 24 hours; n 5 109). Patients were stratified according to tumor stage, PSA levels, and Gleason scores. Neoadjuvant and concurrent ADT (duration not specified) were used in 76% of patients. The primary outcome of interest was biochemical disease-free survival (bDFS), and a statistically significant benefit in favor of the EBRT/ HDR-B was detected (HR, 0.76; P 5.03) after a median follow-up of 30 months. This benefit in favor of the addition of brachytherapy to EBRT was also shown in the comparisons between the tumor stage, PSA levels, and Gleason score groups. No difference was detected in acute toxicity scores between the two arms for grade 2 or higher late bowel or bladder reactions. Health-related quality-of-life scores between the two arms detected a benefit in favor of EBRT/HDR-B (P 5.025) as assessed by the Functional Assessment of Cancer Therapy-Prostate instrument. A second report with a median follow-up of 85 months continued to show superiority of EBRT/HDR-B over EBRT (HR, 0.69; P 5.04). 17 The third trial, a phase III trial, reported in both fully published 6 and abstract form 5 by Morris et al, 5,6 randomly assigned 398 patients with intermediate-and high-risk prostate cancer to either DE-EBRT (whole pelvis EBRT: 46 Gy, 23 fractions followed by conformal EBRT to prostate: 32 Gy, 16 fractions; n 5 200) or LDR-B (whole pelvis EBRT: 46 Gy, 23 fractions followed by an 125 I boost to a minimum dose of 115 Gy to prostate; n 5 198). Patients were stratified by risk category (intermediate v high risk). Twelve months (8 months neoadjuvant, 2 months concurrent, 2 months adjuvant) of ADT was used in all patients. The primary outcome was bDFS as defined by biochemical criteria using the Phoenix (nadir 1 2 ng/mL) threshold. After a median follow-up of 78 months, a statistically significant benefit in favor of EBRT/LDR-B was detected (log-rank P.001). Multivariate analysis confirmed brachytherapy boost (but not risk category) as an independent predictor of bDFS. Assessment of the 5-year cumulative incidence of late grade 3 or higher toxicity detected a significant benefit in grade 3 genitourinary (GU) effects in favor of treatment with DE-EBRT (P.001) but not in grade 4 GU or in grade 3 or higher GI effects. 5 Quality of life was prospectively collected using the Short Form-36 instrument, which assessed physical function, role physical, bodily pain, general health, vitality, social functioning, and emotional and mental health. Additional items to gather data on urinary function, bowel function, and sexual function were added. All items were scored on a scale from 0 to 100. Baselines scores were balanced between treatment arms, but area under the curve differences were detected for bodily pain (P 5.04), general health (P 5.01), sexual function (P 5.02), and urinary function (P 5.006) in favor of treatment with DE-EBRT over LDR-PB. 18 No healthrelated quality-of-life differences were detected for any other domains. The fourth trial, a phase III trial reported in abstract form only by Prestidge et al 15 in 2016, randomly assigned 588 patients with low-intermediate risk prostate cancer (Gleason 6, PSA 10 to 20 ng/mL or Gleason 7, PSA 10 ng/mL) 1:1 to EBRT (45 Gy, 25 fractions mini-pelvis) with LDR boost (110 Gy 125 I or 100 Gy 103 Pd) or LDR alone (145 Gy or 125 Gy, respectively). The primary outcome was progression-free survival (PFS; American Society for Radiation Oncology nadir 1 2 biochemical failure, clinical failure, or death from any cause). After 6.7 years of median follow-up, the independent Data Monitoring Committee recommended releasing the data after the fifth interim analysis. There was no difference in 5-year PFS (85% v 86%; HR, 1.02; futility P.001). There were no differences in acute grade 3 or higher toxicity (8% in each arm) but worse grade 3 or higher late toxicity in the brachytherapy boost arm (12% v 7% overall; 7% v 3% for GU; 3% v 2% for GI; no P values provided). The fifth trial, a phase II trial reported by Morton et al 14 in 2016, randomly assigned 170 patients with low-and intermediaterisk prostate cancer to two HDR monotherapy regimens (ie, no EBRT was used). Patients received 27 Gy, two fractions over 1 week or 19 Gy in a single fraction. Eligible patients also had a prostate volume 60 mL, International Prostate Symptom Score # 18, no previous prostate surgery, and no use of ADT. The primary outcome was grade 2 or higher toxicity. After a median follow-up of 20 months, the only significant difference in acute toxicity detected between the treatment arms was for fatigue in favor of the single fraction (16% v 32%; P 5.029). There were no differences in acute grade 2 or higher GU toxicity, acute grade 2 or higher GI toxicity, or quality of life (measured by Expanded Prostate Index Composite every 6 months). For late toxicity, a difference was detected between treatment arms in favor of the single fraction for grade 2 erectile dysfunction (12% v 29%; P 5.025). No differences in late GI toxicity were reported. bDFS was not reported. There may be higher late GU toxicities associated with LDR-B compared with HDR-B. In the ASCENDE-RT 5 study, there were 20% grade 3 to 4 GU toxicities, half of which were due to urinary strictures requiring dilatation (S. Tyldesley, personal communication, November 2015). In the Hoskin et al study, 6% of patients in the HDR boost arm had urethral stricture at 5 years post-treatment. 17 In a widely used dose fractionation scheme internationally (HDR-B 15 Gy in one fraction followed by EBRT 37.5 Gy, 15 fractions), there was 0.8% grade 3 to 4 GU toxicity (0% strictures). 19 The differences in toxicity between these brachytherapy procedures may be due to relative dose sparing of the membranous urethra, which is associated with lower stricture rates. However, because cross-trial comparisons should only be used for hypothesis generation, we will have to await the results of randomized data. The Canadian Cancer Trials Group launched a national phase III LDR versus HDR monotherapy RCT in 2016 (clinicaltrials.gov NCT pending). # UPDATED RECOMMENDATIONS Please refer to the Bottom Line Box for the updated recommendations and the accompanying Qualifying Statements. †Comprising clinic visits every 6 months until 5 years (yearly thereafter) for prospective collection of patient-and physician-reported adverse effects, complications, and quality of life; PSA and testosterone levels measured every 6 months to assess predefined primary end point of PFS standard nadir 1 2 ng/mL (Phoenix) threshold. # COST CONSIDERATIONS ASCO recognizes that there is often a wide array of choices for treating many cancer types, with often a wide disparity in cost to patients and payers (despite much difference in effectiveness or toxicity). 20 Halpern et al 21 reported that of the radiation modalities used in the treatment of prostate cancer, from the Medicare payer perspective, LDR brachytherapy is the cheapest (compared with SABR, EBRT, or protons). Helou et al 22 showed that in the Canadian health care context, SABR had the higher quality-adjusted life-years and was more cost effective compared with LDR (and both were better than EBRT). Further work is needed to articulate cost, cost-effectiveness, and cost-utility differences between the various prostate cancer treatment approaches. # LIMITATIONS OF THE RESEARCH There are four 5,12,13,15 small-to medium-sized RCTs addressing the question of brachytherapy boost. The largest and most contemporaneously relevant (because the control arm used an external beam dose of 78 Gy in 39 fractions) trial (ASCENDE-RT, Morris et al 5,6 has published the survival outcomes; 6 however, the toxicity data are only available in abstract form. When the toxicity data are published, these guidelines recommendations will have to be revised if the toxicities are significantly higher than was presented to date. There are also insufficient data for comment on a meaningful difference in overall survival, because all trials were powered for PFS only. The guideline panel will re-evaluate the recommendations as new data emerge, especially from the ASCENDE-RT and Radiation Therapy Oncology Group 0232 trials. # AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. We thank Maha Hussain, MD, Cynthia Anderson, MD, and the other members of the ASCO Clinical Practice Guidelines Committee as well as the Cancer Care Ontario Program in Evidence-Based Care Report Approval Panel for their thoughtful reviews and insightful comments on this guideline document. We also thank Rodney Breau, MD, MSc, W. Robert Lee, MD, MS, Med, and Ronald C. Chen, MD, MPH, for reviewing an earlier draft of this guideline. Finally, we thank the original authors of the Cancer Care Ontario guideline (George Rodrigues, Xiaomei Yao, Andrew Loblaw, Michael Brundage, and Joseph Chin) for their contribution to this effort. # AUTHOR CONTRIBUTIONS The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. # Joseph Chin

In Canada in 2010, an estimated 2600 new cases of ovarian cancer will be diagnosed and, of those cases, 1750 women will die, making ovarian cancer the seventh most prevalent form of cancer in Canadian women and their fifth leading cause of cancer death (1). Women with ovarian cancer typically have subtle, non-specific symptoms such as abdominal pain, bloating, changes in bowel frequency, and urinary and/or pelvic symptoms (2), making early detection difficult. Thus, the majority of ovarian cancer cases are diagnosed at an advanced stage when the cancer has spread outside the pelvis (3). Due to the late diagnosis of this disease, the five-year relative survival ratio for ovarian cancer in Canada is only 40% (1). Unfortunately, due to the low-positive predictive values of potential screening tests (CA-125 and ultrasound), there is currently no screening strategy for ovarian cancer (4). Palpation using a bimanual pelvic examination or by radiological imaging (3) can identify an adnexal mass, which is defined as an enlarged lump near the uterus, usually in the ovary or fallopian tube. Adnexal masses include both benign (ovarian cysts, fibroids, and endometriomas) and malignant tumours. There are numerous methods that have been tested in the preoperative identification of adnexal masses suspicious for malignancy. These methods include CA-125, transvaginal and transabdominal ultrasound, MRI, CT scans and the risk of malignancy index (RMI). However, the most appropriate identification method has yet to be determined, mainly due to poor positive and negative predictive values associated with each test in differentiating a benign from a malignant mass. Once the diagnosis of ovarian cancer is confirmed, the patient must undergo surgical staging or debulking. However, which surgical staging and debulking procedure should be used to improve overall survival, progression-free survival, and quality of life in women with ovarian cancer is also unknown. The purpose of this document is to identify evidence that would inform optimal recommended protocols for the identification and surgical management of adnexal masses suspicious for malignancy. The evidence-based series (EBS) guidelines developed by the CCO PEBC use the methods of the Practice Guidelines Development Cycle (5). For this project, the core methodology used to develop the evidentiary base was an update of two previously published systematic reviews: the Agency for Healthcare Research and Quality (AHRQ) report, 2006 (3) and Australian Cancer Network (ACN) Clinical Practice Guideline, 2004 (6). Evidence was selected and reviewed by five members of the PEBC Gynecology Cancer DSG and one methodologist. The systematic review is a convenient and up-to-date source of the best available evidence on the management of an adnexal mass suspicious for malignancy. The body of evidence in this review is primarily comprised of prospective and retrospective cohort studies. That evidence forms the basis of the recommendations developed by the Gynecology Cancer DSG and published in Section 1. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. # Literature Search Strategy Environmental Scan As a first step, an internet search of Canadian and international health organizations and the National Guidelines Clearinghouse (see Appendix 1 for full list) was conducted for existing guidelines and systematic reviews relevant to our research question. Guidelines were included if they were published since 1999 in English. This initial environmental scan yielded 11 practice guidelines; however, one guideline was excluded because the full guideline was available only in French, and another guideline was excluded because only the National Guidelines Clearinghouse summary was available. One evidence report/technology assessment and one clinical practice guideline identified through this environmental scan were deemed to be the most appropriate to answer the guideline questions. The 2006 AHRQ report (3) addressed the identification of an adnexal mass suspicious for malignancy question. The 2004 ACN Clinical Practice Guideline (6) addressed the surgical management of an adnexal mass suspicious for malignancy question. # Update Literature Search Strategy The literature search from the AHRQ report was updated (Appendix 2) using MEDLINE (OVID: January 2004 through week 3, March 2009). In addition, as an exact search strategy for the Australian Cancer Network report was not available, an update of that literature search (Appendix 2) was approximated using the keywords provided in the report using MEDLINE (OVID: January 2004 through week 3, April 2009). This literature search combined diseasespecific terms ('pelvic mass,' 'adnexal mass,' 'pelvic neoplasms,' 'ovarian cancer,' 'ovarian neoplasm,' 'ovarian carcinoma,' 'epithelial ovarian cancer,' 'borderline ovarian tumours' and 'tumours of low malignant potential') with surgical specific terms ('intraoperative pathological examination,' 'frozen section,' 'debulking surgery,' 'fertility sparing,' 'surgical staging,' 'bilateral salpingo-oophorectomy,' 'total hysterectomy,' 'node or nodal dissection,' 'surgical management,' 'treatment,' 'cytoreduction,' 'secondary cytoreduction,' 'interval cytoreduction,' 'laparotomy,' and laparoscopy') for all study designs. Relevant articles and abstracts were selected and reviewed by two reviewers. The reference lists of included studies along with the personal reference lists of the guideline working group were searched for additional studies. # Study Selection Criteria Articles were eligible for inclusion in this systematic review if they were systematic reviews, meta-analyses, clinical practice guidelines, randomized trials, or comparative cohort studies. Studies indentified in the update of the AHRQ report literature search were included based on the same inclusion criteria put forth in the AHRQ report (3). For studies investigating single modality identification of an adnexal mass, the inclusion criteria were: 1) comparison of the test (e.g., bimanual pelvic exam or ultrasound, to histology or negative surgery 2) greater than 20 patients included in study 3) able to construct a 2-by-2 table, which compares the results of the diagnostic test with the definitive histological diagnosis. For studies investigating the use of multi-modality scoring systems (i.e., RMI), the inclusion criteria were: 1) patients with suspicion of cancer 2) studies with scoring, risk score, combined modality approach 3) assesses predictive value of two or more variables using multivariable model 4) greater than 50 patients included in study. Studies identified in the update of the Australian Cancer Network (6) guideline were based on the following selection criteria: 1) greater than 20 patients included in study 2) patients with an adnexal mass suspicious for early stage (I-II) malignancy, 3) two-armed (or greater) study design with a comparison of surgical procedures/techniques/approaches 4) report on at least one of the following outcomes: optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, quality of life. # Synthesizing the Evidence A bivariate, random-effects meta-regression model was used to produce summary estimates of sensitivity and specificity and to plot summary receiver operating characteristic (ROC) curves with 95% confidence regions. This model, described in detail elsewhere (7)(8)(9), has several advantages over the standard summary ROC approach. Chief among these is the preservation of the two-dimensional nature of the data and the incorporation of any correlation that might exist between sensitivity and specificity (8). The model assumes that the logit sensitivities and specificities are normally distributed and makes use of the variance estimates to compute study weights (7). Heterogeneity in the current review was assessed visually. Given that between-study heterogeneity is widespread for measures of diagnostic accuracy (10), a random-effects model was used for all pooling. This bivariate, randomeffects model takes into account the difference in precision by which sensitivity and specificity have been measured within and across studies, and it incorporates and estimates the amount of between-study variability (8). Statistical analyses were executed with the statistical software package STATA version 11 (11) using the metandi command. The outcomes of the meta-analyses were plotted as summary ROC curves and can be seen in Figures 2A-D. The Gynecology Cancer DSG decided not to pool the surgical studies, but rather to present the results of each study individually in a descriptive fashion. # Quality Appraisal and Data Extraction The Appraisal of Guidelines Research and Evaluation (AGREE) tool (12) was used to evaluate the quality of identified evidence-based guidelines. While all scoring domains of the AGREE tool were considered in the evaluation of guidelines, the Rigour of Development domain, describing the rigour of systematic methods in identifying and evaluating evidence, was considered to be most relevant in application for this systematic review. Systematic reviews and meta-analyses were assessed for quality using the AMSTAR tool (13). The quality of primary studies included assessments for study design, type of data collection, sampling method, and blinding. # Updated Literature Search Results # Identification of an adnexal mass literature Four meta-analyses (14-17) and 67 primary studies (Table 1), pertaining to the identification of an adnexal mass suspicious for malignancy, met the inclusion criteria and are included in this review. # Surgical procedures literature A total of 1809 articles were identified in the updated search for the most appropriate surgical procedure, of which 16 met the inclusion criteria (85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100). # Study Design and Quality The ACN evidence-based guideline (6) earned 80.2% for the Rigour of Development domain of the AGREE tool. Since the role of AGREE in the assessment of health technology assessments has not yet been formally evaluated, the AHRQ report was not rated with AGREE but with AMSTAR for systematic reviews. It received an overall quality score of 90%. The meta-analyses by Geomini et al (14), Liu et al (15), Medieros et al (17), and Geomini et al (16) received scores of 73%, 55%, 82%, and 82% respectively. Given that, at the time of inclusion, all patients either have ovarian cancer or they do not, diagnostic accuracy studies are, in principle, cross-sectional in nature (101). The diagnostic tests under study are intended to reduce the clinical uncertainty about their status (101). As such, the terms "cohort-type" or "case-control-type" accuracy studies have been proposed depending on the method of patient recruitment. Using such terminology, two casecontrol type studies and 65 cohort-type accuracy studies were included in this review (Figure 1). Data collection occurred prospectively in 64% of the studies, retrospectively in 33%, and not described in 3%. The sampling method was consecutive in 42% of the studies and not reported in the remaining 58%. Pathologists were blinded to the preoperative index test findings in only 4% of studies and not blinded in 1% of studies, with the remaining 94% of studies not describing any such blinding. In general, the quality of evidence for studies identified for the surgical question was poor. No meta-analyses or systematic reviews were identified. Only one of the 16 eligible surgical studies was an RCT (89), and another was designed as a "historically controlled trial" (95), defined as per the Cochrane Collaboration definition of study designs (102). The remaining 14 eligible studies were all retrospective in nature. As the quality of data collection in a retrospective study is often compromised, it is important to take the inherent limitations of such retrospective review designs into consideration. Furthermore, with the exception of 2 large SEER database reviews, the studies tended to be small and were likely underpowered to detect statistically significant differences in survival outcomes. # Outcomes 1. Identification of an adnexal mass suspicious for malignancy Ultrasonography is the most common diagnostic imaging technique for the noninvasive assessment of adnexal masses and is believed to be both a reliable and reproducible method for preoperative discrimination between malignant and benign pelvic masses (103)(104). # 2D versus 3D In addition to the four studies considered in the AHRQ report that analyzed both 2D and 3D ultrasonography, two new prospective studies were identified through the updated literature search (38,48). Analyzing the 2D ultrasonography data from the six studies using a bivariate random effects model yielded an overall sensitivity of 85.3% and specificity of 87.4% (Table 2, Figure 2A). When the data were pooled from the six 3D ultrasonography studies, the estimates improved to an overall sensitivity of 93.5% and specificity of 91.5% (Table 2, Figure 2A). Morphological scoring systems, based on parameters observed from gray-scale sonography, were developed to overcome limitations with operator subjectivity and tumour variability (3). These scoring systems assign and then sum up the score for established sonographic variables. A predetermined specific cutoff value classifies the mass as either malignant or benign. # Sassone Scoring System The model originally described by Sassone et al ( 105) is based on a weighted sum of the following four morphological features: inner wall structure, wall thickness, septa, and echogenicity. A score of greater than 9 is suggestive of malignancy. The AHRQ report identified and conducted a meta-analysis of 15 studies that explicitly used Sassone's criteria. The meta-analysis by Geomini et al ( 16) included 18 studies with cutoffs that ranged from 4 to 15, although 9 was the most common cutoff as in the original report. While our updated literature search did not identify any additional studies reporting on the Sassone et al model, we elected to conduct a meta-analysis of studies from both the AHRQ report and the Geomini et al meta-analysis that met our inclusion criteria, because neither report alone captured all the available data. A bivariate random effects model of these 22 studies generated a pooled sensitivity of 90.4% and specificity of 76.4%. Limiting our analysis to the 17 studies (42,62,67,71,(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117) reporting a cutoff point of 9, yielded an overall sensitivity of 88.6% and specificity of 77.5% (Table 3, Figure 2B). # Lerner Scoring System Lerner et al (118) devised a scoring system based on a modification to the Sassone model. The Lerner model differs from Sassone's in several ways, including weighted point value assignments, fewer point values per variable studied, the deletion of one variable found not to be significant (wall thickness), and the inclusion of a new variable called shadowing. A cutoff of 3 was determined to best differentiate benign from malignant masses. The AHRQ report did not separately evaluate the Lerner model. Geomini et al (16) reported eight studies that evaluated the Lerner model, in addition to the original, and found a pooled sensitivity of 90% and specificity of 63% (Table 3). Our updated literature search identified one additional study by Lee et al (49) where 137 masses were evaluated in 123 women, and a sensitivity of 82.1% and specificity of 69.7% were reported. We do not believe that the addition of this one study would change the overall estimates reported by Geomini et al and, thus, did not rerun the analysis. # DePriest Scoring System The model described by DePriest et al (119) uses the weighted sum of cystic wall structure, volume, and septum structure. The score ranges from 0 to 12, with the most common cutoff set at 5. The AHRQ report identified six studies that made use of the DePriest scoring system. Geomini et al (16) evaluated 10 studies and reported a pooled sensitivity of 91% and specificity of 69% (Table 3). Our literature search identified an additional study (49) not included in either the AHRQ report or the meta-analysis by Geomini et al. In 123 women with 137 masses, Lee and colleagues reported a sensitivity of 92.9% and specificity of 59.6%. We do not believe the addition of this one study to the Geomini et al meta-analysis would have changed the overall estimates and, therefore, did not repeat the analysis. # Ferrazzi Scoring System Ferrazzi et al (109) developed their model to include four morphological features: wall structure, septa, vegetations and echogenicity. The weighted sum can range from 4 to 18, with 9 used as a cutoff to suggest malignancy. The AHRQ report identified three studies explicitly using the Ferrazzi et al criteria and the meta-analysis by Geomini et al (16) pooled seven studies. An updated search of the literature identified 1 additional study reporting on the Ferrazzi et al scoring system (58). Pooling the nine available, qualifying studies generated an overall sensitivity of 85.2% and specificity of 85.9% (Table 3, Figure 2B). # Finkler Scoring System Finkler et al (120) developed a 10-point scoring system, where scores of 7 or more indicate malignancy. The AHRQ report identified three studies that evaluated the Finkler system, as did Geomini et al (16). However, Geomini et al found that the summary estimates varied widely in the ROC curve. Despite not having identified any additional studies, we felt it was worthwhile to combine all available data in overall summary estimates. Our bivariate random-effects analysis of the five studies (120-124) allowed in our model generated an overall sensitivity of 83.5% and specificity of 78.2% (Table 3, Figure 2B). # Other Scoring Systems The meta-analysis by Geomini et al ( 16) also considered a model developed by Alcazar and Jurado that made use of the Sassone score as a variable in a logistic regression. Although the model was evaluated in four studies, there was too much variability in the sensitivity and specificity to pool the summary estimates. The AHRQ report identified 53 studies that evaluate ultrasonography in the assessment of adnexal mass morphology. These publications included unique, modified, or unclear scoring systems that did not fit into the other scoring system categories. While there was significant heterogeneity in the criteria used for diagnosis, the report did go ahead and pool sensitivity and specificity. The resulting summary estimates were 86% for sensitivity and 83% for specificity. # Explicit Scoring Systems The AHRQ report considered scoring systems that included data combined from the following categories: 1) imaging, including ultrasound, CT, and MRI; 2) patient risk factors, such as age and menopausal status; and 3) laboratory data, primarily CA-125. # Risk of Malignancy Index (RMI) The RMI, first published by Jacobs and colleagues (125), is based on scores from ultrasound (U), menopausal status (M), and CA-125 data in the following manner: RMI = U x M x CA-125. A cutoff of 200 was used to differentiate between malignant and benign masses in the original study. The AHRQ report (3) identified 11 studies in addition to the original that assessed the diagnostic performance of RMI. The meta-analysis by Geomini et al (16) identified 16 studies in which the RMI was evaluated but considered only the 13 studies that used the original cutoff of 200. An updated literature search identified two new studies (21,32) that considered the diagnostic accuracy of RMI. When a bivariate random effects model was used to pool the data from the 13 studies, with 15 data sets, employing a cutoff of 200 to be indicative of malignancy, the summary sensitivity and specificity were 79.2% and 91.7%, respectively (Table 4, Figure 2B). When the analysis was extended to the 23 studies considering a cutoff level of 50, the summary estimates were 82.1% for sensitivity and 87.8% for specificity. Several years after the RMI was published, improvements to the model were attempted. Tingulstad et al (126) proposed the RMI2, which gives new weights to the ultrasound and menopause components of the original model. The same cutoff level of 200 was recommended for the RMI2 model. The AHRQ report identified four studies in addition to the Tingulstand et al original, while Geomini et al ( 16) evaluated seven studies and, at a cutoff level of 200, reported pooled estimates for sensitivity and specificity of 79% and 81%, respectively (Table 4). The updated literature search indentified only one additional study evaluating the diagnostic accuracy of RMI2. In 194 women, Bensaid et al ( 21) reported a sensitivity of 92% (95% CI, 65 to 100%) and specificity of 80% (95% CI, 75 to 84%) at a cutoff of 125. Because data were not available at the recommended cutoff of 200, we did not repeat the analysis to include the data from Bensaid et al. In 1999, Tingulstad et al (127) suggested a further refinement to the two previous RMI models, again with suggested new weights given to the ultrasound and menopause components. Two hundred was once again the recommended cutoff level for this third model. Both the AHRQ report and the meta-analysis by Geomini et al identified only one additional study (128) that evaluated the RMI3 and reported that this validation study found a sensitivity of 74% and specificity of 91%. These results were very similar to the original RMI3 report, which found a sensitivity of 71% and specificity of 92%. We did not identify any additional literature evaluating RMI3. # Tailor's Model Tailor et al ( 129) developed a scoring system based on an artificial neural-network analysis that incorporates age, menopausal status, morphological features, and Doppler indices. The AHRQ report found four additional studies that evaluated this model but did not pool the data sets. They did note, however, that the subsequent studies each reported poorer performance than did the original publication. Geomini et al (16) found five publications that evaluated the original Tailor model. At a suggested cutoff of 50%, the pooled sensitivity and specificity of four data sets were 60% and 93%, respectively (Table 4). Our updated search of the literature did not identify any other studies that evaluated the diagnostic performance of the Tailor et al model. (130) in the late 1990s to predict the malignancy of an adnexal mass. Through complex modelling techniques, the ANN models investigate the possible existence of non-linear interactions or correlation between variables. The ANN1 model combines the predictive value of menopausal status, serum CA-125, presence/absence of papillary structures, and colour score, and uses a cutoff of 45%. The ANN2 model includes, in addition to menopausal status, serum CA-125, and papillary structures as in ANN1, the following set of morphological parameters: smoothness of internal walls, unilocularity, presence of ascites, and whether the mass is bilateral. A cutoff of 60% was used. Timmerman et al found the sensitivity and specificity of ANN1 to be 94% and 90%, respectively. ANN2 performed slightly better with a sensitivity of 96% and specificity of 94%. Two separate studies validated the models (77,115) and also reported a better performance with ANN2 over ANN1, although performance in subsequent replications was poorer. Mol et al (115) reported ANN2 to have a sensitivity and specificity of 90% and 46%, respectively, while Van Holsbeke et al ( 77) reported 98% and 34%, respectively. Our updated literature search did not identify any additional studies that validated the Timmerman ANN models. While other artificial neural networks have been developed over the years, external validation of these additional models is scarce, and they will not be discussed further. # Logistic Regression Models (LR) 1 and 2 The development of algorithms through statistical modeling that assess the probability of malignancy can also be used to distinguish malignant from benign masses preoperatively. One such logistic regression model (LR1) (131), developed in the late 1990s by Timmerman et al, included the following variables in the analysis: menopausal status, CA-125 level, presence of ≥1 papillary growth (>3mm in length), and a colour score indicative of tumour vascularity and blood flow. At a cutoff of 25%, the sensitivity of the LR1 was 95.9% and specificity was 87.1%. Two external validation studies (77,132) found lower estimates upon replication, where sensitivity was found to be 62% by Valentin et al and 78.1% by Van Holsbeke et al, and specificity was 79% in both studies. A second logistic regression model (LR2) developed by the Timmerman group incorporates the same variables as ANN2 (i.e., menopausal status, serum CA-125, papillary structures, smoothness of internal walls, unilocularity, presence of ascites, and whether the mass is bilateral). Timmerman et al (130) reported, at a cutoff of 60%, a sensitivity and specificity of 95.9% and 85.5%, respectively. Again, at external validation, estimates were considerably lower (sensitivity 90% and 84% and specificity 86% and 75% in Mol et al (115) and Van Holsbeke et al (77), respectively). A number of other logistic regression prediction models are found in the literature, but many are without external validation and will not be considered further in this document. # Doppler Sonography Regular gray-scale sonography can be enhanced with Doppler measurements, which assess the direction of blood flow and its relative velocity. Colour Doppler imaging and pulsed Doppler spectral analysis enable evaluation of ovarian tumour blood flow, analysis of the distribution of blood vessels, and quantitative measurement of blood-flow velocity waveforms. These parameters increase the sensitivity and specificity of ultrasound evaluation of ovarian tumours (133). # 2D Power Doppler (2D PD) The updated search of the literature identified five qualifying studies that evaluated 2D PD technology in the preoperative discrimination between malignant and benign adnexal masses. The sensitivity in these studies ranged from 49% to 100%, while specificity ranged from 74% to 100% (Table 5). # 3D Power Doppler (3D PD) The evaluation of 3D PD technology in the differential assessment of adnexal masses was considered in four qualifying studies identified through the updated literature search. The sensitivity in these studies ranged from 68% to 100%, while specificity ranged from 40% to 98% (Table 6). # Resistance Index (RI) Resistance Index (RI), the difference between peak systolic and maximum enddiastolic flow velocity divided by peak systolic flow velocity, is one of the most common flow criteria in colour Doppler scanning. The AHRQ report identified 32 articles that evaluated RI, although one study (134) actually considered a morphology index, not RI, and was excluded from further analyses. Our updated literature search identified five new studies (41,48,(51)(52)55) that assessed the diagnostic accuracy of Doppler scanning using the RI parameter, but the data from Marret et al (52) was not included because this same data was previously published and already included. The analysis of the summary estimates for these four new studies along with the existing qualifying literature included 42 data sets and yielded an overall sensitivity of 77.2% and specificity of 89.8% (Table 7, Figure 2C). # Pulsatility Index Pulsatility Index (PI) is defined as the difference between peak systolic and enddiastolic flow velocity, divided by the time-averaged flow velocity. The AHRQ report analyzed the PI from 20 studies, while the updated literature search identified only one additional study (51) looking at PI that met the inclusion criteria. When we analysed the 21 studies with 22 data sets, using a bivariate random effects model, we obtained an overall sensitivity of 80.6% and specificity of 79.9% (Table 7, Figure 2C). # Peak Systolic Velocity The peak or maximum systolic velocity (PSV) is the maximum flow recorded in any visualized artery and, along with RI and PI, it is one of the most common flow criteria. Our analysis of the six studies included in the AHRQ report plus one additional identified paper (55) yielded an overall sensitivity of 80.0% and specificity of 84.2% (Table 7, Figure 2C). The AHRQ report considered Doppler studies that did not measure or calculate waveforms but, rather, looked at the presence of vascularity within the mass or a direct count of the vessels observed. The report identified 10 such studies with sensitivities that ranged from 77% to 100% and specificities that ranged from 30% to 94%. Pooling these studies resulted in an overall sensitivity of 88% and specificity of 78% (Table 7). Our updated literature search did not identify any additional studies investigating Doppler visualization. # Combined Morphology and Doppler 2D Ultrasonography plus Doppler A combination of morphological and vascular imaging was developed to try to improve the differentiation of malignant and benign adnexal masses. The AHRQ report identified nine studies that described such a combined modality. An additional three studies were identified through our updated search of the literature. When a bivariate random effect model was used to analyses all 12 studies, an overall sensitivity of 91.0% (95% CI, 84.8% to 94.8%) and specificity of 91.7% (95% CI, 81.1% to 96.6%) was obtained. (Figure 2C). # 3D Ultrasonography plus Doppler The updated search of the literature identified two qualifying studies that evaluated 3D ultrasonography plus Doppler technology in the differential assessment of adnexal masses (Table 8). # Other Imaging Modalities MRI The AHRQ report identified 15 articles investigating the performance of MRI in the diagnosis of adnexal masses. An updated search of the literature since the AHRQ report was published identified a meta-analysis ( 15) evaluating, among other things, the MRI modality. Liu et al considered 10 studies reporting 13 data. In addition to this meta-analysis, six primary studies, not included in the Liu et al meta-analysis or the AHRQ report, were also identified during the updated literature search. Again, using a bivariate random effects model, we conducted a meta-analysis of the 15 studies from the AHRQ report, the one study exclusive to the Liu et al meta-analysis that qualified for the current analysis, and the six additional primary studies identified. This analysis of 22 studies with 24 data sets yielded an overall sensitivity of 91.9% and a specificity of 88.4% (Table 9, Figure 2A). The AHRQ report described three studies that looked at the performance of CT in diagnosing adnexal masses. Liu et al (15) evaluated a total of four studies, two of which also appeared in the AHRQ report and two that did not meet the AHRQ inclusion criteria. Our updated search identified an additional four studies evaluating CT in the diagnosis of adnexal masses. A bivariate random effects analysis of these four studies, along with the three studies (with four data sets) considered in the AHRQ report yielded an overall sensitivity of 87.2% and specificity of 84.0% (Table 9, Figure 2A). Three studies investigating positron emission tomography (PET) were evaluated in the AHRQ report. Our updated search identified two additional studies, both investigating the accuracy of the combined PET/CT modality. Since results for PET alone were not available, no further PET analyses were undertaken. The AHRQ report found a pooled sensitivity of 67% and specificity of 79% in the diagnosis of adnexal masses with PET technology (Table 9). # Serum Marker CA-125 The AHRQ report identified 66 studies that investigated the use of CA-125 serum marker in the evaluation of an adnexal mass. An updated literature search identified 11 new studies, with 14 data sets, investigating the use of CA-125 in the diagnosis of an adnexal mass that met our inclusion criteria. In keeping with the AHRQ report and the most commonly used threshold of 35 U/mL, we conducted a meta-analysis of the 51 studies, with 52 data sets, that used a threshold of 35 U/mL. Eight of these studies (20,(31)(32)(33)53,57,58,135) were published since the AHRQ report. The addition of these newer studies to the analysis did little to change the AHRQ summary estimates. We calculated an overall sensitivity of 78.7% and a specificity of 77.9% (Table 10, Figure 2D). Since many of the studies reported a threshold other than 35 U/mL, we re-ran the analysis using 50 U/mL as the cutoff point. The analysis included 66 studies with 72 data sets, including 10 studies published since the AHRQ report. This yielded an overall sensitivity of 79.0% and specificity of 78.3%. # Frozen Section While considered an intraoperative assessment rather than a preoperative one, frozensection diagnosis can help to guide further surgical management of ovarian tumours. Accordingly, the accuracy of this technique is of great consequence and, as such, this method of diagnosing a suspicious adnexal mass was deemed valuable for consideration in this report. The updated search of the literature identified two systematic reviews and 15 primary studies (19,(23)(24)(25)35,37,39,43,56,61,65,66,79,81,82) published in or since 2004 that considered the diagnostic accuracy of frozen-section diagnosis and were not included in either systematic review. All 15 studies were retrospective cohort-like in design, with seven reporting the selection of consecutive patients. Only one study reported the blinding of pathologists from the final histopathologic diagnosis when interpreting results of frozen sections. One study specifically reported that pathologists were not blinded, and the remaining 13 studies made no reference to blinding status. Geomini et al considered the accuracy of frozen-section diagnosis in a 2005 systematic review (14). The literature search ranged from 1966 to mid-2003, with 18 primary studies qualifying for inclusion. When borderline tumours were classified as malignant, the sensitivity of frozen-section diagnosis ranged from 65% to 97% and the specificity between 97% and 100%. Classifying borderline tumours as benign resulted in a sensitivity of 71% to 100% and a specificity of 98.3% to 100%. Medeiros and colleagues (17) also conducted a systematic review and meta-analysis on the accuracy of frozen-section analysis that included 14 primary studies. The literature search period in this review ranged from 1984 to the end of 2003. The pooled sensitivity and specificity of frozen-section diagnosis distinguishing between benign and borderline or malignant ovarian tumours was 99% (95% CI, 89 to 99%) and 88% (95% CI, 86 to 90%), respectively. In our analysis of the 15 primary frozen section studies published since 2004, borderline tumours were considered malignant and counted as such in the 2x2 tables. Furthermore, any deferred cases reported were excluded from the 2x2 tables and, consequently, from the analysis. A bivariate random effects analysis of these 15 studies yielded an overall sensitivity of 89.2% (95% CI, 86.3 to 91.5%) and specificity of 97.9% (95% CI, 96.6 to 98.7%) (Table 10, Figure 2D). # ACOG/SGO Referral Guidelines The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) jointly published guidelines for the referral of women with pelvic masses that are suspicious for ovarian cancer to gynecologic oncologists (136). The referral guidelines are based on patient age, CA-125 level (>200 U/mL for premenopausal, >35 U/mL for postmenopausal), physical findings, imaging results, and a family history of breast or ovarian cancer in a first-degree relative. The referral guidelines were validated, and their role in distinguishing benign from malignant masses was tested in a multicentre setting with 1035 patients (44). In premenopausal women, the sensitivity and specificity of the referral guidelines in differentiating benign and malignant masses was 70% and 69%, respectively. Sensitivity was # D. CA125 and Frozen Section SROC Curves Sensitivity enhanced in postmenopausal women, where the guideline correctly identified 94% of ovarian cancer patients. Specificity in this group was reported to be 58%. The predictive value of the referral guidelines was further evaluated in a prospective cohort study of 837 consecutive patients (30). In premenopausal women, the sensitivity and specificity were 79.2% and 69.8%, respectively. In postmenopausal women, sensitivity was found to be 93.2% and specificity was 59.9%. In considering early-versus late-staged disease, the referral guidelines performed better in terms of sensitivity in late-staged disease, especially in postmenopausal women where sensitivity reached 98.3%. In premenopausal women, the referral guidelines were 92.3% sensitive in distinguishing malignant from benign cases. # Surgical procedures for an adnexal mass suspicious for malignancy The Australian Cancer Network (ACN) 2004 guideline ( 6) on the management of women with epithelial ovarian cancer made recommendations on, among other things, the most appropriate surgical approach to take in such patients. Eight studies were included in the surgery for pelvic mass section of the guideline and are not discussed further here. An updated search of the literature identified an additional 16 studies (Table 11) published since the 2004 ACN guideline that met our inclusion criteria. A randomized controlled trial (RCT) ( 89) of patients undergoing a systematic aortic and pelvic lymphadenectomy versus those undergoing lymph node sampling reported no statistically significant difference in five-year progression-free (p=0.16) or overall survival (p=0.56). However, this RCT was underpowered to detect an effect of systematic lymphadenectomy on survival. The sample size calculation in this study was undertaken to detect a difference in prevalence of lymph node positivity, the study's primary outcome. The targeted sample size required to detect an effect of lymphadenectomy on survival, the secondary outcome, was deemed unattainable by the researchers. Despite the reduced power to detect a statistical difference in the secondary outcomes, the study reported a trend favouring lymphadenectomy in terms of progression-free (HR, 0.72; 95% CI, 0.46 to 1.14) and overall (HR, 0.85; 95% CI, 0.49 to 1.47) survival. Eight additional studies (85-88,90-93) investigated the survival impact of comprehensive surgical staging in women diagnosed with early-stage ovarian cancer. In two large population-based studies (85)(86), consisting exclusively of over 6600 early-stage epithelial ovarian cancer patients, Chan et al found that surgical staging with lymphadenectomy was associated with improved three-year (p<0.001) (86) and five-year disease-specific survival (p<0.001) (85) compared to staging procedures without lymphadenectomy. Similarly, Oksefjell et al reported a statistically significant improvement in 5-year overall survival rates in patients undergoing a lymphadenectomy versus those that did not (87% vs. 64%, respectively; p=0.02). Survival analyses performed by both Skirnisdottir et al ( 91) and Hornung et al ( 88) also demonstrated a statistically significant benefit in disease-free survival (p=0.004 and p=0.0007, respectively) for patients undergoing a lymphadenectomy versus those that did not. Hornung and colleagues also considered overall survival and reported a statistically significant difference (p=0.0008) in the two patient groups in favour of the lymphadenectomy group. Conversely, in 205 patients with pTI-IIb clear cell carcinoma, Suzuki et al (92) found that patients who underwent systemic lymphadenectomy did not show a significant improvement in disease-free (p=0.353) or overall survival (p=0.645) compared to those that did not. Similarly, Cho et al (87) report no significant difference between groups in progression-free and overall survival rates in patients with stage I mucinous epithelial ovarian tumours undergoing complete staging versus those whose staging was incomplete. In an attempt to determine the benefit of surgically staging ovarian low malignant potential (LMP) tumours, Wong and colleagues (93) retrospectively reviewed the records of 247 patients with tumours of borderline malignancy and found no statistically significant difference in rates of recurrence or mortality between patients surgically staged and those who were unstaged. Six studies (94-99, 137) compared laparoscopy versus laparotomy for the surgical management of women with apparent early ovarian cancer or borderline tumours. Patient sample sizes in these studies ranged from 34 to 360. In the three studies (95-97) that considered patients with early epithelial ovarian cancer (EOC), no statistical difference in survival rates was detected between patients undergoing a laparoscopy versus laparotomy. Similarly, in the management of patients with early borderline ovarian tumours, Romagnolo et al (98), Park et al (99), and Desfeux et al (94) found that a laparoscopic versus laparotomic surgical approach did not appear to influence survival rates, although Desfeux et al acknowledged that the number of events was too small to allow for proper statistical testing. Fertility-preserving treatments are often desirable for women of reproductive age who are diagnosed with borderline ovarian tumours (BOT). Two studies compared the impact of conservative fertility-sparing surgeries versus more extensive surgical approaches. Yinon et al (100) specifically compared rates of recurrence in 40 patients who underwent unilateral salpingo-oophorectomy versus 22 patients who underwent cystectomy only. No statistical difference in recurrence rates was detected (27.5% vs. 22.7%, p=0.8). Similarly, in a larger study of 360 women with BOT, Park et al (99) found no difference in disease-free survival between patients that underwent radical or fertility-sparing surgery (p=0.651). # Adverse Events While the surgical technique did not appear to impact patient survival, there were differences detected in surgical outcomes and complication rates. Cho et al (87) found a statistically significant difference in complication rates, with 12.9% experiencing a complication in the completely staged group versus 1.0% in those incompletely staged (p<0.001). Ghezzi et al (95) reported a statistically significant difference in the rates of minor postoperative complications, with 6.7% of patients in the laparoscopy group experiencing such an event compared to 42.1% of patients in the laparotomy group (p=0.047). Romagnolo et al (98) reported a difference in the cases of tumour rupture or spilling during surgery, with 34.6% ruptures recorded in the laparoscopic group compared to 6.6% in patients undergoing a laparotomy (p<0.0001). Similarly, Lecuru et al (96) found 31% of laparoscopic patients experienced intraoperative tumour rupture versus 16% in the laparotomy group. However, this difference did not reach statistically significance. In patients with borderline tumours, the difference in the occurrence of intraoperative tumour rupture was found not to be statistically associated with the surgical approach according to Desfeux et al. ( 94) The basic diagnostic work-up of patients with a suspicious adnexal mass involves a gynecological exam, ultrasound imaging and testing of serum tumour markers. While this approach is often sufficient in detecting advanced disease, the diagnosis of early-staged ovarian cancer is more challenging. In an attempt to determine the best method for the identification and diagnosis of a suspicious adnexal mass, we systematically reviewed existing guidelines and the literature. The intention and necessity of preoperative diagnosis of an adnexal mass is to both triage the patient and better define the surgical options. Recent Canadian guidelines on the evaluation and referral of ovarian masses (138) recommend that patients with a high-level risk of underlying malignancy be reviewed in consultation with a gynecologic oncologist. Indeed, studies considering the impact of physician's specialty on the survival of patients with early stage ovarian cancer have shown a trend towards improved survival when gynecologic oncologists perform the surgery (139)(140). Along with triaging appropriate patients to subspecialists, the preoperative diagnosis of an adnexal mass provides the anatomic details necessary to inform the surgical options. For patients with clearly benign masses, or likely benign masses with health issues, observation only is the usual management. Such preoperative diagnostic information can also help to distinguish patients who require extensive surgery over those for whom a more conservative surgical approach is adequate. Statistical comparisons between diagnostic techniques could not be performed in this review. Instead, the assessment of various modalities in differentiating benign from malignant masses is based on inspection of the summary data obtained from the meta-analyses conducted. These results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each system with equivalent diagnostic competence. Explicit scoring systems did not appear to perform as well as other diagnostic testing methods. Not only was external validation of the models lacking in many cases, where results were available, but performance was often poorer upon subsequent replication. Assessment of an adnexal mass by colour Doppler technology, using the RI, PI, and PSV indices, was neither as sensitive nor as specific as simple ultrasonography. Furthermore, because of overlap of vascular parameters between malignant and benign masses, a firm diagnosis based on Doppler evaluation alone can be problematic (141). Summary estimates from studies considering combined morphology and Doppler assessment were higher than the estimates for either modality alone. Both sensitivity and specificity of this combined approach were high. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT as determined by overlapping confidence intervals. PET did not appear to perform as well as either MRI or CT, although only three studies were considered in the analysis. The measurement of the CA-125 tumour marker appears to be less reliable than other available assessment methods; however, results were not stratified by menopausal status. It is widely reported that differences exist in CA-125 levels between premenopausal and postmenopausal women, even with the same histological diagnosis (75). Finally, frozen-section analysis has both a high sensitivity and an especially high specificity in the assessment of adnexal masses. In the treatment of ovarian cancer, the importance of surgical management is universally recognized. Clearly, complete surgical resection is required to improve a patient's prognosis. However, it is not clear how aggressive a surgical approach is necessary in earlystaged ovarian cancer. The included evidence suggests that systematic lymphadenectomy improves survival, as does proper surgical staging. There is an exception to this benefit, however, with tumours of low malignant potential. In such tumours, conservative fertilitypreserving surgical approaches appear to have no adverse survival effect (99). The accuracy and adequacy of surgical staging by laparotomy or laparoscopic approaches appears to be comparable, with neither approach conferring a survival advantage compared to the other. In spite of this, many surgeons are unwilling to perform laparoscopic surgical staging in early-staged ovarian cancer due to the potential risks of intraoperative tumour rupture, port-site metastasis, and dissemination of the tumour (97). Intraoperative tumour rupture was indeed reported to occur more frequently in patients undergoing laparoscopy versus laparotomy in two retrospective cohort studies (96,98). However, unequivocal prospective comparative data supporting the existence of an increased occurrence of intraoperative tumour rupture in ovarian cancer patients managed by laparoscopy is still lacking (95). The evidence included in this systematic review is not without significant limitations. In the identification of an adnexal mass literature, the population of patients often included women with a suspicious mass undergoing surgery. This inclusion of operative patients could escalate the prevalence of malignancy in comparison to what would be expected in a primary care population of women presenting with a suspicious adnexal mass. This has implications for the generalizability of the results, and it can inflate the test's sensitivity. Furthermore, the included studies did not often allow for stratification by menopausal status. Given the lower likelihood of ovarian malignancy in premenopausal patients, the accuracy of a diagnostic test can be reduced in a sample that includes a high proportion of premenopausal patients. In addition to these methodological issues, the quality assessment of the included literature revealed several further shortcomings, especially in study design and reporting. Blinding is a crucial issue in diagnostic accuracy studies, as it is necessary to prevent information bias (142). While the index test always preceded surgery in the included studies, thereby by nature blinding the outcome, the reference test should also be interpreted without knowledge of the index test results (142). The vast majority of studies considered in the identification of a suspicious adnexal mass did not report such blinding. One third of the diagnostic studies had data collection that occurred retrospectively or was not reported. Retrospective study designs are inherently more prone to bias than are prospective studies and can be more difficult to interpret, especially if the sampling did not include consecutive patients. The reporting of consecutive patient sampling occurred in less than half the included studies. Many of the surgical studies were also prone to biases inherent in their retrospective designs. Moreover, the small sample of included patients meant many studies were underpowered to detect statistically significant results. There is an obvious need for improvement in the quality of primary research in this area. Ideally, future research would consist of randomized clinical trials with a non-inferiority design where survival outcomes are considered. Despite these limitations, the best available evidence with respect to the questions posed was collected and included. A rigorous systematic review and meta-analysis, planned a priori, provided an abundant evidentiary base and the context and direction for the development of recommendations. There are numerous methodologies that have been considered in the preoperative identification of adnexal masses suspicious for malignancy. Results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each morphological system with equivalent diagnostic competence. Explicit scoring systems did not perform as well as other diagnostic testing methods. Assessment of an adnexal mass by colour Doppler technology, using the RI, PI, and PSV indices, was neither as sensitive nor as specific as simple ultrasonography. Summary estimates from studies considering combined morphology and Doppler assessment were higher than the estimates for either modality alone. Both sensitivity and specificity of this combined approach were high. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT. PET did not perform as well as either MRI or CT. The measurement of the CA-125 tumour marker appears to be less reliable than do other available assessment methods. Finally, frozen section analysis has both a high sensitivity and especially high specificity in the assessment of adnexal masses. The evidence suggests that systematic lymphadenectomy and proper surgical staging improve survival. Conservative fertility-preserving surgical approaches are an acceptable option in women with low malignant potential tumours. The accuracy and adequacy of surgical staging by laparotomy or laparoscopic approaches appears to be comparable, with neither approach conferring a survival advantage. # CONFLICT OF INTEREST No conflicts of interest were declared for J Dodge, A Covens, C Lacchetti, L Elit, T Le, M Devries-Aboud, or M Fung Kee Fung. # JOURNAL REFERENCE The following systematic reviews and meta-analysis has been published in Gynecologic Oncology (© 2012 Elsevier Inc.;/): The Gynecology Cancer Disease Site Group would like to thank J Dodge, A Covens, C Lacchetti, L Elit, T Le, M Devries-Aboud, and M Fung Kee Fung for taking the lead in drafting this systematic review with meta-analysis. The PEBC supports a network of disease-specific panels, termed Disease Site Groups (DSGs), as well as other groups or panels called together for a specific topic, all mandated to develop the PEBC products. These panels are comprised of clinicians, other health care providers and decision makers, methodologists, and community representatives from across the province. The PEBC is well known for producing evidence-based guidelines, known as Evidencebased Series (EBS) reports, using the methods of the Practice Guidelines Development Cycle (1,2). The EBS report consists of an evidentiary base (typically a systematic review), an interpretation of and consensus agreement on that evidence by our Groups or Panels, the resulting recommendations, and an external review by Ontario clinicians and other stakeholders in the province for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each document, through the periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original guideline information. # The Evidence-Based Series Each EBS is comprised of three sections: - Section 1: Guideline Recommendations. Contains the clinical recommendations derived from a systematic review of the clinical and scientific literature and its interpretation by the Group or Panel involved and a formalized external review in Ontario by review participants. # DEVELOPMENT OF THIS EVIDENCE-BASED SERIES Development and Internal Review This EBS was developed by the Gynecology DSG of the CCO PEBC. The series is a convenient and up-to-date source of the best available evidence on management of a suspicious adnexal mass, developed through review of the evidentiary base, evidence synthesis, and input from external review participants in Ontario. # Report Approval Panel Prior to the submission of this EBS draft report for external review, the report was reviewed and approved by the PEBC Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. The key issues raised by the Report Approval Panel and the modifications made by the Gynecology DSG are below with the DSG responses bulleted below the comments of the panel members: - If pathology is still the gold standard, as suggested in your last qualifying statement, what is the role of the other diagnostic technologies? o The need to have clarity in the preoperative diagnosis is to 1) triage the patients to a specialist, and 2) better define the surgical options (e.g., conservative vs. radical). We have now added a paragraph to the discussion regarding the intention and necessity of preoperative diagnosis of an adnexal mass. - The authors' first recommendation, and the one for which the most detailed analysis exists, concludes that 3D US, CT and MRI are "all recommended" with considerations of more "local factors" then suggested as determinants of the modality of choice. The authors should reconsider whether they have missed an opportunity to make a more definitive recommendation that accounts for the "equality" in diagnostic efficacy and what can be reasonably assumed about cost, access, harm (e.g., radiation exposure) and patient inconvenience. o We thank the reviewer for his comments. We have taken this opportunity to add further recommendations based on the Working Group's expert consensus opinion that takes into consideration availability, access, and harm. - The authors consider various diagnostic tools separately (e.g., imaging, CA-125). Is there a risk that, in practice, these modalities are used in combination and in doing so, diagnostic properties are changed? Related to this theme, are there important differences in the eligibility of patients included in any analysis of a single modality, in which a second modality criterion was required for inclusion? The bolded text was removed from the recommendations section, and it was further delineated that the recommendations were based on expert opinion. Furthermore, the recommendation on PET was moved to indicate that the role of PET in cervical cancer has not been prospectively evaluated. o In many circumstances, we have evaluated the combination of diagnostic tests such as ultrasound and CA-125 - In contrast to the diagnostic efficacy section, the section that deals with "therapy" (What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for malignancy?) does not include conventional guideline methodology or reporting. As this question is a largely a therapeutic question, standard methodologies would move down a hierarchy of acceptable guidelines, metaanalysis of randomized controlled trials (RCTs), RCTs, non-randomized comparisons, etc. The authors do not provide background in their Methods section about their approach to this question (including literature search criteria). The Results section largely is divided into positive vs. negative studies as opposed to a systematic presentation of the literature. As a result, the juxtaposition of data and conclusions is associated with ambiguity and comes across as potentially representing "expert opinion" as opposed to an evidenced-based recommendation. The authors should reconsider their approach to this question. o We thank the reviewer for these comments. We did indeed use standard methodologies in the development of this section of the guideline but acknowledge that this was not clear in the reporting. As such, we have explained more explicitly in the Methods section what was done. Furthermore, we rearranged the reporting of the results so that the one RCT is discussed first. - The authors might wish to clarify whether the post-diagnostic therapeutic pathway includes multiple modalities that require systematic review in order to assess linkage. Again, while this comment may reflect lack of content expertise, if these patients should be considered for adjuvant therapy using another modality, does the use of that subsequent modality interact with the choice of the surgical approach? In addressing the surgical approach, and especially if best therapy involves sequential use of multiple modalities, the authors may need to carefully dissect out the prognostic importance of patients being able to undergo a more extensive surgical procedure vs. the therapeutic benefit of that intervention. o There is indeed a link between surgery and adjuvant therapy. However, the Working Group viewed these two interventions separately, both in terms of prognosis and as therapeutic approaches. As such, a discussion on adjuvant therapy in patients with a suspicious adnexal mass was deemed beyond the scope of this document. # External Review by Ontario Clinicians and Other Experts The PEBC external review process is two-pronged and includes a targeted peer review that is intended to obtain direct feedback on the draft report from a small number of specified content experts and a professional consultation that is intended to facilitate dissemination of the final guidance report to Ontario practitioners. Following the review and discussion of Section 1: Recommendations and Section 2: Evidentiary Base of this EBS and the review and approval of the report by the PEBC Report Approval Panel, the Gynecology Cancer DSG circulated Sections 1 and 2 to external review participants for review and feedback. Box 1 summarizes the draft recommendations and supporting evidence developed by the working group. # BOX 1: DRAFT RECOMMENDATIONS (approved for external review 2011-04-08) QUESTIONS - What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? 2. What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer? # TARGET POPULATION The target population of this guideline is adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic. # INTENDED USERS This guideline is targeted for clinicians managing the care of women with a suspicious adnexal mass, specifically general gynecologists and gynecological oncologists. # RECOMMENDATIONS Identification of an Adnexal Mass Suspicious for Ovarian Cancer ➢ Sonography, particularly three-dimensional (3D) sonography, magnetic resonance imaging (MRI), and computerized tomography (CT) imaging are each recommended for differentiating malignant from benign ovarian masses. However, the working group offers the following further recommendations, based on their expert consensus opinion and the consideration of availability, access, and harm: - Transvaginal sonography should be the first modality of choice, where technically feasible, in patients with a suspicious, isolated ovarian mass. # - MRI is the most appropriate test to help clarify the malignant potential in patients where ultrasound may be unreliable. - CT is most useful in cases where extra ovarian disease is suspected or needs to be ruled out. # Key Evidence - The diagnostic performance of each diagnostic technology was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. - A meta-analysis of six cohort studies that investigated 3D sonography (1-6) indicated an enhanced sensitivity of 93.5% and specificity of 91.5% with 3D technology (Section 2, Figure 2A). - A meta-analysis of 22 cohort studies with 24 data sets that investigated the effectiveness of MRI in the diagnosis of adnexal masses (7-28) found an overall sensitivity of 91.9% and specificity of 88.4% (Section 2, Figure 2A). - A meta-analysis of seven studies with eight data sets considering CT technology (2,10,12,14,22,29,30) yielded an overall sensitivity of 87.2% and specificity of 84.0% (Section 2, Figure 2A). # ➢ Evaluation of an adnexal mass by Doppler technology alone is not recommended. Doppler technology should be combined with a morphological assessment. # Key Evidence - This recommendation is based on the results of several meta-analyses on Doppler indices but not direct comparisons between them. Rather, the summary data from these meta-analyses were inspected, and reasonable sensitivities and specificities were noted. - A meta-analysis of the resistance index (RI) included 35 cohort studies (2,5,17, with 42 data sets and yielded an overall sensitivity of 77.2% and specificity of 89.8% (Section 2, Figure 2C). - A meta-analysis of 21 cohort studies with 22 data sets that evaluated the Pulsatility Index (PI) found an overall sensitivity of 80.6% and specificity of 79.9% (Section 2, Figure 2C). - A meta-analysis of the peak systolic velocity (PSV) included seven cohort studies (32,33,37,42,50,51,62) and found an overall sensitivity of 80.0% and specificity of 84.2% (Section 2, Figure 2C). # Qualifying Statement - Assessment of an adnexal mass by colour Doppler technology, using the RI, PI and PSV indices, was neither as sensitive nor specific as simple ultrasonography. Furthermore, because of the overlap of vascular parameters between malignant and benign masses, a firm diagnosis based on Doppler evaluation alone can be problematic. ➢ Morphological scoring systems can be used to differentiate benign from malignant adnexal masses. The choice between the scoring systems should be made based on demonstrated accuracy and clinician preference. # Key Evidence - The diagnostic performance of each morphological scoring system was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. - A meta-analysis of 17 cohort studies (32,33,46,52,57,63-74) assessing the Sassone model at a cutoff of 9, found an overall sensitivity of 88.6% and specificity of 77.5% (Section 2, Figure 2B). - A meta-analysis of nine studies (33,35,63,65,70,(75)(76)(77)(78) considering the Ferrazzi scoring system reported an overall sensitivity and specificity of 85.2% and 85.9%, respectively (Section 2, Figure 2B). - A meta-analysis of five studies (36,(79)(80)(81)(82) measuring the performance of the Finkler scoring system found an overall sensitivity of 83.5% and specificity of 78.2% (Section 2, Figure 2B). - A meta-analysis of data from 13 RMI studies (70,(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94), with 15 data sets, employing a cutoff of 200 to be indicative of malignancy, reported the summary sensitivity and specificity were 79.2% and 91.7%, respectively (Section 2, Figure 2B). ➢ As a stand-alone modality, serum CA-125 is not recommended for distinguishing between benign and malignant adnexal masses. # Key Evidence - This recommendation is based on a meta-analysis of 49 2D). # Qualifying Statement - CA-125 values are of limited use in premenopausal women and elevated in only 50% of early-stage ovarian cancers. Caution should be used in interpreting values in such patients. ➢ Frozen section for the intraoperative diagnosis of a suspicious adnexal mass is recommended in settings where availability and patient preferences allow. # Key Evidence - This recommendation is based on a meta-analysis of frozen section diagnoses that included 15 cohort studies (7,(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145) and yielded an overall sensitivity of 89.2% and specificity of 97.9% (Section 2, Figure 2D). # Surgical Procedures for an Adnexal Mass Suspicious for Malignancy ➢ Comprehensive surgical staging with lymphadenectomy is recommended for the surgical management of patients with early-stage ovarian cancer to improve survival. # Key Evidence # QUALIFYING STATEMENTS The Gynecology Cancer Disease Site Group (DSG) acknowledges that, despite definitions and criteria, it is unrealistic to expect that 100% of ovarian cancers will be identified as suspicious preoperatively. Pathology remains the gold standard. Targeted Peer Review: During the guideline development process, two targeted peer reviewers from Ontario and one from the USA considered to be clinical and/or methodological experts on the topic were identified by the working group. Several weeks prior to completion of the draft report, the nominees were contacted by email and asked to serve as reviewers. Three reviewers agreed, and the draft report and a questionnaire were sent via email for their review. The questionnaire consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a guideline. Written comments were invited. The questionnaire and draft document were sent out on April 8, 2011. Follow-up reminders were sent at two weeks (email) and at four weeks (telephone call). Professional Consultation: Feedback was obtained through a brief online survey of health care professionals who are the intended users of the guideline. Gynecologists and gynecologic oncologists in the PEBC database were contacted by email to inform them of the survey. Participants were asked to rate the overall quality of the guideline (Section 1) and whether they would use and/or recommend it. Written comments were invited. Participants were contacted by email and directed to the survey website where they were provided with access to the survey, the guideline recommendations (Section 1) and the evidentiary base (Section 2). The notification email was sent on April 13, 2011. The consultation period ended on June 10, 2011. The working group reviewed the results of the survey. Targeted Peer Review: one reviewer out of the three that were invited provided a response. This reviewer's responses are summarized in Table 1. No significant barriers or enablers were reported. # Summary of Written Comments The reviewer advised that references by L. Cohen and A. Fleischer be added to the evidence base. The authors were not able to gather more information from this reviewer regarding exactly which publications had been missed. The authors examined whether references by Cohen and/or Fleischer had been considered at any time during the guideline development process. Cohen (2001) was considered by the AHRQ review and reported in Section 2 under "Other Scoring Systems". An additional paper by Cohen and Fleischer was excluded by the AHRQ. One Fleischer paper was included in the evidence base for the guideline. In the end, no modifications to the evidence base were made on the basis of this reviewer comment. Professional Consultation: Sixty responses were received. Key results of the feedback survey are summarized in Table 2. 3. I would recommend this guideline for use in practice. 0(0) 0(0) 7( 13) 22( 39) 31( 55) # What are the barriers or enablers to the implementation of this guideline report? Practitioners listed barriers to the implementation of this guideline and suggested ways that uptake could be enhanced or enabled. The feedback included the following: Some practitioners mentioned that lack of awareness of the guideline would be a barrier to uptake. They recommended making primary care physicians aware of the guideline, and one reviewer suggested presentation of the guideline at group rounds to make the entire team aware of current literature and recommendations. Many practitioners reported that lack of resources would be a barrier to implementation of the guideline, especially in smaller communities. Specific resources that were noted as lacking included: - Gynecologic oncologists (e.g., for staging using lymphadectomy). - MRI only available in larger communities and delays with MRI booking. - CT access. - Patients may not always have easy access to an ultrasound department and quality of reporting is variable. - Pathologists with experience in gynecologic pathology for frozen section diagnoses. - Regional Minimally Invasive Surgery programs in the community. In order to enable the implementation of the guideline, practitioners also suggested: - A summary table outlining the sensitivities and specificities of the various diagnostic procedures. - Guidance for referral of patients to a gynecologist or gynecologic oncologist for nongynecologist clinicians who identify an adnexal mass. - Educating radiologists about appropriate use of ultrasound. - Boundaries to indicate whether the risk for a specific woman is low or high after being investigated. - A recommendations regarding CA-125 use for post-op women. - A summary table outlining the sensitivities and specificities of the various diagnostic procedures is presented in Section 2 of the report. - Referral criteria are considered to be outside of the scope of this review and guideline. For more information on referral criteria, readers may refer to a guideline published in 2009 by the Society of Obstetricians and Gynaecologists of Canada: Initial evaluation and referral guidelines for management of pelvic/ovarian masses (138). - Cutoffs for the scoring systems included in the report were added to Appendix 2 in Section 1. - CA-125 use post-op is outside of the scope of this guideline. In the event that the reviewer meant that we should clarify the recommendation regarding CA-125 use as a stand-alone modality in postmenopausal women, we amended the CA-125 recommendation so that it no longer refers only to premenopausal women, but to all women, as there is no evidence for its efficacy as a stand-alone modality for any age group. # Summary of Written Comments Twenty of the sixty responders to professional consultation provided additional written comments. The majority indicated that the document was of high quality and would be of use to practitioners. Suggestions for improvements or additions to the document included: - Mention of specific suspicious features may prove useful for the radiologist colleague accessing this guideline. 2. There is clear operative requirement of staging and lymphadectomy, but the role of tertiary referral is not clear. 3. Several comments were made relating the scoring systems described in the report. The feedback generally indicated that there are many practitioners in the province who are not aware of these scoring systems. A direct link from the recommendations to the scoring systems was requested. It was also suggested that the guideline recommend one scoring system that would be the most reliable. Other comments related to scoring systems include: a. Many practitioners are using the Risk of Malignancy Index (RMI) and it should be available as an appendix to this guideline. Also related to RMI: i. Recommendation on the use of RMI II and how the general gynecologist should use it for guidance when considering referral to a tertiary care centre. ii. Reference to RMI cutoff of 200 instead of 400 which is what is commonly used. 4. There was also a request for an appendix for ultrasound features of malignancy and definitions of resistance index (RI) pulsatility index (PI), and Peak Systologic (sic) Velocity (PSV). - As specific suspicious features are described in Section 2 of the report, no changes were made based on this comment. 2. The topic of referral is beyond the scope of this guideline and was therefore not considered for inclusion. As mentioned above, readers may refer to the Society of Obstetricians and Gynaecologists of Canada guideline Initial evaluation and referral guidelines for management of pelvic/ovarian masses (138). 3. Response to comments related to the scoring systems: a. An appendix was added to Section 1 with descriptions of the Sassone, DePriest, Ferrazzi, Lerner, Finkler, and RMI scoring systems. References to the original publications were also added to Section 2 of the report. Because the sensitivity and specificity are comparable for these scoring systems, it is not possible to recommend one of them as most reliable. Therefore, the wording of the recommendation was adjusted to make this clear and to indicate that the choice of scoring system should be based on clinician preference. b. The recommendation was also reworded to state that choice of version of the RMI should be based on clinician preference as they all have comparable sensitivity and specificity. c. The cutoff value of 200 for the RMI was based on the cutoff used in the initial report by Jacobs et al. The sensitivity and specificity values reported here are based on this cutoff. This was also reported in the AHRQ report as the most common cutoff value, therefore, the group decided to not to include reference to a cutoff of 400. d. Other definitions such as RI, PI, and PSV can be found in Section 2 of the document. This EBS report reflects the integration of feedback obtained through the external review process with final approval given by the Gynecology Cancer Disease Site Group, and the Report Approval Panel of the PEBC. Updates of the report will be conducted as new evidence informing the question of interest emerges. In September 2015, this document was assessed in accordance with the PEBC Document Assessment and Review Protocol and was determined to require a review. As part of the review, a PEBC methodologist conducted an updated search of the literature. A clinical expert (TL) reviewed and interpreted the new eligible evidence and proposed the existing recommendations could be endorsed. The Gynecology Cancer Disease Site Group (DSG) endorsed the recommendations found in Section 1 (Clinical Practice Guideline) on September 9, 2016. # DOCUMENT ASSESSMENT AND REVIEW RESULTS # Questions Considered - What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? - What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer # Literature Search and New Evidence The new search (January 2011 to January 2016) yielded 9386 papers. Three hundred and eighty six were retained for full text review. After the full text review, 93 studies were retained. Brief results of these searches are shown in the Document Review Tool. # Impact on Guidelines and Its Recommendations The new data supports existing recommendations. Hence, the Gynecology Cancer DSG ENDORSED the 2011 recommendations on management of a suspicious adnexal mass. A new qualifyling statement was added to the recommendation on ultrasound-based morphological scoring systems. "Ultrasound diagnostic criteria using a set of simple rules to distinguish between benign and malignant masses, and the IOTA (International Ovarian Tumour Analysis) predictive adnexal model had been extensively studied with acceptable sensitivity and specificity. This can serve as potential alternative diagnostic strategy to the RMI score." The following paragraphs are the justification for the inclusion of this qualifying statement.. Inconclusive result can be classified using subjective assessment by an experienced ultrasound operator. This strategy has been recently validated in 4848 patients with adnexal masses against histopathologic diagnosis with a sensitivity of 99.7% and specificity of 33.7%. In addition, the IOTA group also constructed an Assessment of Different Neoplasias in the adneXa (ADNEX) model. This is a risk prediction model to differentiate between benign, borderline tumours, stage I invasive, stage II-IV invasive ovarian cancer and secondary metastatic cancer. The ADNEX model consists of three clinical predictors and six ultrasound predictors. The clinical predictors are age (years), serum CA-125 (U/mL) and type of center to which the patient has been referred for ultrasound examination. Type of center was divided into oncology centers versus other hospitals. The ultrasound predictors are the maximal diameter of the adnexal mass (mm), proportion of solid tissue (%), number of papillary projections (0, 1, 2, 3, > 3), presence of more than 10 cyst locules (yes/no), acoustic shadows (yes/no), and presence of ascites (yes/no). The model performed well in differentiating between benign and malignant masses with the area under the receiver operating characteristic curves (AUC) of the ADNEX model of 0.954 (95% confidence interval 0.947 to 0.961) on the development data and 0.943 (0.934 to 0.952) on the validation data. The sensitivity for diagnosis of malignancy was 96.5% and specificity was 71.3% on the validation data set. 3. What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? 4. What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for ovarian cancer? The target population of this guideline is adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic. # Study Section Criteria: Articles were eligible for inclusion in this systematic review if they were systematic reviews, meta-analyses, clinical practice guidelines, randomized trials, or comparative cohort studies. Studies identified in the update of the AHRQ report literature search were included based on the same inclusion criteria put forth in the AHRQ report (3). For studies investigating single modality identification of an adnexal mass, the inclusion criteria were: 1) comparison of the test (e.g., bimanual pelvic exam or ultrasound, to histology or negative surgery 2) greater than 20 patients included in study 3) able to construct a 2-by-2 table, which compares the results of the diagnostic test with the definitive histological diagnosis. For studies investigating the use of multi-modality scoring systems (i.e., RMI), the inclusion criteria were: 1) patients with suspicion of cancer 2) studies with scoring, risk score, combined modality approach 3) assesses predictive value of two or more variables using multivariable model 4) greater than 50 patients included in study. Studies identified in the update of the Australian Cancer Network (6) guideline were based on the following selection criteria: 1) greater than 20 patients included in study 2) patients with an adnexal mass suspicious for early stage (I-II) malignancy, 3) two-armed (or greater) study design with a comparison of surgical procedures/techniques/approaches 4) report on at least one of the following outcomes: optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, quality of life. The SUVmax of malignant tumors was significantly higher than that of benign and borderline lesions (mean, 7.8, 1.7, 2.4; P < 0.05). Among malignant tumors, SUVmax was significantly lower in mucinous adenocarcinomas compared with nonmucinous malignant tumors (mean, 3.3, 8.4; P < 0.05) and lower in clear cell adenocarcinomas compared with other subtypes of nonmucinous malignant tumors (mean, 6.0, 9.4; P < 0.05). The SUVmax cutoff that best differentiated malignant lesions from benign/borderline lesions was 2.4 for mucinous and 4.0 for nonmucinous tumors. These cutoffs correctly classified lesions as malignant or not in 88 The frequency of invasive malignancy was 10% in small tumors, 19% in medium-sized tumors and 40% in large tumors; 11% of the large tumors were borderline tumors vs 3% and 4%, respectively, of the small and medium-sized tumors. The type of benign histology also differed among the three subgroups. For all methods, sensitivity with regard to malignancy was lowest in small tumors (56-84% vs 67-93% in medium-sized tumors and 74-95% in large tumors) while specificity was lowest in large tumors (60-87%vs 83-95% in medium-sized tumors and 83-96% in small tumors. The DOR and the AUC value were highest in medium-sized tumors and the AUC was largest in tumors with a largest diameter of 7-11 cm. # Author Study type Comparison N Results Frozen sections were compared with final paraffin sections 27 cases had a diagnostic discrepancy. # Rakhshan 2009 Not stated Frozen section diagnosis of adnexal masses was compared with permanent section diagnosis as the gold standard. The overall accuracy of frozen section diagnosis was 95.7%. The sensitivity of frozen section diagnosis for benign, borderline and malignant lesions was 99, 60, and 92%, respectively. The tumor size in discrepant cases was larger than the concordant cases, however no association between mucinous histology and inaccurate diagnosis was found. # OUTCOMES DEFINITIONS - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of the Web site and each page is watermarked with the phrase "ARCHIVED". - ENDORSED -An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. - DELAY -A Delay means that there is reason to believe new, important evidence will be released within the next year that should be considered before taking further action. - UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.

To determine the risk of cutaneous malignant melanoma (herein referred to as melanoma) associated with use of indoor tanning devices, including impact of age at first use and frequency of use on the relative risk of developing melanoma. # TARGET POPULATION All users of indoor tanning beds are the target population of this guideline. # INTENDED USERS This guideline is intended for use by clinicians, other health care providers, users and potential users of indoor tanning devices in Ontario. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # RECOMMENDATION 1 Use of indoor tanning devices should be avoided to reduce risk of melanoma. # Summary of Key Evidence for Recommendation 1 A systematic review with meta-analysis (1) based on pooling of 27 cohort and casecontrol studies found a significant association between ever use of indoor tanning devices and increased risk of developing melanoma (relative risk 1.25: 95% confidence interval 1.09-1.43; p<0.05). # Justification for Recommendation 1 There is strong evidence linking the use of indoor tanning devices to an increased risk of developing melanoma. Although the meta-analysis (1) lacked detail on some elements of interest for the included studies, the current systematic review of the literature verified the clinical homogeneity of the pooled studies. The Use of Indoor Tanning Devices Guideline Development Group (GDG) believes that the current evidence informs a strong recommendation. # Qualifying Statements for Recommendation 1 The International Agency for Research on Cancer (IARC) recently declared solar ultraviolet radiation (UVR) from indoor tanning devices a carcinogen (2). Both UVA and UVB have been shown to cause direct DNA damage through production of DNA mutations (UVA at a lower level than UVB), as well as indirect DNA damage via production of reactive oxygen species. Although UVB radiation can initiate the production of vitamin D in the skin, there are no data to support that artificial UVR is superior to oral supplementation with vitamin D to increase serum levels of this vitamin. Given the significant risk of melanoma as a consequence of using tanning devices, the GDG concludes that risks that arise from the use of tanning devices far outweigh any perceived benefit to their use. This systematic review evaluated studies from 2000 to present with the goal of capturing the impact of modern tanning beds, which have been designed to more accurately mimic UVR. However, the identified meta-analysis conducted by Boniol et al (1) included studies published from 1981 through 2012 and evaluated an older generation of tanning beds. It is hypothesized that future studies assessing the impact of modern tanning beds could potentially amplify the effects found in the current review. # RECOMMENDATION 2 All individuals should avoid use of indoor tanning devices, especially those at a younger age. # Summary of Key Evidence for Recommendation 2 A recent and comprehensive systematic review with meta-analysis (1) found an increased risk of melanoma in those who initiated tanning devices use at a younger age (RR, 1.59: 95%CI, 1.36-1.85; p<0.05). Data were pooled from 13 studies, 12 of which adjusted for confounders related to sun exposure and sun sensitivity. # Justification for Recommendation 2 Both the rate of tanning device use in youths, as well as the incidence of melanoma diagnosis in 15 to 34 year olds has been increasing. Moreover, the meta-analysis by Boniol et al (1) demonstrated that the younger a person starts using indoor tanning devices, the higher the risk of developing melanoma in their lifetime. These are concerning statistics, and the GDG concludes that the current evidence informs a strong recommendation. # Qualifying Statements for Recommendation 2 Based on the evidence, the GDG has not set an age cut-off for "younger age." The identified meta-analysis defined young age as under age 35 (1). However, not all the studies included in the analysis defined an age for younger age; in those that did, younger age was defined as anywhere from 18 to 35. In the three included case-control studies that found an increased risk of melanoma with a definitive age cut-off, younger age was defined as less than 25 years (3), less than 35 years (4) and less than 18 years (5). The GDG concludes that these data point to an association between tanning bed use and increased risk of developing melanoma at any younger age of first use: defining a specific age cut-off would only be speculative and would not add to the recommendation. # RECOMMENDATION 3 There is no safe lower limit of exposure to artificial UVR from indoor tanning devices. # Summary of Key Evidence for Recommendation 3 When evaluating the risk associated with frequent use of indoor tanning devices, both number of sessions and length of tanning sessions were considered. The meta-analysis conducted by Boniol et al (1) found a 1.8% increased risk of developing melanoma for each additional session of tanning device use per year (95%CI, 0.0-3.8%; p<0.05). Additionally, when Boniol et al ( 1) conducted an analysis of 14 studies that reported relative risks with frequent tanning bed use, they found a 42% increased risk of developing melanoma with high tanning bed use (RR, 1.42; 95%CI, 1.15-1.74; p<0.05). One additional case-control study (6), which was not included in the Boniol et al meta-analysis (1), similarly found an association between increased risk of melanoma and both the number of sessions and length of sessions (p=0.04). # Justification for Recommendation 3 Based on the association between ever use of indoor tanning devices and increased risk of developing melanoma, plus the greater risk associated with frequent use of indoor tanning devices, the evidence indicates that there is no safe lower limit of exposure to artificial UVR from indoor tanning devices. Updating All PEBC documents are maintained and updated through an annual assessment and subsequent review process. This is described in the PEBC Document Assessment and Review Protocol, available on the CCO website at:

# RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION RECOMMENDATION 1 DNMT3A mutation testing should be included as a biomarker test in cytogenetically normal AML patients. # Summary of Key Evidence for Recommendation Four (8,10,13,15) of the eight studies (8)(9)(10)(11)(12)(13)(14)(15) included in the systematic review reported a statistically significant difference in Overall Survival (OS) between DNMT3A wild type (DNMT3A-wt) and DNMT3A-mutated (DNMT3A-mut) populations favouring the non-mutated gene; the remaining four that did not provide statistical data did demonstrate a similar trend. The meta-analysis of these data resulted in an overall estimated hazard ratio 1.66 (95%CI, 1.23-2.24; p=0.0010) favouring patients that are DNMT3A wild type. This strongly suggests that the mutational status of DNMT3A has prognostic value. However, the interpretation of the meta-analysis using OS may be limited by the fact that two studies were omitted as complete information was not available. # Justification for Recommendation 1 The available evidence shows DNMT3A mutation status has good prognostic value in this patient population. # Qualifying Statements for Recommendation 1 This recommendation is based on evidence currently available. Despite the heterogeneous nature of the studies included, the likelihood of having a series of large homogenous studies done in this patient population is low due to the nature of the disease and its management. # FUTURE RESEARCH Currently, there are no ongoing trials on DNMT3A mutation status in this patient population. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

# TARGET POPULATION All adult MM patients considered for treatment that includes blood or marrow transplantation. # RECOMMENDATIONS AND SUPPORTING EVIDENCE Autologous SCT is the recommended treatment option for patients with newly diagnosed MM, as part of the initial treatment plan. # Supporting evidence Evidence included in four Clinical Practice Guidelines (CPGs) (1)(2)(3)(4) suggests that a single transplant with autologous SCT should be offered to all MM patients who are free from severe co-morbidities and who are younger than 65 years of age, following the initial treatment with high-dose chemotherapy. The SCT Steering Committee acknowledged that, while the evidence upon which the CPGs were based almost uniformly excluded patients older than age 65, there was no reason not to offer SCT to patients 65 or older who have good performance status and no co-morbidities that would be a contraindication to transplantation. The SCT Steering Committee also acknowledges that ongoing trials are investigating the value of upfront treatment with combinations of novel agents and the deferring of transplantation to a later date. # Tandem (double) autologous SCT is an option for patients with MM who respond to the first autologous transplant with less than a very good partial response, but not progressive disease. # Supporting evidence Evidence included in two CPGs (1,2) suggests that double autologous SCT should be offered to patients who did not achieve a complete remission after their initial autologous SCT. While the CPGs recommended a second transplant be offered to patients who did not achieve complete remission following their first transplant, the SCT Steering Committee acknowledged that offering a second transplant to patients who achieve less than a very good partial response is reasonable as long as there is no progressive disease. # Allogeneic transplantation is an option for patients with high-risk MM preferably within the context of an investigative study. # Supporting evidence Evidence from three of the CPGs did not support the use of allogeneic SCT from HLA-matched related donors as a primary treatment, but the conclusion is that it may be offered to patients <50 years of age who are not expected to benefit from autologous SCT (e.g., chromosome 13 deletion) within the investigative setting only (1,2,4). # Repeat autologous transplantation is an option for patients with MM who relapse after a long remission (> 2 years) to a single autologous transplant. Supporting evidence Despite a lack of good quality evidence, the SCT Steering Committee's consensus opinion is that patients who relapse after a long remission following a single transplant should be offered a second transplant. # QUALIFYING STATEMENT The patient selection process and the ultimate decision to perform an SCT should take into account not only disease-related characteristics, but also comorbidities and patient preferences. Evidence on the role of SCT in the management of MM is emerging rapidly. This topic is also the subject of Program in Evidence-based Care (PEBC) Evidence-based Series (EBS) 6-6, which will be updated to incorporate new data. EBS 6-6 differs from this report in that it includes only evidence comparing high-dose chemotherapy and SCT in patients with MM, whereas this report includes comparisons of all interventions including SCT such as radiotherapy and other treatment modalities. # FUTURE RESEARCH Future research in this setting should continue to explore novel chemotherapy and supportive therapy options along with SCT. Better management of co-morbidities may allow clinicians to offer SCT to patients currently not eligible for treatment. # IMPLICATIONS FOR POLICY Transplantation for myeloma remains the most frequent indication in Ontario for autologous transplantation. As of this report, and in the foreseeable future, it is highly unlikely that the indication for transplant in such patients will change. With the use of more effective induction regimens, it is possible that more patients will be eligible for transplant with myeloma. # RELATED PROGRAM IN EVIDENCE-BASED CARE REPORTS The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# GUIDELINE OBJECTIVES # INTENDED USERS This guideline is intended for provincial policy makers, primary care physicians, nurse practitioners, radiologists, respirologists, thoracic surgeons, thoracic oncologists, and any health professionals involved with patients who may be at risk for developing lung cancer. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION Screening High-risk Populations for Lung Cancer: The Working Group is in favour of screening high-risk individuals for lung cancer with LDCT. The primary evidence base for this proposal is the NLST, a large (>50,000 participants) RCT that compared LDCT screening with CXR and showed a 20% decrease in death from lung cancer in high-risk persons (4). The primary benefit associated with LDCT screening is a statistically significant reduction in mortality, both lung cancer specific and all cause. LDCT can identify smaller nodules than can CXR and thus can detect lung cancer at an earlier stage when a cure is more possible. Under current circumstances, most lung cancer patients are diagnosed at an advanced stage, and lung cancer accounts for more than a quarter of all cancer deaths (6). LDCT screening is not without risk. CT scanning, with its acquisition of multiple images, exposes an individual to a greater radiation dose than does CXR and may place patients at increased risk of lung and breast cancer. Based on models from official bodies and commissioned studies of estimates of harm from radiation, Bach et al estimate using the NLST data that one cancer death may be caused by radiation from imaging per 2500 persons screened (5). The serial CT scans required as part of a screening program necessitate judicious and efficient use of the technology with strict rules pertaining to quality control and training. The information obtained from a CT scan of the chest provides more precise visualization of lung nodules leading to a higher rate of detection of lung nodules. Although the majority of these nodules (>90%) will be benign, the detection of these nodules may lead to further imaging and follow-up that can involve invasive diagnostic procedures and possibly to harmful and unnecessary treatment. Completely addressing the clinical and cost implications of this high false-positive rate is critical and remains a challenge. In the interim, the Working Group endorses a strict application of screening to only a high-risk targeted population. In general, the recommendations below reflect the parameters of the NLST (4). Where there are deviations from those parameters, we provide justification. While there are still ongoing trials comparing LDCT with usual care, none are as large (and therefore as statistically powerful) as the NLST, and it is unlikely that another trial the size of the NLST will be undertaken. Some aspects of the ongoing trials may affect the recommendations once their results are known, and we have qualified our recommendations to acknowledge these uncertainties. # RECOMMENDATIONS AND SPECIFIC EVIDENCE Main Recommendation Recommendation 1: Screening for lung cancer with LDCT is recommended in high-risk populations defined as persons 55 to 74 years of age with a minimum smoking history of ≥30 pack-years who currently smoke or have quit within the past 15 years and are disease free at the time of screening. Pack-years = number of cigarette packs smoked per day x the number of years smoked. # Key Evidence - Among the studies in the collaborative review, the age for initiation of screening ranged from 47 to 60 years in the RCTs and from 40 to 60 years in the single-arm studies (5). - The upper age for screening ranged from 69 to 80 years in the RCTs and 73 to 85 years in the single-arm studies (5). The NLST initiated screening in persons ≥55 years of age and stopped at age 75 years (4). - The minimum smoking history in the RCTs ranged from ≥15 to ≥30 pack-years, and in the single-arm studies from ≥10 to ≥20 pack-years (5). The NLST enrolled persons with a smoking history of ≥30 pack-years and former smokers who had quit within the previous 15 years (4). - Seven RCTs reported previous cancer history in the eligibility criteria, stipulating a minimum numbers of years disease free since a previous cancer diagnosis. These ranged from 5 years to an indefinite period with variations for different types of cancers. Among 11 single-arm studies, this criterion was described as a minimum of 5 years since a previous cancer diagnosis, any previous lung cancer, any known pulmonary metastases, and any previous cancer diagnosis (5). In the NLST, exclusion criteria were a previous diagnosis of lung cancer, a previous diagnosis of other cancer within the previous 5 years, chest CT scan within 18 months before enrollment, haemoptysis, or unexplained weight loss >6.8 kg in the preceding year (4). - There is no evidence to support a specific age to initiate screening, a specific age to cease screening, or a specific screening-frequency interval. The highest quality and most compelling evidence is from the NLST. As such, the parameters used in this trial were endorsed by the Working Group as clinically reasonable. Patient acceptability, cost-effectiveness, feasibility, and system capacity may influence whether or not these parameters are reasonable and implementable. - Smoking history is a subjective risk factor, and we acknowledge that it cannot be precisely measured. If smoking is begun in early adulthood (i.e., early 20s) as it commonly is, by age 50 to 55, most people will have exceeded 20 pack-years. Although the NLST enrolled participants with a minimum smoking history of 30 pack-years, several other studies used a threshold of 20 pack-years or less. These studies had lung cancer detection rates similar to those of the NLST. It is anticipated that an increased detection rate would lead to a mortality reduction. The Working Group agreed on a 30 pack-year smoking history threshold to recommend lung cancer screening, aligning with that study entry criterion in the NLST. The panel will update this recommendation when the results of the NELSON trial (which had a 15 pack-year requirement) are published. - It is reasonable to define the screening population by age and smoking history, but there is currently insufficient evidence to include participants based on other risk factors such as family history, passive smoking, occupational exposure, radon exposure, previous cancer, and other diseases. # Qualifying Statements Screening may be a reasonable option in persons with a smoking history of <30 packyears. However, as this risk group was not included in the NLST, an explicit recommendation in favour of screening such persons cannot be made at this time. A current trial (NELSON) includes patients with a minimum smoking history of 15 pack-years and may provide additional data to determine the minimum smoking history appropriate for screening. # Defining a Positive Result on LDCT and Follow-up of a Positive Result # Key Evidence - Most of the studies published since 2008 used multi-detector CT scanners. The voltage ranged from 100 to 140 kVp, with all but one study using 120 to 140 kVp. The current ranged from 20 to 100 mAs, with all but one study not exceeding 60 mAs. The average effective dose was reported in 5 studies and ranged from 0.6 to 1.5 mSv (5). The NLST used multi-detector scanners with a minimum of 4 channels, 120 to 140 kVp, 20 to 30 mAs, and an average effective dose of 1.5 mSv (4). - Among the studies, collimation ranged from 0.75 to 10 mm (5). Collimation in the NLST was ≤2.5 mm (4). - Nodule size found on LDCT warranting further investigation ranged from a minimum size of any diameter to a maximum of >15 mm (5). In the NLST, nodules measuring ≥4 mm received further work-up (4). - Nine studies defined tumour growth. Growth can be determined with calliper measurements of diameter (6 studies) or 3-dimensional volume measurements (4 studies). One RCT and one single-arm study described significant growth as an increase in tumour diameter of ≥1 mm. Three single-arm studies described significant growth as an increase in diameter in at least 1 dimension. Two RCTs described growth as a change in tumour volume of ≥25%. One single-arm study defined growing lesions as those with volume-doubling time between 30 and 400 days, and another used tumour volume and time between high-resolution CT scans to calculate doubling time (5). A definition of growth was not reported in the NLST. - Guidance on the presentation and clinical work-up of a lung cancer diagnosis is detailed in the CCO Lung Cancer Diagnosis Pathway (7). - For screening modality, the parameters listed in the recommendations are derived from the NLST and ongoing studies. - With respect to collimation, newer scanners are able to provide 1-mm collimation with a short breath-hold time, but a large amount of images are produced making scrolling and reading cumbersome. At the current time, the collimation used in the NLST is recommended. - With respect to nodule size warranting further investigation, the recommendation deviates from the parameters of the NLST. In general, the smaller the nodule that defines a positive scan, the larger the number of positive scans, and the larger the number of false-positive results and unnecessary investigations for benign nodules. Based on a 4-mm threshold, 7191 of 26,309 (27.3%) scans in the NLST were positive; 6921 (96%) of the positive results were false positive. A 5-mm threshold will lower the rate of false-positive results, and if nodules between 4 and 5 mm are assessed on an annual scan, it is unlikely a significant finding will be missed. A prospective study of 1035 high-risk individuals found that nodules <5 mm identified by LDCT could be safely monitored at 1-year intervals (8). A retrospective study of two cohorts of patients (n=1000 and n=1897) determined that had no immediate attention been given to nodules between 3 and 5 mm until the first annual repeat screening, immediate further work-up would have been recommended in only 13% of patients rather than the 28% that received diagnostic interventions (9). Raising the threshold for a positive scan from a diameter of 4 mm to a diameter of 5 mm will help lower the false-positive rate without sacrificing the early detection of curable lung cancers. A recent study has suggested that increasing the threshold for a positive scan to 7 or 8 mm may decrease further work-up without delaying diagnosis (10). This will be revisited in future versions of this guideline when more information becomes available. - The recommended follow-up is based on common standard of care actions in the presence of positive findings. Short-term follow-up CT scans are recommended in the event of a positive-screening CT scan to assess the growth of a parenchymal nodule. These CT scans do not need to cover the entire chest; it is sufficient to limit the scan to the location of a nodule (i.e., a slab of a few centimetres covering the location of the nodule). This can substantially decrease the radiation exposure to the patient. # LDCT Screening Interval Recommendation 3: Persons at high risk for lung cancer should commence screening with an initial LDCT scan followed by annual screens for 2 consecutive years, and then once every 2 years after each negative (-ve) scan. a A positive (+ve) test is defined as a solid nodule ≥5 mm or a non-solid nodule (part solid or ground glass) ≥8 mm. b If the nodule appearance dictates a different approach (e.g., bronchoscopy or PET), this can be chosen at the discretion of the reading physician. c Doubling time of between 30 and 400 days. d Lung Cancer Diagnosis Pathway (7). # Key Evidence - LDCT was done on an annual basis in 18 studies; on years 1, 2, and 4 in one study; every 6 months in one study; and after 2 years in one study (5). The NLST conducted LDCT screens annually for 3 years (4). - The MILD trial did not demonstrate a shift to higher stage disease with biennial screening compared with annual screening. Of 49 lung cancers, 20 were detected in the biennial group and 29 in the annual group (11). - The current evidence stems from research studies on lung cancer screening, which by definition have a beginning and an end (e.g., in the case of the NLST, three rounds of screening). This guideline, however, extends this evidence to a screening program, which does not have a defined end. The annual to biennial approach is based on best evidence balancing expected benefit from regular scanning with accumulated harms from costs, radiation, and burden on the health care system. - The current evidence is not sufficient to confirm the benefit of a specific screening interval. The recommendation of annual screening for 3 years is subject to change when longer term trial evidence or further stratification methods become available from the NELSON trial. # Organized Versus Opportunistic Screening The decision to implement an organized, population-based screening program involves many factors, not just the existence of supportive RCT clinical evidence. However, because the benefit of screening to date has only been demonstrated in the context of an organized screening effort (i.e., a randomized clinical trial that compared two types of screening technology), it is the opinion of the Working Group that screening should be conducted in a manner similar to the NLST trial: that is, in an organized fashion. The ASCO guideline also supports screening of high-risk individuals, but only in the settings that can deliver comprehensive care such as that provided to NLST participants. The NLST authors themselves advise restraint in contemplating lung cancer screening recommendations on the basis of the NLST findings claiming the need for rigorous analysis of the cost-effectiveness of LDCT, and the weighing of the reduction in mortality against the harms of positive screening results, overdiagnosis, and cost (4). However, we are aware that these issues would be examined by provincial policy makers before screening policy decisions were made and approved. Because of the potential harms that may arise with LDCT screening done contrary to the recommendations above, a program is required that explicitly describes the target population that will benefit the most, the referral process, the frequency and duration of screening, the locations where screening may take place, the personnel involved in performing and interpreting the scans, and the precise criteria that define a positive scan. The inclusion of smoking-cessation counseling within the screening program is crucial. If elements of data collection and monitoring, quality assurance, and evaluation are built into the screening program from the start, it can be modified while in operation. Opportunistic screening takes the form of CT scans applied to individuals who are asymptomatic, may not qualify for the test, or are referred on an ad hoc basis outside of a programmatic structure. These scans often include contrast, are not done with the low-dose technique, and lack appropriate follow-up of detected lung nodules. This type of screening results in unnecessarily high radiation to the individual, potential side effects from contrast, and invasive procedures for potentially benign lesions. The Working Group believes strongly that screening outside a centre with experience and expertise in identifying the high-risk population, interpreting results and counselling patients, and performing the appropriate diagnostic techniques is ill advised. Such ad hoc screening will lead to an increase in the false-positive rate and in peri-procedure morbidity and mortality, and will threaten to mitigate some or all of the benefits of the screening process. # Next Steps The Lung Cancer Screening Working Group believes that the benefits of screening highrisk populations for lung cancer with LDCT outweigh the harms. The benefits stem from the documented improvement in mortality observed in the NLST showing that LDCT can not only detect small, early-stage lung cancers, but it can also facilitate curing an individual of lung cancer. The harms stem from the investigation itself (radiation exposure) and the sequelae from the false-positive results (detection of lung nodules that ultimately turn out to be benign), and the risk associated with diagnostic evaluation. We address the concern over radiation exposure by recommending a low-dose regimen and by increasing the screening interval to every 2 years after three negative annual scans. We also suggest that the follow-up CT of a suspicious nodule be done as a limited scan to further reduce the radiation exposure. We address the impact of false-positive results by the definition of a positive CT scan: we intentionally deviated from the parameters of the NLST in this instance. In the NLST, the threshold for a positive result was a nodule ≥4 mm in diameter. At baseline, >27% of the screening tests were positive and 96% of those were false-positive results. By increasing the threshold of a positive test to 5 mm, the rate of positive baseline scans can be reduced to <20% while still detecting early-stage, curable lung cancers. We also recommend a follow-up algorithm of CT-detected nodules that is simple and straightforward based on size and growth, and results in an extremely low rate of invasive procedures for benign lesions (12). Lung cancer screening with LDCT is recommended and can be most effectively and safely offered through an organized screening program and administered by specialized centres with multidisciplinary care teams. To determine whether or not a population-based screening program is appropriate for Ontario will require the CCO Prevention and Cancer Control division to investigate the other criteria relevant to the decision-making process. Priorities include: - Safety and effectiveness (long-term) Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# INTENDED PURPOSE - This recommendation report is primarily intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. - This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality systematic review from the U.S. Agency for Health Research and Quality (AHRQ) (1) that included primary study literature for the period from 2003 to March 2008. # Diagnosis/Staging PET is not recommended for primary diagnosis of pancreatic cancer. Eleven prospective studies were identified that evaluated the role of PET or PET/CT in the diagnosis of a suspicious pancreatic mass. Sensitivity ranged from 69% to 97%, and specificity ranged from 61% to 97% (Giorgi et al Nishiyama et al Rasmussen et al van Kouwen et al Bang et al Heinrich et al Lemke et al Lytras et al Maemura et al Sperti et al Casneuf et al. Meta-analysis of four prospective studies evaluating the diagnostic performance of PET for the purpose of primary diagnosis (Giorgi et al Nishiyama et al Rasumussen et al van Kouwen et al yielded a pooled positive likelihood ratio (+LR) of 4.28 (95% CI 2.07 to 8.86) and negative likelihood ratio (-LR) of 0.21 (CI 0.12 to 0.40). These LRs had moderate heterogeneity, presenting some difficulties in determining overall accuracy. Meta-analysis of seven prospective studies evaluating the diagnostic performance of PET with the purpose of primary diagnosis and staging (Bang et al Casneuf et al Lemke et al Lytras et al Maemura et al Ruf et al Sperti et al yielded a +LR of 2.77 (CI 1.62 to 4.73) and -LR of 0.19 (CI 0.10 to 0.34). There was considerable heterogeneity, limiting determination of the overall accuracy of PET. Meta-analysis of three studies on PET/CT (Casneuf et al Heinrich et al Lemke et al yielded a homogenous +LR of 2.69 (CI 1.84 to 3.94) and -LR of 0.16 (CI 0.10 to 0.26). These pooled LRs suggest that PET and PET/CT offer small benefit in ruling in and ruling out pancreatic cancer when investigating a suspicious pancreatic mass; therefore, they may be useful in establishing a diagnosis when standard investigations are not confirmatory. Five studies compared PET or PET/CT with CT in the diagnosis of a suspicious pancreatic mass. In two that compared PET, PET/CT, and CT (Lemke et al Casneuf et al, PET/CT had the better diagnostic performance. # Qualifying Statements - The gold standard as well as the clinical goal is biopsy. When biopsy is inconclusive or not possible and the diagnosis remains in doubt, the above evidence supports the use of PET/CT where a positive result would lead to surgical resection for purposes of both diagnosis and treatment. Neuroendocrine tumours of the pancreas are known to be unreliably fluorodeoxyglucose (FDG) avid. PET is recommended for staging if a patient is a candidate for potentially curative surgical resection as determined by conventional staging. In four studies (Bang et al Heinrich et al Nishiyama et al Sperti et al, staging and treatment strategy changed after PET or PET/CT scan in 12% to 69% of cases. In one study (Heinrich et al with 46 patients with pancreatic carcinoma, standard staging followed by PET/CT improved the detection of distant metastases compared with standard staging alone (88% vs 56%, p=0.06 McNemar test). In Nishiyama et al 16 of 42 patients were found to have distant metastases by radiologic evaluation or cytological verification. With the combination of PET and CT, all metastatic sites were detected. Based on the above studies, staging and hence surgical management are impacted in a substantial proportion of patients who are candidates for surgery. # Qualifying Statement - The clinical importance of change in treatment strategy as an outcome, despite a lack of strong evidence, is noted. # Assessment of Treatment Response A recommendation cannot be made for or against the use of PET to guide clinical management based on assessment of treatment response due to insufficient evidence. One study (Bang et al showed that PET was superior to CT in the detection of treatment response after chemoradiation. Of 102 patients evaluated for a suspicious pancreatic mass, 15 with confirmed pancreatic cancer received chemoradiation. CT did not detect any responders while PET detected 5/15 therapy responders. The response after chemoradiation correlated with longer time to progression (TTP) compared with nonresponders (399 vs 233 days). A second study (Maemura et al showed that in 23 patients who received chemoradiation, an SUV <7.0 was correlated with improved survival. The above results are based on two small nonrandomized studies and therefore are not strong enough to make a recommendation for using PET in evaluating treatment response outside of a clinical trial. # Qualifying Statement - A recommendation for PET cannot be made in the setting of incomplete resection due to lack of evidence. Recurrence/Restaging PET is not recommended for clinical management of suspected recurrence, nor for restaging at the time of recurrence, due to insufficient evidence and lack of effective therapeutic options. One study (Ruf et al compared PET with CT in 31 patients who had suspected recurrence based on symptoms or increased CA 19-9 levels. While PET had higher sensitivity than CT for the detection of recurrence overall (96% versus 39%), and for nonhepatic intra-and extraabdominal metastases, CT had a superior sensitivity for the detection of liver metastases (92% vs 42%). However, patient outcomes based on these results were not reported. In a subset of 12 patients in Casneuf et al (12) who were being screened for recurrent pancreatic cancer, the sensitivity, specificity, and accuracy were not different between PET, PET/CT, and CT. In neither study was a reported change in management identified based on scanning modality. # Qualifying Statement - Pancreatic cancer has high overall mortality, and recurrence is uniformly fatal. At this time, there are insufficient treatment options that improve the outlook in patients who recur after surgical resection that would allow PET to contribute to management. PET imaging in recurrent disease should be restricted to clinical trials. # Solitary Metastasis Identified at Time of Recurrence A recommendation cannot be made for or against the use of PET for staging if a solitary metastasis is identified at recurrence as there are no trials that identify the utility of PET scanning in this setting. No studies exist that examine PET in this setting. # Qualifying Statement

For further information about this report, please contact the authors through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO Web site at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca # GUIDELINE OBJECTIVE To provide the optimal strategy to assess patients diagnosed with rectal cancer prior to treatment. This includes: 1. Investigations to assess for distant metastases and synchronous lesions in patients with rectal cancer 2. Imaging for local staging of rectal cancer 3. The optimal MRI protocol to locally stage rectal cancer 4. The optimal MRI criteria to locally stage rectal cancer 5. The optimal MRI criteria to select patients for neoadjuvant therapy 6. The role of multidisciplinary cancer conferences (MCCs) 7. The role of restaging MRI after neoadjuvant therapy # TARGET POPULATION Newly diagnosed patients with rectal cancer 1 undergoing elective treatment comprise the target population. # INTENDED USERS This guideline is intended for radiologists, surgeons, radiation oncologists, medical oncologists, and pathologists. This guideline coincides with the introduction of colorectal cancer Diagnostic Assessment Programs in Ontario. Diagnostic Assessment Programs provide coordination of care using a clinical navigator, fast tracking of diagnostic tests and a multidisciplinary team approach. They are an Ontario-wide strategic priority designed to improve patient access and outcomes, and are outlined in Ontario Cancer Plan 2005and Ontario Cancer Plan 2011-2014. # RECOMMENDATIONS AND KEY EVIDENCE/JUSTIFICATION # RECOMMENDATION 1 - Staging for all rectal cancer patients should include: -CT of the abdomen and pelvis -CT of the chest or chest X-ray. - Complete colonic examination by colonoscopy should be performed preoperatively, if possible. - Serum carcinoembryonic antigen (CEA) should be assessed preoperatively. # Qualifying Statements - While CT chest is preferred, chest x-ray may be used as an alternative method of chest imaging. The choice of CT of the chest or chest X-ray should be consistent with the modality used for postoperative surveillance. If CT of the chest is used for postoperative surveillance, then CT of the chest should be done at the same time as staging CT of the abdomen and pelvis. If chest X-ray is used for postoperative surveillance, then CT of the chest is recommended only if abnormalities requiring further investigation were found on chest X-ray. - When CT of the chest is performed in combination with CT of the abdomen and pelvis, intravenous contrast is recommended. However, when CT of the chest is the sole investigation, intravenous contrast is potentially helpful but not required. - If the use of intravenous contrast is contraindicated, abdominal MRI or ultrasound may be used to supplement CT to further assess for liver metastasis. - Colonoscopy is preferred but CT colonography can be used to complete the assessment when the colonoscopy is incomplete. If not completed preoperatively, a complete colonoscopy should be performed postoperatively. - This recommendation applies to patients undergoing elective treatment only (i.e., does not include patients with obstruction or perforation). # Key Evidence/Justification This recommendation was adapted from the NICE 2011, NZGG 2011, SIGN 2011 and PEBC 2006 guidelines, which were based on consensus, as there were no high-quality studies to support this recommendation (2)(3)(4)(5). While NICE 2011 and SIGN 2011 have recommended CT of the chest, NZGG 2011 and PEBC 2006 have recommended chest X-ray. The main advantages of CT of the chest discussed by the Guideline Development Group include: (i) the early detection of pulmonary nodules that may lead to a change in management (i.e., first-line chemotherapy, metastasectomy) (6) and (ii) a baseline CT of the chest for comparison if CT of the chest is used for postoperative surveillance. The main disadvantage of CT of the chest discussed by the Guideline Development Group included the high sensitivity and low specificity of CT to detect indeterminate pulmonary nodules and lack of consensus as to how these nodules should be managed (7). The cost of performing a CT of the chest was discussed by the Guideline Development Group and was considered to be neither an advantage nor disadvantage, as the added cost and time required to conduct a CT of the chest in conjunction with a CT of the abdomen/pelvis is minimal. Although there is limited evidence, the Guideline Development Group has made the recommendation to endorse CT of the chest for pulmonary staging. The main reasons for this were the increased risks of pulmonary metastases alone with rectal cancer compared to colon cancer (8,9) and the ability to have a baseline CT chest for comparison during the surveillance period. Serum CEA was recommended preoperatively only by the NZGG 2011 and postoperatively by NZGG 2011, NICE 2011 and SIGN 2011 (2)(3)(4). The evidence for these recommendations were based on four meta-analyses that show intensive follow-up programs that include CEA testing lead to significantly improved overall survival and detection of asymptomatic recurrences compared to a less intensive follow-up. The advantages of preoperative CEA testing discussed by the Guideline Development Group include: (i) the recommendation and evidence for CEA testing for postoperative surveillance and (ii) limited value of postoperative CEA testing if no preoperative CEA is available for comparison. The Guideline Development Group did not identify or discuss any disadvantages to use of preoperative CEA testing. Therefore, a recommendation to perform preoperative CEA was made and is consistent with the colorectal cancer Diagnostic Assessment Programs in Ontario. # RECOMMENDATION 2 - Patients with rectal cancer should undergo MRI pelvis in order to assess T and N categories and the distance to the MRF. # Qualifying Statements - For the purpose of this guideline, the distance to the mesorectal fascia (MRF) will be used and represents the potential CRM. The use of the term MRF is more appropriate, because CRM is a pathologic term determined by the extent of surgical resection. - For low rectal cancer, defined as 0-5 cm from the anal verge, if local excision (with transanal excision or transanal endoscopic microsurgery) is being considered, transrectal ultrasonography (TRUS) performed by those with demonstrated expertise is preferred to MRI, in order to more accurately discriminate between T1 and T2 lesions. TRUS should not be used to predict CRM involvement. - For upper rectal cancers, defined as 10-15 cm above the anal verge, in which the mesorectal fascia is not threatened, MRI may not provide significantly more information than CT of the pelvis. - MRI is used for local staging of the rectum and does not adequately assess regional disease at the level of the inferior mesenteric artery or distant disease; CT of the abdomen and pelvis should be used to assess for distant metastases and regional disease including lymph node involvement along the inferior mesenteric artery. - If there are contraindications to MRI, CT of the pelvis and/or TRUS are recommended. # Key Evidence/Justification The evidence for this recommendation was based on the NICE 2011, NZGG 2011, SIGN 2011 and PEBC 2006 guidelines (2-5). These guidelines discussed the results of two systematic reviews by Kwok et al 2000 and Bipat et al 2004 that assessed the diagnostic accuracy of MRI, CT and US for T and N category (10,11). These studies showed that ultrasound had the highest sensitivity and specificity for T-category, followed by MRI and CT, respectively. Two additional systematic reviews assessing the diagnostic accuracy of MRI only to assess MRF involvement have shown that MRI has good sensitivity and specificity to predict MRF involvement (12,13). Taken together, these studies suggest that transrectal ultrasound has the best diagnostic accuracy for T-category, in particular T1 and T2 tumours, followed by MRI and CT, and MRI has the best diagnostic accuracy to detect MRF involvement. Therefore, based on these studies, we have recommended MRI as the modality of choice for preoperative staging of rectal cancer. To date, there are only a few, poor-quality studies that have directly compared the diagnostic accuracy of CT and MRI for the prediction of MRF involvement, and therefore, there is currently insufficient evidence to support the use of CT to assess distance to the MRF and MRF involvement. However, many experts would likely consider the added benefit of MRI relative to CT relatively small for the assessment of upper rectal and rectosigmoid tumours in which the mesorectal fasica (i.e., potential CRM) is not threated or involved. The reviews by Kwok et al 2000, Bipat et al 2004, and Lahaye et al 2005 also show that all modalities have moderate accuracy to detect nodal involvement (10)(11)(12). Therefore, the Guidelines Development Group endorsed the recommendations from the NICE 2011, SIGN 2011 and NZGG 2011 guidelines to use MRI for local staging of rectal cancer. # RECOMMENDATION 3 - At a minimum, axial, coronal and sagittal T2-weighted images of the pelvis and highresolution T2-weighted sequences perpendicular to the long axis of the rectum at the level of the tumour using phased-array coil are required. # Qualifying Statements - A high-resolution MRI meets the specifications outlined by the MERCURY Group Protocol and is shown in Appendix 1. - For low rectal cancer, coronal high-resolution images along the long axis of the anal canal should be considered in addition to or instead of the long axis of the rectum in order to better assess the relationship of the tumour to the sphincter components. - Additional sequences, bowel preparation, anti-peristaltics, luminal distension, and intravenous contrast are believed to be supplemental and are not a mandatory requirement for a high-quality MRI. # Key Evidence/Justification A review of the literature for MRI protocols including optimal sequences, bowel preparation, enemas, anti-peristaltic agents, and intravenous contrast was performed. There was only one study that suggested rectal distension may improve the accuracy of T-category assessment while having little effect on MRF or lymph node involvement (14). Four studies assessed use of gadolinium-enhanced T1 images compared to T2 unenhanced images (10,(15)(16)(17). However, these studies generally found no difference in T or N staging, and therefore, use of gadolinium was not recommended as a mandatory component of the MRI protocol. Two meta-analyses demonstrated that multiple readers resulted in better prediction of T category and MRF involvement than when these criteria were assessed by single readers (13,18). While consensus reading is preferred, due to issues with respect to work load and feasibility, The Guideline Development Group also did not recommend this manoeuvre as a mandatory component of the MRI protocol. Based on these limited data, the Guideline Development Group endorsed the MRI protocol used by the MERCURY study group, which was a prospective, European, multidisciplinary project that demonstrated the accuracy and feasibility of MRI as a method of assessing rectal cancer. The evidence to support this recommendation can be found in Appendix 1. This is also the MRI protocol endorsed by the Surgical Oncology Program (available here: ) (19). # Key Evidence/Justification The Guideline Development Group endorsed the synoptic MRI report, which was based on evidence and multidisciplinary consensus. The evidence and justification to support these MRI criteria are available here (19). It is important to note that the overall rationale for the synoptic MRI report was to provide clear definition for each item on the synoptic report and to improve overall consistency and completeness (but not necessarily accuracy) of MRI reports across the province. # RECOMMENDATION 5 - According to current practice, patients with stage II or III rectal cancer should be offered preoperative therapy using T and N categories to preoperatively stage patients. # Qualifying Statement - To date, there is insufficient evidence to change the current selection criteria from T and N categories to distance to the MRF (i.e., potential CRM), extramural depth of invasion (EMD) and/or extramural vascular invasion (EMVI). # Key Evidence/Justification Several RCTs have been done showing that preoperative radiation or chemoradiation leads to a decrease in the risk of local recurrence (21)(22)(23)(24). These RCTs assessed T and N category with digital rectal examination and/or TRUS to select patients for neoadjuvant therapy. While there have been no RCTs that have used MRI criteria to select patients for preoperative therapy, more recently, two prospective non-randomized cohort studies used distance to the MRF of less than 1 mm on MRI to select patients for preoperative therapy (25,26). In these studies, patients with distance to the MRF of greater than or equal to 1 mm on MRI, regardless of T and N category, were treated with surgery alone. The results for these patients suggested that the rate of positive CRM was 1.5% (2/134) (25), and local recurrence was 3.3% (4/122) (26). These studies are clinically relevant because they suggest that preoperative radiation or chemoradiation may not be necessary in as many patients when MRI is used to select patient for preoperative therapy. This has significant clinical implication because preoperative radiation has been shown to lead to poorer bowel and sexual function compared to surgery alone (27). While these findings are important, the Guideline Development Group recommended that higher quality evidence is required before a change in the selection criteria can be recommended. # RECOMMENDATION 6 - All rectal cancer patients in Ontario, independent of their geographic locale, should have their case presented at a multidisciplinary cancer conference (MCC). # Qualifying Statement - Alternatively, each case should be reviewed through collaborative discussion(s) and/or multidisciplinary clinic with appropriate clinicians (surgeon, radiation oncologist, radiologist, medical oncologist and pathologist). The goal is to provide clinical correlation, decide on an individualized treatment plan, and provide feedback to the radiologist and other members of the team. # Key Evidence/Justification The effect of having an MCC discussion on patient outcomes was weak and conflicting. One study did find fewer positive CRM rates for those patients who were discussed at an MCC, but another study did not (28,29). Three studies investigated the effect of having an MCC on survival and did not find an association (30)(31)(32). Four studies suggested that patients were more likely to receive appropriate therapy if they were reviewed at an MCC (33)(34)(35)(36). The Guideline Development Group chose to recommend that all patients with rectal cancer be discussed at an MCC, which is consistent with CCO's MCC standards document (37). # RECOMMENDATION 7 - Restaging MRI following preoperative chemoradiation is optional. # Qualifying Statement - No recommendation can be made to support or refute the routine use of restaging MRI following neoadjuvant therapy. However, restaging MRI may be appropriate in cases where there is suspected MRF involvement or when complete response would change management, on a per patient basis. # Key Evidence/Justification The Guideline Development Group did not recommend routine use of restaging MRI following neoadjuvant therapy due to lack of evidence. In particular, there were no studies assessing the effect of restaging MRI on surgical management or patient outcomes. However, two studies have shown that a lower tumour regression grade score (i.e., TRG 1 and 2) on restaging MRI was an independent and positive predictor of overall and disease-free survival (38,39). In addition, one of these studies showed that MRF involvement on restaging MRI was an independent and positive predictor of local recurrence (38). Two other studies found that tumour reduction volume was a significant predictor of disease-free survival (40,41) and overall survival (41). Due to lack of evidence, the Guideline Development Group does not recommend routine use of restaging MRI. However, the Guideline Development group believed that restaging MRI in select patient populations where observation following a complete response on MRI would be considered a reasonable treatment option (e.g., high-risk surgical patients, patients requiring abdominoperineal resection) or in patients with a potentially threatened CRM to ensure adequate response to chemoradiation prior to surgery. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # FUTURE RESEARCH

- Does the addition of chemotherapy (CT) to radiotherapy (RT) improve outcome for patients with squamous cell cancer of the anal canal? 2. What are the optimal CT drugs for the treatment of patients with squamous cell cancer of the anal canal? 3. Does the use of induction CT before concurrent CT and RT improve outcome for patients with squamous cell cancer of the anal canal? 4. What is the best management for patients with squamous cell cancer of the anal canal who are human immunodeficiency virus (HIV) positive? Outcomes of interest are colostomy rate, local failure, survival, disease-free survival, acute and late adverse effects, and quality of life. # TARGET POPULATION These recommendations apply to adult patients (age ≥18 years) with a primary diagnosis of biopsy-proven squamous cell cancer of the anal canal, including basaloid, cloacogenic, and transitional cell tumours. These recommendations do not apply to patients who have previously undergone resection of their tumour. The management of patients who later develop extra-pelvic metastases is not considered in this guideline. - For all stages of localized squamous cell cancer of the anal canal, concurrent CT and RT is recommended over RT alone to improve local control and decrease colostomy rates. - The optimal CT drug combination for squamous cell cancer of the anal canal is 5fluorouracil (5FU) plus mitomycin C (MMC), given concurrently with radiation treatment. - At this time, induction CT before concurrent CT and RT should be considered an investigational approach. - It is the expert opinion of the Gastrointestinal Cancer Disease Site Group (GI DSG) that HIV-positive patients with squamous cell cancer of the anal canal should be managed in the same way as patients without known HIV. Treating physicians should be aware that a greater than average risk of toxicity is possible. # QUALIFYING STATEMENTS - No randomized controlled trials (RCTs) were identified that addressed the management of squamous cell cancer of the anal canal in HIV-positive patients. See the Discussion in Section 2 for a description of non-randomized data available on this topic. - Only two RCTs included patients with T1 lesions of the anal canal, and results were not reported by disease stage. See the Discussion in Section 2 for further discussion on management of patients with T1N0 disease. - Two RCTs included patients with squamous cell cancer of the perianal skin. A limited discussion of perianal cancer is included in the Discussion in Section 2. - James et al. 2013 (ACT II), studied maintenance chemotherapy versus none following chemoradiation and found that maintenance chemotherapy does not improve overall survival or colostomy-free survival. Therefore, maintenance chemotherapy following chemoradiation is not recommended in the management of squamous cell carcinoma of the anal canal. See Section 4 for more details. - In the trials using MMC in the 5FU-MMC combination regimens, MMC schedules include dose of 12 or 15mg/me day 1 only, and a 10mg/m2 Day 1, 29 dosing. There is no comparative data to allow a recommendation of a preferred schedule. # KEY EVIDENCE The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# Section 1: Recommendations # RECOMMENDATIONS Recommendation 1: General Measures Committee Responsible for Policy and Procedures for Hazardous Drugs It is strongly recommended that all institutions administering hazardous drugs form such a committee. It is also strongly recommended that this committee include, but not be limited to, representatives from various departments and services such as: occupational health and safety, joint health and safety committee, pharmacy, nursing, medical oncology (physician), environmental services, risk management, and a patient representative. This committee would be responsible for clear processes of developing, reviewing, and revising policies and procedures related to hazardous drugs. A risk assessment and gap analysis should be routinely conducted to identify gaps and to inform policies and procedures. In addition, this committee is responsible for ensuring that there is a process in place for orientation and ongoing education for the identified target population. This committee is responsible for implementation and follow-up of the Risk Prevention Management Program related to the use of hazardous drugs. # Continuing Education and Orientation Program It is legislated that initial and ongoing hospital-approved education be provided to all staff involved with hazardous drugs throughout the medication circuit including safe handling and spill or leak management (6). It is strongly recommended that all staff have initial and ongoing training related to best practice standards in place at the time. It is legislated that there is documentation that annual training of safe handling of hazardous drugs has occurred (6). This should be documented by the institution's Committee Responsible for Policy and Procedures for Hazardous Drugs # Identification and Safety It is strongly recommended that each institution maintain a list of hazardous drugs that are used in their facility, that is reviewed regularly, when policy is updated, and whenever a new agent or dosage is used (7). It is legislated that hazardous drugs and their waste be properly identified with the symbol capital "C" and, under it, the words "CYTOTOXIC/CYTOTOXIQUE" in capital letters (8,9). It is legislated that all hazardous waste under the Ministry of Environment, Conservation and Parks regulation (guideline C-4) include bilingual wording and both the words and the symbol appear on a dark grey rectangle (8,9). Other countries may have their own systems for labeling and should be adhered to. # Purchasing of Drugs When purchasing hazardous drugs, it is strongly recommended that institutions consider vendors that include safe handling measures such as pre-wiped or protective containers, or smaller receptacles to decrease volume of potential spills. # Spills Kit It is strongly recommended that a spill-management kit be available in all areas where hazardous drugs are stored, transported, handled, and administered (10). # Precautionary Reassignment It is strongly recommended that all staff be fully informed of the potential reproductive hazards of hazardous drugs (11). It is strongly recommended that the facility consider alternative duties for staff who are pregnant, breast feeding or actively trying to conceive. # Recommendation 2: PPE It is legislated that a worker work in compliance with the Occupational Health and Safety Act and regulations and use or wear the equipment, protective devices, or clothing that the employer requires to be used (1). It is legislated that the appropriate PPE for the task (as described in Table 2-1) be worn throughout the medication circuit (1). It is the employer's responsibility to provide the necessary protective equipment and training on how to use the equipment. The gloves used to handle hazardous drugs are strongly recommended to comply with ASTM standard D-6978-(05)-13 and be powder free (12). Gloves are recommended to be nitrile, polyurethane, neoprene, or latex (12). Latex is a known allergen; therefore, it is strongly recommended that this be taken into consideration for glove selection. It is strongly recommended that vinyl gloves not be used (13). It is strongly recommended that the frequency of glove changes be adjusted according to the level of exposure at each step in the medication circuit. For example, when administering reconstituted medications, it is strongly recommended that workers change gloves immediately if torn, punctured, or visibly contaminated with a hazardous drug, and to ensure following Routine Practices (14). Gloves should be changed every 30 minutes unless otherwise recommended by the manufacturer's documentation (7,10). It is strongly recommended that great care be taken in the removal of gloves to not contaminate the skin. When two pairs of gloves are required, put on the first pair before putting on the gown. See Appendix 4 for the donning and doffing of one pair of gloves and Appendix 5 for the donning and doffing of two pairs of gloves. It is strongly recommended that the gowns used for handling hazardous drugs be disposable, made of lint-free, low-permeability fabric, have long sleeves with tight-fitting cuffs and fasten in the back. Gowns need to be changed in the event of contamination, spillage, rips, and at the end of the procedure. It is strongly recommended that the supplier be able to certify that the gown protects against hazardous drugs (10). For medication preparation and administration, gowns need to be changed halfway through a shift or every 3 and a half hours (7, 10). It is strongly recommended that care be taken to avoid contamination of the hands by avoiding touching the outside of the gown when removing the gown. # Facial Protection Surgical/procedure masks are required while handling and preparing medications in a BSC and, in this instance, are worn to prevent microbial contamination of the sterile field. Goggles and a face shield or full face-piece respirator should be worn when there is a risk of spills or splashes of hazardous drugs or hazardous waste materials when working outside of a BSC such as administration of hazardous drugs in the surgical suite, working at or above eye level, or cleaning a spill (7, 10). Head and hair coverings (including beard and moustache, if applicable), and sleeve covers provide protection from contact with hazardous drug residue. Disposable sleeve covers may be used to protect areas of the arm that may come in contact with hazardous materials. Disposable sleeve covers made of polyethylene-coated polypropylene or other laminate materials offer better protection than those made of uncoated materials (7). It is strongly recommended that full-facial protection be worn whenever there is a risk of splashing (e.g., during certain drug administration procedures). The use of a full-facial shield is preferred. If goggles are used, they need to be worn in conjunction with a fluid-resistant mask. For further information, see Canadian Standard Association (CSA) standard. Eyeglasses alone or safety glasses with side shields do not protect the eyes adequately from splashes. Face shields in combination with goggles provide a full range of protection against splashes to the face and eyes. Face shields alone do not provide full eye and face protection (7). # Respiratory Protection Devices It is strongly recommended that fit-tested respirators such as NIOSH-certified N95 or N100 be used when there is a risk that airborne powder or aerosol will be generated. It is legislated that respirators be used in accordance with a respiratory protection program such as that outlined in Use and Care of Respirators" (16). Caps are only required in the sterile preparation room and are worn to prevent microbial contamination of the sterile field. # Shoe Covers Disposable shoe covers are worn to prevent contamination of the healthcare workers' shoes, and it is strongly recommended that they be worn when in the sterile preparation room or in the event of a spill. It is strongly recommended that shoe covers be removed immediately when leaving the sterile prep room to avoid contamination of other areas. When compounding hazardous drugs, a second pair of shoe covers must be donned before entering the Containment Secondary Engineering Control (C-SEC) and doffed when exiting the C-SEC (7, 10). Abbreviations: G = gastric tube, J = jejunostomy tube, NG = nasal gastric tube, RPD= respiratory protection device. Although the risk of contamination with oral medications is minimal, the Working Group members believe that consistency of practice for any handling of hazardous drugs is of primary importance, and the preference is to wear a standard chemotherapy glove. † Although hazardous, they are not cytotoxic # Recommendation 3: Receiving and Transport # Handling Hazardous Drug Delivery Containers It is strongly recommended that all receiving-dock workers receive training in the proper handling of hazardous drugs. It is strongly recommended that the receiving-dock workers check the integrity of the external packaging upon receipt; in the event of breakage or a damaged parcel likely to cause a spill, apply the Spill Protocol from your institution. It is strongly recommended that delivery containers be taken immediately to the Pharmacy Department by the receiving-dock workers or the distributor. It is strongly recommended that the receiving-dock or storeroom workers not open the delivery containers. It is strongly recommended that the delivery containers be handled with care to avoid breakage of the hazardous drug containers and not be left unattended in a corridor. Only trained workers (e.g., pharmacy technicians) are to proceed with the unpacking and subsequent steps. # Damaged Containers/Spill It is strongly recommended that damaged containers be handled like spills. It is strongly recommended that the manufacturer or distributor be notified if the container is received in a damaged state. To limit exposure, it is strongly recommended that a damaged container not be returned to the manufacturer or distributor unless they require it returned. The damaged container will need to be returned in an impervious box. Notify the pharmacy if any damaged containers are suspected (7). See Recommendation 10: Management of Waste, Accidental Exposure, Spills and Returns. # Recommendation 4: Unpacking and Storage Packaging can have high levels of contamination. It is strongly recommended that there be an unpacking area in the pharmacy limiting exposure risks. It is strongly recommended that the unpacking area be a separate dedicated space, separate from eating areas, and preferably a separate room. It is regulated that there be adequate ventilation in the area, negative pressure, and preferably vented to the outside. It is strongly recommended that there be a receptacle for hazardous waste in the unpacking area, for the disposal of secondary packaging (6, 10, 17). It is strongly recommended that workers at risk of exposure wear a protective gown and two (2) pairs of gloves when unpacking and cleaning hazardous drugs, from the opening of the external packaging to the placing of the secondary and/or primary packaging in their storage space. It is strongly recommended that workers check the integrity of all packaging at every step of the unpacking process. In the event of breakage or leaking, it is strongly recommended that the damaged contents be treated as a spill. It is strongly recommended that the primary and or secondary packaging be cleaned prior to being placed in storage. It is strongly recommended that a regular cleaning protocol be in place either at this stage or prior to storage in the clean room. It is strongly recommended that all drug containers be cleaned to reduce external contamination. An example is the use of pre-moistened towelettes. It is important to ensure that the procedure does not damage the container or interfere with the reading of the label. It is also important to ensure than any product that is used will not further contaminate the product or work environment. However, it is strongly recommended that this procedure not increase the risk of incidents/accidents due to damage to the hazardous drug container or label. It is strongly recommended that procedures be in place to minimize the risk of contamination of surfaces during the cleaning of vials (e.g., use of a disposable, plastic-backed, absorbent pad). It is strongly recommended that all surfaces be cleaned when the task is complete. Establish a dedicated negative-pressure storage area for hazardous drugs that minimizes the risk of contamination (10). When removing or transporting drugs out of the storage area, it is strongly recommended that one pair of gloves and a gown be worn and a spill kit be readily available.. # Recommendation 5: Planning the Oncology Pharmacy It is strongly recommended that the oncology pharmacy be in compliance with relevant guidelines from the Canadian Society of Hospital Pharmacists and Accreditation Canada standards. While the specific details of oncology pharmacy planning are beyond the scope of this document, details and some important considerations may be found in the National Association of Pharmacy Regulatory Authorities (NAPRA) guideline and CSA document CSA Z8000-11 (5, 10, 18). It is strongly recommended that special requirements for heating, ventilation, and airconditioning systems in healthcare facilities be taken into consideration (10, 17). A class II type B BSC is required with preference for the type B2 because it ensures that there is no recirculation of air within the cabinet (4, (5, 10). There is emerging evidence suggesting some robotic devices that prepare hazardous drugs improve the accuracy of medication preparation and reduce potentially harmful staff safety events. Further studies are required to establish the cost effectiveness of these robotic implementations. Each healthcare facility will need to assess the need for such devices in their environment (5,(19)(20)(21)31). It is strongly recommended that all mixing, and preparation of administration sets with a hazardous drug be performed in one centralized area in a specially designated class II type B BSC (17) that: a. is exhausted through a HEPA filter to the outside atmosphere in a manner that prevents recirculation into any inside area; b. has exhaust and ventilation systems that remain in operation for a sufficient period of time to ensure that no contaminants escape from the BSC into the workplace; and c. is equipped with a continuous monitoring device to permit confirmation of adequate airflow and cabinet performance. It is recommended that airlocks be considered if there are particular concerns about the propagation of airborne hazardous drugs. It is strongly recommended that priming of administration sets be prepared in the manner mentioned above. It is strongly recommended that the layout allow and facilitate the unimpeded cleaning of all surfaces (walls, floors, ceilings, doors, diffusers, windows). It is strongly recommended that the furniture and equipment in the sterile preparation room be kept to a bare minimum. It is strongly recommended that there be a visual link; for example, a sealed window and a way to communicate between the sterile preparation room and the pharmacy, to view the work in progress. It is strongly recommended that access to the sterile room be limited to trained and authorized workers (10). A pass-through window can be installed to minimize the risk of contamination when transferring products into and out of the clean room. The pass-through should be equipped with an interlocking system or procedure that prevents both doors from being open at the same time (10) Limit worker traffic, particularly near unpacking and storage areas (to avoid accidental breakage) and near preparation cabinets (to avoid interfering with their proper operation). It is legislated that the facilities include an emergency eyewash that may or may not be hooked up to the airlock sink (1). As a minimum, it is strongly recommended that emergency eyewash be able to provide 15 minutes of flushing to both eyes ( 22). It is strongly recommended that a full shower be accessible nearby (e.g., in the oncology units/clinics). Closed system drug-transfer devices (e.g., PhaSeal®) are not a substitute for class II type B BSC. There is evidence from studies (23-30, 32-42, 57,58) that closed system drug-transfer devices can reduce contamination during preparation and increase or extend the beyond use date of a drug. Further emerging evidence suggests that when these devices are not used as specified, they could become open to the environment. Further research is needed to evaluate this possibility. In the non-sterile drug preparation process (e.g., oral preparations), it is strongly recommended that the same level of worker protection be adhered to. # Pharmacy Policies and Procedures Establish policies and procedures regarding preventive maintenance, monitoring, certification and the optimal use of facilities and equipment (45). # Recommendation 6: Hazardous Drug Preparation The following recommendations apply but are not limited to the preparation of all hazardous medications including parenteral, oral, and topical, both sterile and non-sterile preparations. It is strongly recommended that policies and procedures include the use of appropriate PPE, the equipment for preparation including appropriate ventilation, and other automated equipment for packaging and a dedicated work area. It is strongly recommended that workers (pharmacists or pharmacy technicians) wear a cap, surgical/procedure mask, shoe covers, a protective gown and two (2) pairs of gloves (see Table 2-1) to make sterile preparations of hazardous drugs in preparation cabinets. # Organization of the Work Organize the work to limit microbial and environmental contamination. For both sterile and non-sterile preparations, it is strongly recommended that workers cover the work surface with a disposable, absorbent, sterile, plastic-backed pad to absorb any liquid contamination that may occur during handling. It is strongly recommended that the pad not cover the front and rear grilles of the preparation cabinet. It is strongly recommended that it be changed after 3.5 hours of continuous work or for a new batch of preparations (e.g., a set of vials of a given drug) or in the event of a spill or contamination (13). It is legislated that the pad be disposed of in a hazardous waste receptacle (7,9). Limit the quantity of supplies and hazardous drugs in the cabinet, to avoid adversely affecting the laminar flow and to facilitate regular cleaning of the work surface. Place the sterile products in the centre and the non-sterile products (e.g., waste receptacle) along the sides of the cabinet. # Removal of Packaging Remove the packaging, when applicable, and clean all the drug containers before taking them into the preparation cabinet. For sterile preparations, adhere to aseptic technique for sterility. # Handling Techniques Use handling techniques that limit the risk of injury or accidental exposure. Direct CSTD spikes can be used to connect the hazardous medication bag directly to the tubing if spiking must occur at the bedside. When this adaptor is not used, IV bags containing hazardous drugs should only be spiked in a BSC to prevent exposure. # Preparation, Priming and Removing Air from the Tubing It is strongly recommended that hazardous drugs be reconstituted in the pharmacy environment as described above. It is strongly recommended that the drug containers not be overfilled to avoid compromising the integrity of the container. It is strongly recommended that the techniques used for priming and removal of air minimize the exposure risks. It is recommended to only remove air from an IV tubing that does not contain a solution with a hazardous drug(s). It is strongly recommended that IV tubing is primed and air removed in the pharmacy, prior to adding the hazardous drug(s) to the infusion solution. Glass containers are not recommended due to increased risk of breakage and exposure. # Labeling and Final Packaging It is legislated that hazardous drugs be labeled to inform those handling these preparations of the nature of the drugs and the precautions to be taken. It is legislated that hazardous drugs display the "Cytotoxic" hazard symbol or the word "Cytotoxic" (8,9). It is strongly recommended that the outside surface of the hazardous drug containers (e.g., syringes, infusion bags, tubing) in the preparation cabinet be cleaned in the cabinet. Place each hazardous drug container (e.g., syringe, bag), as well as the administration supplies (e.g., tubing), in a clear, leak-proof plastic bag (e.g., Ziploc® type) to facilitate identification by the nurse without having to remove the container from the bag. Following final verification in the pharmacy, it is strongly recommended that the plastic bags containing the hazardous drugs be placed in a rigid transport container (ideally opaque), properly identified with the "Cytotoxic" hazard symbol (7, 10). It is strongly recommended that everything that comes out of the cabinet be wiped clean. It is strongly recommended that all contaminated waste be disposed of in the chemotherapy waste stream. # Recommendation 7: Transport and Storage Following Preparation On-site Transport of Hazardous Drugs Transport hazardous drugs using a method that will prevent contamination of the environment in the event of breakage. It is strongly recommended that hazardous drugs be placed in a closed, single-use leak-proof plastic bag (e.g., Ziploc® type). It is strongly recommended that transport of the hazardous drug in a single-use closed, leakproof plastic bag from the pharmacy to an area not adjacent to the preparation area (e.g., care unit, outpatient clinic), be done in a rigid, shock-resistant, leak-proof container made of a material that can be easily cleaned and decontaminated in the event of a drug leak (5). It is strongly recommended that the bottom be covered with an absorbent, plastic-backed cloth. It is legislated that the transport container be identified with the "Cytotoxic" hazard symbol and be cleaned regularly (8,9). This container should be cleaned according to the protocol outlined by a committee responsible for hazardous drug handling. It is strongly recommended that mechanical transport systems, such as pneumatic tubes, not be used because of the stress they put on the contents, and the whole transport system would be compromised if a leak occurred (5, 7). It is strongly recommended that prepared medications be stored in a designated area prior to administration. It is strongly recommended that this area be cleaned regularly. # Off-site Shipping and Transport of Hazardous Drugs Establish policies and procedures regarding the shipping of hazardous drugs (46). In the event that hazardous drugs are shipped off-site (e.g., from one institution to another), it is strongly recommended that they be packed separately from other drugs, according to the recommendations from the manufacturer and distributor. It is strongly recommended that pharmacy be consulted in the packaging of hazardous drugs. It is strongly recommended that hazardous drugs be packed in a double plastic bag and placed in a box that is properly identified with the "Cytotoxic" hazard symbol. If necessary, immobilize the drug with packing (5) material. It is legislated that the "Cytotoxic" hazard symbol be visible on the outside of the delivery (8) container. It is strongly recommended that reusable delivery containers be cleaned regularly. Ensure that the courier company will handle hazardous drugs. # Recommendation 8: Drug Administration It is strongly recommended that safe handling and administration techniques be used to minimize possible exposure to individuals and the environment when administering hazardous drugs. - It is legislated that appropriate PPE be made available to all healthcare workers and be worn as prescribed by the employer (Table 2-1) (1). - It is strongly recommended that Luer lock connectors and needleless administration systems be used to administer any IV medications. - Closed system drug-transfer devices may offer additional protection. - It is strongly recommended that disposable plastic-backed absorbent pads be used over work surfaces and placed under tubing or bag connections and ports when attaching any tubing, bag or syringe that has been exposed to a hazardous drug. - Unless a closed system is used, never disconnect tubing from hazardous drug bags. Discard bag with attached tubing into an appropriate waste container as a single unit. - It is legislated that safety engineered needles be used as per Needle Safety Regulation 474/07 made under the Occupation Health and Safety Act Labour, 2010 (47). Do not purge air from the needle before administration. - It is strongly recommended that oral hazardous drugs be handled in a manner that avoids skin contact, liberation of aerosols or powdered medicine into the air, and cross-contamination with other (48) medicines. - It is strongly recommended that solid oral preparations (tablets) of hazardous drugs be crushed or cut within the BSC. If patients are unable to take in the solid format, it is strongly recommended that the pharmacy provide these drugs in an oral syringe or dissolve and dose container, in a ready-to-administer, liquid oral form. - It is strongly recommended that application of topical hazardous drugs be done using appropriate PPE and in a way that prevents contamination of the environment. Between applications, it is strongly recommended that the hazardous medication (i.e., tube or jar) be kept in a safe container (i.e., Ziploc®) and in a secure place that prevents contamination of the surrounding environment. - With any intravesical administration, e.g., bladder instillation, ensure there are detailed procedures in place to avoid risks of splashing. - Use caution when administering intrathecal hazardous drugs, as there is risk of splashing due to increased intrathecal pressures. A closed system (i.e., Luer lock) should be used when possible. # Recommendation 9: Home Care Home Care of Patients who Have Received Hazardous Drugs It is strongly recommended that all hazardous drug preparations be compounded in pharmacies meeting the requirements for hazardous drug preparation (5). It is strongly recommended that hazardous drugs be transported, administered and disposed of by individuals who have received appropriate training. It is strongly recommended that hazardous drug transport containers are not reused by patients for domestic purposes, which may expose the family to cytotoxic drugs (e.g., toy box, sewing basket, etc.). It is legislated that the healthcare provider who administers hazardous drugs in the home wear PPE as outlined in It is strongly recommended that other waste (soft items, such as tubing, protective equipment, etc.) be placed in leak-proof and tear-resistant containers, identified with the "Cytotoxic" hazard symbol (7). For final disposal outside the institution, it is legislated that all hazardous waste be in a rigid, leak proof, container identified with the "Cytotoxic" hazard symbol and scheduled for transport outside the institution (9). It is legislated that any excess fluid from hazardous drugs (e.g., drug loss) be disposed of in a sealed container and placed in a rigid container, the bottom of which is to be covered with an absorbent pad. This rigid container will be handled like other hazardous waste (9). It is recommended that disposable/incontinent briefs soiled by patients who have received hazardous drugs be placed in a hazardous waste container. It is legislated that hazardous waste be incinerated according to ministry guidelines (9, 50). It is legislated that hazardous waste not be disposed of in the receptacles used for infectious biomedical waste (which may be autoclaved and then sent to a landfill site) (9). It is legislated that every area where hazardous drugs are handled will have an appropriate hazardous waste receptacle as close as possible to the work area (9). The lids of hazardous drug receptacles must remain closed, except when depositing waste. Bins with foot pedals and lids, which lock automatically when full, are recommended to minimize exposure. It is strongly recommended that workers be careful to avoid contaminating the outside of the receptacle when depositing waste. It is legislated that the transport of hazardous waste receptacles be assigned to properly trained workers (6). It is strongly recommended that workers who handle hazardous waste receptacles wear two pairs of disposable gloves and have a spill kit at their disposal. It is strongly recommended that the waste go through as few care units, public areas and areas containing food or linens as possible. It is legislated that the final storage areas for hazardous waste receptacles be secure. Refer to Ontario storage (8, 9) requirements. # Recommendation 11: Accidental Exposure Be aware of any mandatory reporting requirements under the Occupational Health and Safety Act and report requirements to Workplace Safety and Insurance Board (WSIB) (6). Establish policies and procedures regarding accidental worker exposure. If a hazardous drug accidentally comes into contact with a worker's skin or clothing, it is strongly recommended that the worker immediately remove the contaminated clothing and thoroughly wash the skin of the affected area with soap and water and continue to rinse for 15 minutes. If appropriate, it is strongly recommended that the contaminated worker take a shower. It is strongly recommended that a deluge shower be made available in the vicinity (e.g., in the oncology clinics/units). It is strongly recommended that all contaminated clothing be discarded in hazardous waste. Workers should seek medical attention after exposure. If a hazardous drug comes into contact with a worker's eyes, it is strongly recommended that the worker flush their eyes at an eye wash station. Alternatively, it is recommended that the workers use an isotonic solution to flush their eyes (e.g., sterile NaCl 0.9%). It is strongly recommended that eyes be flushed for at least 15 minutes (22). It is strongly recommended that that if contact lenses are worn, they be removed immediately prior to flushing. Workers should seek medical attention after eye exposure. In the event of a needlestick or sharps injury, let the wound bleed freely. Under running water, gently and thoroughly wash the area with soap. Contact Occupational Health. Ensure that facility policies for needlestick or sharps injury are followed including completion of an incident report and reporting to WSIB if indicated. # Recommendation 12: Spills Management It is strongly recommended that the facility develop policies and procedures for spills management that take into account the types of spills (i.e., amount, location, concentration, powder vs. liquid, etc.), incidence reporting, surveillance of spills and restocking of equipment. All staff working in environments where hazardous drugs are handled should be trained in the use of a spill kit. It is strongly recommended that a spill kit be readily available in all areas where hazardous drugs are stored, transported handled and administered. It is strongly recommended that a spill kit be readily available in the home in case of accidental spills, but institutions must ensure patients, or their caregivers are trained on the use of the spill kit and PPE. It is legislated that disposable items from the clean-up of spills be placed in the hazardous waste receptacle (9). Non-disposable items should be thoroughly cleaned and decontaminated. The area of the spill should be decontaminated deactivated and disinfected (10). Most spills can be contained and managed by trained staff (e.g., leaking IV tubing). When a spill is not contained or easily managed (e.g., exposure to large volume of fluid that is a risk to the environment or a large crate of vials filled with powder broken in the receiving area), it is strongly recommended that a Code Brown or equivalent be called. It is strongly recommended that healthcare providers follow the same recommendations outlined in Recommendation 8 -Drug Administration It is strongly recommended that a spill kit be readily available in the home in case of accidental spills. It is strongly recommended that patients be informed of and be provided with written instructions and PPE for the safe handling of hazardous drugs. It is strongly recommended that contact information be provided for home care patients who require assistance with safe handling of hazardous. # Hazardous Drug Waste in the Home It is strongly recommended that the institution have a clear process to address the issue of hazardous waste from patients in their homes, in compliance with municipal or local hazardous waste rules. It is strongly recommended that this process include patient and caregiver education. It is strongly recommended that caregiving staff provide the patients/caregivers involved in administering cytotoxic drugs in the home with a process for appropriate disposal of hazardous waste, including leftover drugs. # Recommendation 10: Management of Waste Bodily Fluid Waste It is strongly recommended that workers who handle the biological fluids, excreta, contaminated bedding, and soiled equipment of patients who have received hazardous drugs wear two (2) pairs of gloves and a protective gown. It is strongly recommended that face protection be worn when there is a risk of splashing. # Cytotoxic Drug Waste Establish policies and procedures as per provincial legislation regarding hazardous waste management. The term "hazardous waste" includes any material that comes into contact with hazardous drugs during their storage, handling, preparation, administration and disposal (e.g., packaging material, protective equipment, preparation supplies, such as syringes, tubing, drug bags; soiled disposable incontinent briefs of patients who have received hazardous drugs during the previous 48 hours or longer depending on the drug ; hood pre-filters and HEPA filters, etc.). It is legislated that hazardous waste be placed in a waste container clearly identified with the "Cytotoxic" hazard symbol. It is legislated that hazardous waste be disposed of in the appropriate containers (9). It is legislated that sharps be placed in rigid containers with a leak proof lid; CSA standard Z316.6--07 specifies the use of the colour red for the rigid containers (49). If the containers are another colour, follow the instructions of the company ensuring the final disposal (9). # Recommendation 13: Environmental Cleaning Establish environmental cleaning policies and procedures for all surfaces where contact with hazardous drugs may occur. Areas should be decontaminated deactivated and disinfected following legislative procedures. Examples may include unpacking and storage, preparation, administration, and disposal areas. Pharmacy counters are among the most contaminated surfaces (5, 7, 10). It is strongly recommended that cleaning of the BSC be performed by trained personnel following manufacturer's and NAPRA's guidelines (7, 10). # Use of Pumps to Administer Hazardous Drugs Make sure there is an appropriate policy to clean and inspect the equipment between uses. Ensure the facility complies with the Occupational Health and Safety Act -Ontario Regulation for Health Care and Residential Facilities (6). Contaminated items should be placed in sealable bags and washed separately from other items (5). # Recommendation 14: Medical Surveillance and Environmental Monitoring # Medical Surveillance Methods used to investigate potential health effects of exposure to hazardous drugs are inconclusive and difficult to interpret. The ideal test should meet several requirements -it should be sensitive, specific, quantitative, rapid, and reproducible. Importantly, the procedures for taking a sample should be non-invasive and should not cause unnecessary duress or anxiety to the individual (7). Unfortunately, there is currently no suitable test to meet these requirements. Therefore, there is conflicting information and opinion about the value of routine biological monitoring for employees handling hazardous drugs. Employers do have a responsibility to ensure that they remain aware of and apply any future developments for monitoring the health of employees in the handling of hazardous drugs. The panel supports further research to determine if there are adverse health effects that result from exposure to hazardous drugs. Adherence to agreed standard operating procedures with sufficient initial and regular ongoing training in safe handling/administration is paramount to reducing potential for exposure and risk. There is evidence in the literature of a higher rate of spontaneous abortion among women working in roles that expose them to hazardous drugs (51, 52). There are no other identified medical conditions known to result from chronic exposure of healthcare workers to hazardous drugs, no exposure limits set for hazardous drugs, and no standards for interpretation of test results of exposed healthcare workers to enable meaningful interpretation or action based on biological monitoring results. # Environmental Monitoring It is recommended that the facility implement an environmental monitoring program. Surface testing would audit contamination of the environment (e.g., pharmacy counters, patient bedside tables) and provide a quality indicator of cleaning effectiveness and adherence to recommended work practices (5).

# INTENDED PURPOSE - This recommendation report is primarily intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality systematic review from the U.S. Agency for Health Research and Quality (AHRQ) (1) that included primary study literature for the period from 2003 to March 2008. # Diagnosis/Staging PET is not recommended for the determination of diagnosis or grading in gliomas. Five studies (Chen et al Cher et al Liu et al Potzi et al Stockhammer et al assessed diagnostic accuracy and prognostic influence of PET scanning on survival, but none have demonstrated any additional diagnostic accuracy or prognostic influence over and above that provided by magnetic resonance imaging (MRI) and histology in a multivariate model. # Qualifying Statement # Assessment of Treatment Response A recommendation cannot be made for or against the use of PET for the assessment of treatment response in gliomas due to insufficient evidence. None of the studies discuss this question. # Qualifying Statement - Anecdotal evidence exists that PET/CT may differentiate radiation necrosis from tumour recurrence, but there is no gold standard for the diagnosis of radiation necrosis in glioblastoma multiforme. # Recurrence/Restaging A recommendation cannot be made for or against the use of PET or PET/CT in the assessment of patients with recurrent gliomas due to insufficient evidence. Two studies evaluating the use of PET included patients with recurrent gliomas (Chen et al Potzi et al. In both studies, fluorodeoxyglucose (FDG) PET was not the focus of the study but a comparison test for the tracer of interest, F-DOPA-PET in Chen et al (2) and Methionine-PET in Potzi et al (5). The evidence was insufficient to generate a recommendation on the use of FDG PET. # Qualifying Statements - PET or PET/CT has not been examined in a prospective cohort of gliomas to assess the treatment effect on PET imaging before and after treatment and correlate this with survival. Radiation necrosis is a major factor in assessing recurrent gliomas. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

New data and old data integrated in new Full Report Updated web publication. # Not Applicable # Table of Contents # INTENDED USERS This guideline is targeted for clinicians involved in the delivery of systemic treatment for cancer patients. # RECOMMENDATIONS AND KEY EVIDENCE Recommendation 1a First-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is not recommended in unselected (patients who have not undergone mutation testing) or clinically selected populations of patients. Available data would suggest that first-line EGFR TKI is inferior to platinum-based chemotherapy in this group of NSCLC patients. The use of clinical characteristics such as Asian ethnicity, female sex, adenocarcinoma histology and light/never smoking status is not recommended to select patients for first-line EGFR TKI therapy, as this strategy does not reliably select patients who have mutations. # Key Evidence Twenty-six randomized first-line studies in unselected and clinically selected populations were used to formulate this recommendation. The results of these trials showed no benefit for the use of an EGFR inhibitor in unselected and clinically selected patients. # Recommendation 1b In patients with EGFR mutation-positive NSCLC, first-line therapy with an EGFR TKI such as gefitinib, erlotinib or afatinib is the preferred treatment compared to platinum-based therapies. There is no evidence to support one EGFR TKI over another, so the decision about which EGFR TKI to use should take into consideration the expected toxicity of the drug as well as the cost. EGFR TKI therapy is associated with higher response rates, longer PFS and improved quality of life. # Qualifying Statement There is no clear difference in overall survival. Many patients in these trials randomized to platinum-doublet chemotherapy, crossed over to an EGFR TKI as subsequent therapy. The likely effect of this cross-over is to dilute any survival difference between the groups, making comparison of overall survival less informative. # Key Evidence Seven randomized trials and two meta-analyses comprised the evidence base. The trials and meta-analyses based on data from these trials showed that PFS was prolonged in molecularly selected patients when an EGFR was used as first-line treatment (27)(28)(29)(30)(31)(32)(33). - Six trials were included in the initial meta-analysis that showed a hazard ratio (HR) of 0.35 (95% confidence interval (CI), 0.28-0.45; p<0.00001) (27)(28)(29)(30)32,33). A second meta-analysis done on PFS that included subsets of EGFR-positive patients from first-line trials had similar results with an HR of 0.38 (95% CI, 0.31-0.44; p<0.00001) (20,21,(28)(29)(30)(32)(33)(34). All seven trials showed a decrease in adverse effects with an EGFR inhibitor compared to chemotherapy (28)(29)(30)(31)(32)(33)(34). # Recommendation 2 In patients well enough to consider second-line chemotherapy, an EGFR TKI can be recommended as second-or third-line therapy. There is insufficient evidence to recommend the use of a second EGFR TKI, such as afatinib, in patients whose disease has progressed following chemotherapy and gefitinib or erlotinib, as available data does not demonstrate any improvement in overall survival # Qualifying Statements There are data to support the use of an EGFR TKI in patients who have progressed on platinum-based chemotherapy. Erlotinib is known to improve overall survival and quality of life when used as second-or third-line therapy, in comparison to best supportive care. However, available data would suggest that second-line therapy with either chemotherapy or an EGFR TKI results in similar PFS and overall survival. Available evidence would support the use of either erlotinib or gefitinib in this situation. Data from a randomized phase II trial suggests improved PFS for dacomitinib versus (vs) erlotinib, but these data require confirmation in a phase III trial. The Lux Lung 1 study failed to meet its primary outcome of improved overall survival. However, the study showed improved PFS for patients randomized to afatinib and was associated with improvements in lung cancer symptoms. # Key Evidence - Three studies examined an EGFR inhibitor as a second-line treatment against a placebo and best supportive care (35)(36)(37). One study reported on the use of erlotinib and showed a significant improvement in PFS (p=0.001) and overall survival (p=0.001) (35). The other two studies evaluated gefitinib, with one study finding significant results for response rate (p<0.0001) (37) and the other for PFS (p=0.002) (36). A meta-analysis done on seven second-line studies showed no improvement with EGFR TKIs vs chemotherapy for progression-free survival (HR, 0.99; 95% CI 0.86-1.12, p=0.67) and overall survival (HR, 1.02; 95% CI, 0.95-1.09, p=0.56) (38-44) One phase II study that compared erlotinib to dacomitinib (45)showed significant results for dacomitinib for response rate (p=0.011) and for PFS (p=0.012). The Lung Lux 1 study examined the use of afatinib in the third-and fourth-line setting against a placebo. This study showed improved PFS (HR, 0.38; 95% CI, 0.31-0.48, p<0.0001) but no difference in overall survival (HR, 1.08; 95% CI, 0.86-1.35, p=0.74) (46). # Recommendation 3 An EGFR TKI is recommended as an option for maintenance therapy in patients who have not progressed after four cycles of a platinum-doublet chemotherapy. No recommendation can be made with respect to the choice of gefitinib or erlotinib. # Qualifying Statements - Trials have evaluated both erlotinib and gefitinib, but no trials directly compare these two agents as maintenance therapy. However, the strongest data would support the use of erlotinib in this setting, although the overall survival advantage is modest for both agents. There are competing strategies of maintenance chemotherapy without an EGFR TKI, such as pemetrexed, that are not addressed in this guideline. The recommendation for TKI above should not be taken as excluding these other strategies as reasonable options; as this evidence was not reviewed, no statement can be made for or against these other strategies. The Lung Disease Site Group (DSG) plans to develop a separate guideline on maintenance therapy as soon as possible. This recommendation applies to both EGFR mutation positive and wild-type patients. # Key Evidence Six studies evaluated the use of an EGFR inhibitor in the maintenance setting (47)(48)(49)(50)(51)(52). - Two of the trials reported a statistically significant survival benefit with erlotinib: one for response rate (p=0.0006) when compared to placebo (47) and one for progression-free survival when combined with bevacizumab against bevacizumab alone (p<0.001) (51). One study comparing erlotinib and gemcitabine did not report significance but found a higher response rate with erlotinib (15% vs 7%) and 9.1 months vs 8.3 months for overall survival (50). Two trials evaluating gefitinib found a statistically significant benefit for PFS in the maintenance setting, p<0.001 when combined with chemotherapy and against chemotherapy (48) and p<0.0001 compared to a placebo (49). Another trial evaluated gefitinib and showed a higher response rate, but this was not significant (p=0.369) (52). # Recommendation 4 The most common toxicities from EGFR inhibitors were diarrhea and rash. Fatigue was also noted to be more prevalent with EGFR inhibitors. Rarer adverse events include interstitial lung disease (ILD). The newer TKIs (icotinib, dacomitinib and afatinib) were noted to have greater incidence of diarrhea, dermatitis and hepatotoxicity. # Key Evidence - Two randomized phase II trials (53)(54), each involving more than 200 patients randomized to either 250 mg or 500 mg of gefitinib daily, identified that grade 3 or 4 toxicity was higher with the higher dose gefitinib. Interstitial lung disease-type events occurred in only one of the two trials, and only with 500 mg/day gefitinib (1% of patients) (53). One study comparing dacomitinib to erlotinib identified a greater predilection to diarrhea, dermatitis and paronychia with dacomitinib (45). One study comparing icotinib to gefitinib identified a greater incidence of elevated liver transaminases with gefitinib (12.6% vs 8%) (54). # RELATED GUIDELINES A previous version of this guideline is contained in: Feld R, Sridhar SS, Shepherd FA, Mackay JA, Evans WK, Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care. Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review. J Thorac Oncol. 2006;1(4):367-76.

# Cancer Care Ontario Sequence Variants in Hereditary Cancers Guideline: An Endorsement of the 2015 Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology # Section 1: Guideline Endorsement The Molecular Oncology and Testing Advisory Committee of Cancer Care Ontario endorses the recommendations of Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, published by the American College of Medical Genetics and Genomics (ACMG) regarding inherited cancers, as modified by the endorsement process described in this document. Caveats and clarifications about the recommendations as they pertain to Ontario are discussed below (Table 1-1 # Additional update in March 2022 Additional refinements and tools have been developed for a consistent implementation of the ACMG/Association for Molecular Pathology guideline 1. The ClinGens Sequence Variant Interpretation Group (/) supports the refinement and the evolution of the guideline through providing recommendations and tools for consistent implementation. When using databases, clinical laboratories should (i) determine how frequently the database is updated, whether data curation is supported, and what methods were used for curation; (ii) confirm the use of Human Genome Variation Society nomenclature and determine the genome build and transcript references used for naming variants; (iii) determine the degree to which data are validated for analytical accuracy (e.g., low-pass next-generation sequencing versus Sanger-validated variants) and evaluate any quality metrics that are provided to assess data accuracy, which may require reading associated publications; and (iv) determine the source and independence of the observations listed. While it is recognized that it is not always possible to determine methods or frequency of curation for public databases, laboratories should adhere to these principles to the extent this is possible. # PS4 PM2 BA1 BS1 BS2 variant frequency and use of control populations In general, an allele frequency in a control population that is greater than expected for the disorder is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1) or, if over 5%, it is considered as stand-alone support (BA1). For some disorders, very high frequencies (>5%) may be found in specific populations due to founder effect, and may be associated with some clinical risk. This possibility should be assessed through a careful consideration of available literature and other information, if possible. # PP1 BS4 segregation analysis On the other hand, lack of segregation of a variant with a phenotype provides strong evidence against pathogenicity. Careful clinical evaluation is needed to rule out mild symptoms of reportedly unaffected individuals, as well as possible phenocopies (affected individuals with disease due to a nongenetic or different genetic cause). Incomplete penetrance, variable expressivity and later age of onset should be considered when establishing evidence against pathogenicity. # PP4 using phenotype to support variant claims In general, the fact that a patient has a phenotype that matches the known spectrum of clinical features for a gene is not considered evidence for pathogenicity given that nearly all patients undergoing diseasetargeted tests have the phenotype in question. If the following criteria are met, however, the patient's phenotype can be considered supporting evidence: (i) the clinical sensitivity of testing is high, with most patients testing positive for a pathogenic variant in that gene; (ii) the patient has a well-defined syndrome with little overlap with other clinical presentations (e.g., Gorlin syndrome including basal cell carcinoma, palmoplantar pits, odontogenic keratocysts); (iii) the gene is not subject to substantial benign variation, which can be determined through large general population cohorts (e.g., Exome Sequencing Project); and (iv) family history is consistent with the mode of inheritance of the disorder. Age of onset of a disease should also be taken into consideration. # Variant reanalysis For reports containing variants of uncertain significance in genes related to the primary indication, and in the absence of updates that may be Laboratories are encouraged to develop policies around the steps to be taken when a variant proactively provided by the laboratory, it is recommended that laboratories suggest periodic inquiry by health care providers to determine whether knowledge of any variants of uncertain significance, including variants reported as likely pathogenic, has changed. By contrast, laboratories are encouraged to consider proactive amendment of cases when a variant reported with a near-definitive classification (pathogenic or benign) must be reclassified. Regarding physician responsibility, see the ACMG guidelines on the duty to recontact. undergoes reclassification such that clinical management decisions would be changed. Any such policies should be developed with input from the associated genetic clinic. # Evaluation and reporting variants in GUS based on the indication for testing Genome and exome sequencing are identifying new genotype-phenotype connections. When the laboratory finds a variant in a gene without a validated association to the patient's phenotype, it is a GUS. This can occur when a gene has never been associated with any patient phenotype or when the gene has been associated with a different phenotype from that under consideration. Special care must be taken when applying the recommended guidelines to a GUS. In such situations, utilizing variant classification rules developed for recognized genotype-phenotype associations is not appropriate. Generally, GUS should be considered as research findings, and not at the same level as clinically actionable and validated genes. Abbreviations: ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; GUS, genes of uncertain significance We would like to thank the following individuals for their assistance in developing this report: # Cancer Care Ontario Sequence Variants in Hereditary Cancers Guideline: An Endorsement of the 2015 Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Section 2: Endorsement Methods Overview # THE PROGRAM IN EVIDENCE-BASED CARE The Program in Evidence-Based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO). The PEBC mandate is to improve the lives of Ontarians affected by cancer through the development, dissemination, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer control. The PEBC is a provincial initiative of CCO supported by the Ontario Ministry of Health and Long-Term Care (OMHLTC). All work produced by the PEBC is editorially independent from the OMHLTC. # BACKGROUND FOR GUIDELINE The Molecular Oncology and Testing Advisory Committee (MOTAC) of CCO recognized that guidance around interpretation of sequence variants in patients with hereditary cancers was necessary. # GUIDELINE DEVELOPERS This endorsement project was sponsored by MOTAC. MOTAC is comprised of geneticists, pathologists, medical oncologists, and clinical hematologists (see Appendix 1 for membership) and served as the Expert Panel for this endorsement. The project was led by a small Working Group comprised of clinical and medical geneticists practicing in Ontario, who were responsible for reviewing the recommendations in Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in detail and making an initial determination as to any necessary changes, drafting the first version of the endorsement document, and leading the response to the external review. The Working Group members are noted in Appendix 1. All members contributed to the endorsement process, refinement of the endorsement document, and approval of the final version of the document. Conflict of interest declarations for all Guideline Development Group members are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. # CHOICE OF GUIDELINE FOR ENDORSEMENT The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guideline was identified a priori by MOTAC and was determined to be a good candidate for endorsement by the Working Group due its acceptability in Ontario, scope, and relevance. Further, the Working Group felt that investing extensive effort to replicate the ACMG/AMP guideline would not be justified given the number of experts involved in its creation. # DESCRIPTION OF ENDORSED GUIDELINE The recommendations regarding the classification of germline sequence variants were developed by the ACMG, the AMP, and the College of American Pathologists in 2013. The recommendations were developed through expert opinion, consensus, and community input and are applicable to variants in all Mendelian genes. # ENDORSEMENT PROCESS The Working Group reviewed the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in detail, and reviewed each recommendation of that guideline to determine whether it could be endorsed, endorsed with changes, or rejected. This determination was based on the agreement of the Working Group with the interpretation of available evidence presented in the guideline, and whether it was applicable and acceptable to the Ontario context, and feasible for implementation. All recommendations from the original ACMG/AMP guideline requiring caveats or clarifications as they pertain to Ontario are summarized in Table 1-1. All references to the Health Insurance Portability and Accountability Act were modified to refer to the Personal Health Information Protection Act to reflect Ontario legislation. Similarly, references to the Clinical Laboratory Improvement Amendments were modified to refer to the Institute for Quality Management in Healthcare. # ENDORSEMENT REVIEW Members of MOTAC reviewed the draft endorsement and seven of the eight members voted (87.5% response rate). Of those that voted, all (100%) approved the endorsement. MOTAC will review the endorsement on an annual basis to ensure that it remains relevant and appropriate for use in Ontario

# INTENDED PURPOSE - This recommendation report is primarily intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. - This recommendation report may also be useful to inform clinical decision making regarding the appropriate role of PET imaging and to guide priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality United Kingdom (U.K.) Health Technology Assessment (HTA) systematic review (1) that included systematic review and primary study literature for the period from 2000 to August 2005 and update searches based on those in that original systematic review and undertaken to retrieve the same level of evidence for the period from August 2005 to May 2010. For the staging workup of patients with esophageal cancer who are potential candidates for curative therapy, PET is recommended to improve the accuracy of M staging. There is a significant role for PET for its incremental value in detecting distant disease, in addition to CT +/-endoscopic ultrasound (EUS). Especially in the absence of EUS, PET provides an incremental benefit. HTA review (1): One systematic review containing three primary studies showed the superiority of PET to CT or EUS in detecting distant metastases. Another systematic review of 12 primary studies showed that PET had a sensitivity of 67% and a specificity of 97%, corroborating the first systematic review. One additional primary study showed the incremental benefit of adding PET to CT and EUS, giving a sensitivity of 74% compared with 53% for PET alone and 64% for PET plus CT. A 2008 systematic review by van Vliet et al, 2008 (2), with two primary studies not included in Facey et al, 2007 (1), and two studies from the update search (Kato et al, 2005 and Katsoulis et al, 2007 showed higher detection rates for distant metastases with PET than with CT, but the difference was not statistically significant. When the effect of PET is evaluated, based on whether staging is changed, a correct change occurred in approximately 30% of cases in two studies (one in van Vliet et al and one in Katsoulis et al from the updated search). There is some evidence that PET/CT is superior to PET alone for nodal staging (Yuan et al, 2006. also showed the significant impact of PET and PET/CT on the clinical management, prognostic stratification of patients with newly diagnosed esophageal cancer, prediction of regional and locoregional lymph nodes, and improvement on the accuracy of pretreatment staging compared to CT and EUS alone. # Qualifying Statement The data supporting this recommendation are compelling but sparse. The recommendation is based on patients with a new diagnosis of esophageal cancer. # Assessment of Treatment Response A recommendation cannot be made for or against the use of PET (post or neoadjuvant therapy) for the purpose of predicting response to neoadjuvant therapy due to insufficient evidence. There is some evidence that PET, either early in treatment or at the completion of neoadjuvant therapy, can predict complete pathologic response, and therefore, predict the longer-term outcome in terms of survival and event-free survival. HTA 2007 review (1): One systematic review of four primary studies plus one additional study showed that PET may be superior to CT and comparable to EUS in the assessment of response and of prognosis after neoadjuvant therapy. One additional study showed PET/CT to be more sensitive for the evaluation of response than either CT or endoscopic ultrasound. and Shenfine et al, 2009. Perhaps more importantly, there is evidence that PET response is related to longer-term clinical outcomes, including disease-free survival and overall survival (Duong et al Kim et al Wieder et al Higuchi et al and Shenfine et al. The best cutoff point to use for defining responder versus non-responder remains to be defined. Data derived from the receiver operating characteristic (ROC) curves would suggest a 30% to 50% reduction as a useful parameter (Wieder et al Smithers et al). The prognostic value of PET is further supported by the fact that responders and nonresponders have significantly different SUV change profiles. The value of PET as an early indicator for future response was evaluated in three studies (Gillham et al, 2006 Westerterp et al, 2006 Wieder et al, 2007 and Vallbohmer et al, 2009. While a significant difference existed between pathological responders and nonresponders, further study is required to establish the best criteria and standardized conditions to use if this modality is to be routinely incorporated into clinical practice to guide treatment decisions. One study evaluated PET as an early tool to predict a response allowing neoadjuvant therapy to be abandoned in favour of early surgery (Lordick et al, 2007. This study confirmed that responders had better outcomes in terms of survival and disease-free survival. # Qualifying Statement Whether the use of PET to assess treatment response would translate into an improved outcome remains to be established, but it is potentially useful in minimizing toxicity related to futile treatment. The optimal parameters to use for defining responders require further validation. Recurrence/Restaging A recommendation cannot be made for or against the use of PET for the evaluation of suspected recurrence due to insufficient evidence. Two studies from the 2005-2010 update (Guo et al, 2007 and Jingu et al, 2010 showed PET/CT to be accurate in detecting regional and distant recurrence and in predicting the prognosis in patients with postoperative recurrent esophageal cancer. The findings of these studies require corroboration before a recommendation can be made. # Qualifying Statement Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# GUIDELINE OBJECTIVES To update the 2015 guideline of the Program in Evidence-Based Care (PEBC) Ontario Health (Cancer Care Ontario) to provide guidance for managing surveillance of patients with stage I, II, III, or resectable IV melanoma who are clinically disease-free after treatment with curative intent (following the definition of American Joint Committee on Cancer Pathological Prognostic Stage Groups in the 2017 Cancer Staging Manual, the 8 th edition). # TARGET POPULATION These recommendations apply to patients with stage I, II, III, or resectable IV melanoma who are clinically disease-free after treatment with curative intent. Pathological staging is according to the 8 th edition AJCC staging system (Appendix 1). # INTENDED USERS Intended users of this guideline are medical oncologists, dermatologists, surgical oncologists, radiation oncologists, family doctors, and other clinicians who are involved in the follow-up care of patients with melanoma in the province of Ontario. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION The strength of recommendations for this guideline includes three categories: Recommendation, Weak Recommendation, and No Recommendation (definitions and corresponding verb wording are provided in Appendix 2). # Recommendation 1 For patients with stage IA, IB, or IIA melanoma who are clinically disease-free after receiving curative-intent treatment: 1.1 Clinical follow-up with history and physical examination with full skin and lymph node examination by a dermatologist (with photo-surveillance and dermoscopy if indicated), and/or a surgeon, family physician, cancer nurse specialists should occur every six to 12 months for three years, then annually for two years or as clinically indicated. # Recommendation 3 For patients with stage IIIA, IIIB, IIIC, IIID, or resected IV melanoma: 3.1 Clinical follow-up with history and physical examination with full skin and lymph node examination by a dermatologist (with photo-surveillance and dermoscopy if indicated), and/or a surgeon, medical oncologist, or cancer nurse specialist should occur every three to six months in years 1 to 3, then every six months in years 4 to 5, or as clinically indicated. 3.2 Routine biomarker or blood tests to screen for asymptomatic recurrence or metastatic disease are not recommended. 3.3 CT or PET/CT scans every six to 12 months should be considered to screen for asymptomatic recurrence or metastatic disease in years 1 to 3, then annually in years 4 to 5. 3.4 Annual brain MRI can be considered for years 1 to 5. MRI (no radiation) of the brain is preferred for routine screening where available, otherwise, head CT may be considered after discussing with patients. 3.5 For patients with a positive sentinel lymph node, ultrasound scans of the draining nodal basin should be done every four to six months for years 1 to 3, and then every six months for years 4 to 5, if no complete lymph node dissection is performed.

Evidence-based Series 4-9 Version 2 A Quality Initiative of the Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Follow-up after Primary Therapy for Endometrial Cancer Members of the Gynecology Cancer Disease Site Group An assessment conducted in November 2022 deferred the review of Evidence-Based Series (EBS) 4-9 Version 2. This means that the document remains current until it is assessed again next year. The PEBC has a formal and standardized process to ensure the currency of each document (PEBC Assessment & Review Protocol) EBS 4-9 Version 2 is comprised of 4 sections.# Journal Citation (Vancouver Style): Fung Kee Fung M, Dodge J, Elit L, Lukka H, Chambers A, Oliver T; on behalf of the Cancer Care Ontario Program in Evidence-based Care Gynecology Cancer Disease Site Group. Follow-up after primary therapy for endometrial cancer: a systematic review. Gynecol Oncol 2006;101:520-9. # Guideline Report History What is the most appropriate strategy for the follow-up of patients with endometrial cancer who are clinically disease free after receiving potentially curative primary treatment? Specifically, do differences in follow-up intervals, diagnostic interventions, clinical setting, or specialty influence patient outcomes related to local or distant recurrence, survival, or quality of life? # Target Population Women without evidence of disease after primary potentially curative treatment for any stage of endometrial cancer comprise the target population. Of particular interest are outcomes from follow-up strategies reported for patients at a lower risk of recurrence (i.e., stage IA or IB, grade 1 or 2) and those at a higher risk of recurrence (i.e., stage IA or IB, grade 3, or stage IC or advanced stage). These guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making. Please see Section 4: Document Review Summary and Tool for a summary of updated evidence published between 2005 and 2016, and for details on how this Clinical Practice Guideline was ENDORSED. There is a lack of randomized controlled trial evidence related to the clinical questions. Based on the interpretation of evidence from retrospective studies and expert consensus opinion, the Gynecology Cancer Disease Site Group recommends the following: - It is recommended that all patients receive counselling about the potential symptoms of recurrence of endometrial cancer, because the majority of recurrences in the identified studies were symptomatic. Symptomatic signs of possible recurrence can include, but are not limited to, unexplained vaginal bleeding or discharge, detection of a mass, abdominal distension, persistent pain, especially in the abdomen or pelvic region, fatigue, diarrhea, nausea or vomiting, persistent cough, swelling, or weight loss. - The most appropriate follow-up strategy is likely one based upon the risk of recurrence, with individual patient preferences for more or less follow-up taken into account. For patients at a surgically or pathologically confirmed low risk of recurrence (i.e., stage IA or IB, grade 1 or 2): A general examination, including a complete history and a pelvicrectal examination, conducted semi-annually or annually for the first three years and annually for the next two years. For patients at high risk of recurrence (i.e., stage IA or IB, grade 3, or stage IC or advanced stage). A general examination, including a complete history and a pelvic-rectal examination, every three to six months for the first three years and semi-annually for the next two years. - Since the majority of patients with recurrence were symptomatic and virtually all recurred within five years, it seems reasonable that patients return to annual population-based general physical and pelvic examination after five years of recurrence-free follow-up. - There is insufficient evidence to inform the optimum clinical setting or type of specialist required for follow-up; however, it is recommended that all patients be followed by a health care professional who is knowledgeable about the natural history of the disease, and who is comfortable performing speculum and pelvic exams, in order to diagnose or detect a local (vaginal) recurrence. If a patient is initially followed by a specialist, it seems reasonable that they be followed by a qualified general practitioner after three to five years of recurrence-free follow-up. - It is recommended that all patients undergo a targeted investigation to rule out recurrence if symptomatic, since patients with local recurrence are potentially curable with further therapy. - There is insufficient evidence to inform the routine use of Pap smear, chest x-ray, abdominal ultrasound, computed tomography (CT) scan or CA 125 testing to detect asymptomatic recurrences. - Where treatment with radiotherapy is involved, it is recommended that patients be counselled on the potential adverse effects of radiotherapy. Adverse effects associated with radiotherapy can include complications with the rectum, urinary bladder, vagina, skin, subcutaneous tissue, bones, and other sites. # Key Evidence - Sixteen non-comparative retrospective studies provided the evidence basis for this report. Twelve studies evaluated follow-up programs, while four studies evaluated the role of the tumour-marker cancer antigen (CA) 125 in detecting disease recurrence. - In 12 studies, overall (local and distant) recurrence rates ranged from 8% to 19%, with a weighted mean of 13% (95% confidence interval ; 11%-14%). In four studies that categorized patients by risk of recurrence, recurrence rates ranged from 1% to 3% for low-risk patients and 5% to 16% for high-risk patients. - In 12 studies, 41% to 100% of all recurrences were symptomatic, the weighted mean being 77% (95% CI; 74%-81%). - In 9 studies, 68% to 100% of recurrences occurred within approximately three years of followup. - The number of asymptomatic patients with recurrences detected by a routine follow-up test alone was not consistently reported; however, with the available data, as a percentage of total recurrences: Seven studies reported 5% to 33% of recurrences were detected by physical examination, Four studies reported 0% to 4% of recurrences were detected by Pap smear, Six studies reported 0% to 14% of recurrences were detected by chest x-ray, Two studies reported 4% and 13% of recurrences were detected by abdominal ultrasound, Two studies reported 5% and 21% of recurrences were detected by CT scan, and One study reported 15% of recurrences in selected patients were detected by CA-125 level. # Contact Information For further information about this series, please contact the authors through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Questions 1. Should primary care providers routinely perform total-body skin examination on members of the general population to screen for melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin? 2. Should primary care providers routinely counsel members of the general population to perform skin self-examination for early detection of melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin? 3. Should individuals at high risk for melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin be offered surveillance by a physician, including total-body skin examination and counselling to perform skin self-examination? 4. What characteristics should clinicians assess in order to determine risk for melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin? Very limited evidence was available to inform the following recommendations on screening. No prospective studies have evaluated the impact of screening on survival, quality of life, or morbidity from treatment for skin cancer nor are there data on the adverse effects of screening for skin cancer. As experts in the treatment and epidemiology of skin cancer, the guideline panel members were aware that some individuals are at increased risk for skin cancer because of personal characteristics or history. They reviewed key papers on risk and identified groups of patients who might be expected to benefit from increased surveillance for skin cancer. Separate recommendations are offered for two groups at increased risk (very high risk and high risk) and the general population. # Very high risk of skin cancer Individuals with any of the following risk factors have a very high risk of skin cancer (approximately 10 or more times the risk of the general population): -on immunosuppressive therapy after organ transplantation, -a personal history of skin cancer, -two or more first-degree relatives with melanoma, -more than 100 nevi in total or 5+ atypical nevi, -have received more than 250 treatments with psoralen-ultraviolet A radiation (PUVA) for psoriasis -received radiation therapy for cancer as a child Individuals at very high risk should be identified by their primary health care provider and offered total body skin examination by a dermatologist or a trained health care provider on a yearly basis. They should also be counselled about skin self-examination and skin cancer prevention by a health care provider (e.g., physician, nurse practitioner, or public health nurse). In the case of childhood cancer survivors, the site of radiation therapy should be monitored. # High risk of skin cancer Individuals with two or more of the main identified susceptibility factors are at a high risk for skin cancer (roughly 5 times the risk of the general population): -a first-degree relative with melanoma, -many (50-100) nevi, -one or more atypical (dysplastic) nevi, -naturally red or blond hair, -a tendency to freckle, -skin that burns easily and tans poorly or not at all Other factors that may influence the risk of skin cancers that are environmental include an outdoor occupation, a childhood spent at less than latitude 35 0 the use of tanning beds during teens and twenties, and radiation therapy as an adult. Individuals at high risk should be identified by their primary health care provider and counselled about skin self-examination (specifically focused on the site of radiation for those having had therapeutic radiation) and skin cancer prevention by a health care provider (e.g., physician, nurse practitioner, or public health nurse). High-risk individuals should be seen once a year by a health care provider trained in screening for skin cancers. # The general population not at increased risk of skin cancer There is at this time no evidence for or against skin cancer screening of the general population at average risk of developing skin cancer. Based on the limited evidence available at present, routine total body skin examination by primary care providers is not recommended for individuals at average or low risk for skin cancer (i.e., those not included in the increased risk groups described above). Based on the limited evidence available at present, routine counselling on skin selfexamination by primary care providers is not recommended for individuals at average or low risk for skin cancer. # Key Evidence (Please see Section 2 for the complete systematic review of the evidence conducted by the Skin Cancer Screening Guideline Panel) The guideline panel reviewed three evidence-based guidelines on screening for skin cancer (1-3), results from a pilot randomized controlled trial of a community-based screening program, a comparative cohort study of work-place screening and a case-control study of skin self-examination. The pilot phase of a randomized trial demonstrated the feasibility of implementing a screening program consisting of community education, general practitioner education and screening clinics to promote self-screening and whole-body screening by general practitioners. Early results detected an increase in the percentage of subjects reporting whole-body skin examination by a physician (4). The randomized trial and the work-place screening study both found that people were more likely to perform skin self-examination if they had undergone a whole-body skin examination by a physician (4,5). A case-control study detected the reduced risk of melanoma and reduced mortality from melanoma associated with skin self-examination (6). Epidemiologic studies have found that people who have any of the following characteristics have a very high risk of developing skin cancer: on immunosuppressive therapy after organ transplantation, a personal history of skin cancer, two or more first-degree relatives with melanoma, more than 100 nevi in total or 5+ atypical nevi, have received more than 250 treatments with PUVA for psoriasis, or received radiation therapy for cancer in childhood. The risk of skin cancer is more than 10 times higher in these individuals than in the general population. There are other factors associated with significant but lower relative risks (roughly 5 times the risk of the general population for multiple susceptibility factors), such as a first-degree relative with melanoma, many (50-100) nevi, one or more atypical (dysplastic) nevi, naturally red or blond hair, a tendency to freckle, or skin that burns easily and tans poorly or not at all. Because risk is assumed to be multiplicative, overall risk can be estimated from the products of the relative risk associated with each factor present in an individual. Those who have two or more of the high-risk traits have a higher than average risk of developing skin cancer. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms: they include epithelial neuroendocrine carcinomas originating in multiple sites throughout the body as well as tumours of modified neurons arising in sympathetic or parasympathetic ganglia and the adrenal medulla (1,2). The latter express tyrosine hydroxylase to synthesize dopamine and, therefore, readily take up 131 I-and 123 I-MIBG; however, the former express somatostatin receptors as a distinguishing feature and are amenable to ablation with radiolabeled somatostatin analogues (1,2). Although therapy with both MIBG and radiolabeled somatostatin analogues has been provided in Ontario, it has not been made broadly available: barriers to access have resulted in out-of-country requests. A systematic review was conducted to inform the recommendations for the selection of agents for therapy and to inform the development of criteria for access to radionuclide therapies for NET patients in Ontario. The details of the method and results of this systematic review are shown in Section 2. There are no randomized controlled trials (RCTs) examining the effectiveness of any of the peptide receptor radionuclide therapy (PRRT) agents or 131 I-MIBG in the treatment of neuroendocrine cancer patients. Trials have not been conducted to compare either PRRT or 131 I-MIBG with placebo, systemic therapy, tumour debulking treatment, or long-acting somatostatin analogues. Furthermore, no trials have been conducted to make direct comparisons between or among the eight agents reviewed. # RECOMMENDATIONS AND KEY EVIDENCE The Expert Panel and the Working Group offer the following recommendations based on the evidence reviewed: - PRRT appears to be an acceptable option in adult patients with neuroendocrine cancer who are inoperable, have residual disease following surgery or other ablative therapy, or have metastases. PRRT is relatively safe and well tolerated with renal protection using lysine and arginine amino acid solution, especially for 90 Y-DOTALAN and 177 Lu-DOTATATE. However, renal function must be monitored. - Treatment with PRRT in Ontario should be conducted as part of one or more RCTs, or in large comparative clinical trials if an RCT is not feasible, under the authority of a Clinical Trials Agreement, to clarify the further effects of PRRT (for example, comparing 177 Lu-DOTATATE with sunitinib in an RCT). - 131 I-MIBG may be effective for malignant neuroblastoma, paraganglioma, or pheochromocytoma, but there is insufficient evidence to suggest its efficacy for adult neuroendocrine carcinoma patients. However, the hematologic toxicity, severe infections, and secondary malignancies possible afterwards should be considered. # Qualifying Statements - There is limited evidence, based on a historical comparison of studies from a single centre (see Key Evidence below), that 177 Lu-DOTATATE may be associated with greater OS, PFS, and overall response rate (defined as the sum of complete response, partial response, and minor response rates) compared with 90 Y-DOTATOC or 111 In-DTPAOC. Therefore, 177 Lu-DOTATATE would be an appropriate agent to include in the future clinical trials described above. - Prior to the administration of therapy, the tumours from NET patients who are to receive PRRT or 131 I-MIBG should demonstrate a positive uptake of the related diagnostic agent. - A recommendation cannot be made for or against the use of PRRT in early-stage NET patients, as there is no relevant evidence. # Key Evidence Peptide Receptor Radionuclide Therapy - Fifteen prospective single-arm articles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) and one prospective comparative study (18) met the study selection criteria; of the nine published after 2005, all investigated the effects of 90 Y-DOTATOC, 90 Y-DOTATATE, or 177 Lu-DOTATATE (9-17). The total sample size was 1179. All the patient tumours showed a higher or the same uptake on octreoscan than on liver uptake before PRRT. All but one study (12) reported the overall response rate as determined by three different imaging criteria in a variety of stage III-IV NET subgroups. Across all agents, overall response rates ranged from 5% to 75% in various tumour subgroups, with wide 95% confidence intervals (CI) (See Figure 2 in Section 2). - Three studies were conducted in the same clinical centre to investigate the effects of 111 In-DTPAOC, 90 Y-DOTATOC, and 177 Lu-DOTATATE at different time periods (5,10,13). The median OS and PFS time was 37 and 14 months, respectively, for 90 Y-DOTATOC at five-year follow-up (10), and 46 and 33 months, respectively, for 177 Lu-DOTATATE at four years (14). The overall response rate was 18% (CI, 6% to 30%) for patients with progressive stage III-IV NET treated with 111 In-DTPAOC, 21% (CI, 11% to 31%) for patients with stage III-IV neuroendocrine gastroenteropancreatic tumours (GEP-NET) treated with 90 Y-DOTATOC, and 46% (CI, 40% to 52%) for patients with stage IV GEP-NET disease treated with 177 Lu-DOTATATE. - Eight of the 16 articles reported survival outcomes, with six reporting median OS times ranging from 15 to 46 months for various stage III-IV NET subgroups (10,11,13,(15)(16)(17). There was no significant difference in OS time between the intervention (14 patients treated with 111 In-DTPAOC and five patients treated with 131 I-MIBG) and control arm in the unique comparative trial (18). - Of the fifteen articles that reported on toxicity, 11 specified one of two criteria used for grading toxicity. Nausea and vomiting were common during therapy. The severe toxicities included the following: for 111 In-DTPAOC, 8% of patients developed myelodysplastic syndrome (MDS) and/or leukemia in one study (5); for 90 Y-DOTATOC, 0.9% to 3.4% of patients developed grade 4 renal toxicity in three studies (9-11), with 2% of patients developing MDS in one study (10); for 90 Y-DOTALAN, no severe toxicity was found in one study (6); for 90 Y-DOTATATE, 30% of patients developed grade 2 renal toxicity at two years in one study (16); and for 177 Lu-DOTATATE, 0.6% of patients developed hepatic insufficiency, 0.8% developed MDS, and 0.4% developed renal insufficiency in one study (13). For studies investigating the effects of 90 Y-DOTATOC, 90 Y-DOTATATE, and 177 Lu-DOTATATE, lysine and arginine amino acid solution was infused to protect kidney function. # I-MIBG Therapy - Six prospective single-arm, one retrospective comparative, and one retrospective singlearm study examining the effectiveness of 131 I-MIBG were eligible; the total sample size was 612. All the patients showed at least one lesion as positive on the 123 I-MIBG or 131 I-MIBG scintigraphy. The overall tumour response rate on imaging by various imaging criteria ranged from 32% to 75% for stage III-IV pediatric neuroblastoma patients with a median age of 2.0 to 6.6 years old (19)(20)(21)(22)(23) and was 26% for adult and stage III-IV NET patients (24) (including 22 neuroblastomas, 10 pheochromocytomas, three paragangliomas, six medullary thyroid carcinomas, and four carcinoids) and 27% for patients with stage IV paraganglioma or pheochromocytoma (25) (See Figure 3 in Section 2). - The Sywak et al study was the unique comparative study for comparing standard therapies alone with standard therapies plus 131 I-MIBG in stage IV patients with midgut carcinoid (26). The OS rate was 63% (CI, 47% to 75%) in the intervention group and 47% (CI, 34% to 59%) in the control group at five years, without statistical significance (p=0.10). - Of seven studies reporting on toxicity, three used different criteria, and four studies did not specify the criteria for toxicity grading. Hematologic toxicities were the main severe side effects. Forty-three percent of patients had bone marrow replacement (BMR), and one patient developed secondary leukemia in one study (19). Five percent of patients in one study (20) and 2% of patients in another study (22) developed leukemia or MDS. In a retrospective study, five (4%) three-to five-year-old neuroblastoma patients developed secondary malignancies after 131 I-MIBG therapy either as part of first-line therapy or as salvage therapy for resistant or recurrent disease: one acute nonlymphoblastic leukemia at one and a half years, one chronic myelomonocytic leukemia at four years, one malignant schwannoma at seven years, one rhabdomyosarcoma at 14 years, and one angiomatoid malignant fibrous histiocytoma at 10 years after 131 I-MIBG (21). In a fifth study, 39% of patients needed autologous BMR, and 9% of patients died ( 23) where 131 I-MIBG was utilized as the first-line treatment. Forty-one percent of patients had grade 2-3 hematologic toxicities in a sixth study (24). After an accumulative dose of at least 63.3 gigabecquerels (GBq) 131 I-MIBG therapy, 4% of patients who did not have prior radiation or chemotherapy developed MDS and acute myeloid leukemia at two and five years, respectively, in the seventh study (25). In addition, 4% of patients in that same study developed acute respiratory distress syndrome, 4% developed bronchiolitis obliterans organizing pneumonia, and 2% had a pulmonary embolism. # Treatment Alternatives An RCT has shown somatostatin analogs to be more effective than placebo in the control of tumour growth in patients with metastatic midgut NETs (27). Recently, investigators of two studies have reported positive results in the use of biologic agents for the treatment of malignant pancreatic NETs: one was the tyrosine kinase inhibitor sunitinib, and the other was the mTOR (mammalian target of rapamycin) inhibitor, everolimus (28,29). Both trials were phase III, multicentre, double-blind, randomized, placebo-controlled trials with sufficient numbers of patients to yield clear statistical results. Sunitinib, as compared with placebo, caused more than a doubling in PFS (11.4 versus 5.5 months, respectively, p<0.001). Everolimus caused a 65% reduction in the estimated risk of progression (PFS of 11.0 months for everolimus vs. 4.6 months for placebo, p<0.001). # FUTURE RESEARCH The recent publications that report positive results with the biological agents of sunitinib, everolimus, and octreotide long-active release (LAR), particularly with regard to PRRT, raise many important questions that could be the subject of further investigation. Should these drugs be used before, after, or in combination with PRRT? Can these drugs be used alone or in combination with PRRT as adjuvant or neoadjuvant therapy (with surgery)? For malignant NET patients with negative uptake on octreoscan or renal insufficiency and positive uptake on 123 I-MIBG scintigraphy, does 131 I-MIBG work well? Furthermore, the use of PRRT early in the treatment of NET patients (i.e., before maximal medical treatment) has not been explored and should be an option for further study in Ontario. The development of a standardized program for the assessment, treatment, and follow-up of NET patients in Ontario is essential to ensure the existence of an appropriate infrastructure for the evaluation of promising new therapies that would provide patients suffering from NETs with high-quality, evidence-based care. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Given the potential toxicities associated with alemtuzumab, and given the limited nature of the clinical trials testing its use in broad populations of patients with CLL, the use of alemtuzumab in patients with important co-morbidities may be associated with excessive risks. Currently, there are no published randomized controlled trials (RCTs) evaluating alemtuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory CLL. One RCT evaluated alemtuzumab administered to consolidate a complete or partial response to first-line fludarabine-containing chemotherapy in patients with CLL (1). The study was stopped early due to the occurrence of the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2.0 grade III/IV infection-related toxicity in seven of the first 11 patients randomized to the alemtuzumab arm. Patients in that arm had a significantly improved progression-free-survival (PFS) compared to observation (no progression versus a mean PFS of 24.7 months, p=0.036). Six single-arm studies evaluated disease response for alemtuzumab as a single agent in the treatment of patients with relapsed/refractory CLL post-fludarabine. The pooled overall response rate was 38% (complete response 6%, partial response 32%). Median time-to-progression was reported in three of those trials and ranged from four to 10 months. Seventeen studies evaluated the toxicities associated with alemtuzumab as a single agent for the treatment of relapsed/refractory CLL: o Mild infusion-related side effects (e.g., grade I/II fever, rigors, vomiting, rash, dyspnea, and hypotension) were observed in most patients treated with intravenous alemtuzumab. Severe reactions (grade III/IV) were observed in up to 20% of patients treated with intravenous alemtuzumab; subcutaneous administration was rarely associated with severe infusion-related toxicity. o Thrombocytopenia and neutropenia (grade III/IV) were each observed in approximately one third of patients. o Infections were common (46% overall), often severe (18% grade III/IV), and included opportunistic, systemic viral, and invasive fungal diseases, despite antimicrobial prophylaxis. Cytomegalovirus (CMV) reactivation was commonly reported but effectively managed with adequate surveillance and treatment (usually intravenous ganciclovir); invasive CMV disease was rarely reported. Death due to infection occurred in approximately 4-5% of patients. Alemtuzumab is being compared to chlorambucil for first-line treatment of newly diagnosed patients with CLL in a large, multicentre, phase III RCT (2). Alemtuzumab in combination with fludarabine is being compared to fludarabine alone for patients with relapsed CLL in a large, multicentre, phase III industry-sponsored study. Alemtuzumab continues to be investigated in phase II studies as consolidation therapy for both newly diagnosed patients (fludarabine/rituximab/alemtuzumab) and patients with relapsed/refractory CLL (Pentostatin/cyclophosphamide/rituximab/alemtuzumab).# Is alemtuzumab a beneficial treatment option, with respect to outcomes such as survival, response rate, response duration, time-to-progression, and quality of life, for patients with Bcell chronic lymphocytic leukemia (CLL)? 2. What toxicities are associated with the use of alemtuzumab? 3. Which patients are more likely, or less likely, to benefit from treatment with alemtuzumab? # Target Population This evidence summary applies to adult patients with CLL. - Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens. Qualifying Statements The evidence supporting treatment with alemtuzumab comes principally from case-series studies that evaluate disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and remain speculative at this time. Treatment with alemtuzumab is associated with significant and potentially serious adverse treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Is alemtuzumab a beneficial treatment option, with respect to outcomes such as survival, response rate, response duration, time-to-progression, and quality of life, for patients with B-cell chronic lymphocytic leukemia (CLL)? 2. What toxicities are associated with the use of alemtuzumab? 3. Which patients are more likely, or less likely, to benefit from treatment with alemtuzumab? # CHOICE OF TOPIC AND RATIONALE Chronic lymphocytic leukemia is the most common form of adult leukemia in the Western hemisphere, with an incidence rate of 4 out of 100,000; in patients over age 70, the incidence approaches 50 out of 100,000. Established diagnostic criteria allow CLL to be differentiated from related subtypes of indolent non-Hodgkin lymphomas (1). Patients requiring therapy are usually treated either with systemic alkylator-based chemotherapy or with a purine analogue (fludarabine). Unfortunately, CLL remains incurable with conventional chemotherapeutic approaches, and patients will relapse even after a favourable response to front-line therapy. Several randomized, controlled trials (RCTs) in patients with untreated, advanced stage CLL have documented superior response rates and response duration in patients randomized to fludarabine in comparison with alkylator-based chemotherapy (2)(3)(4). Despite those encouraging results, an improvement in overall survival has not been shown. Patients with disease refractory to standard chemotherapy have a particularly poor prognosis, and there is currently no accepted standard treatment. In order to improve outcomes for patients with CLL, new therapies and treatment approaches are needed. Monoclonal antibodies are an emerging class of drugs with a unique mechanism of action that represents a novel approach to cancer treatment; rituximab, a humanized anti-CD 20 monoclonal antibody, has proven to be particularly effective for patients with B-cell lymphomas. Alemtuzumab, a humanized anti-CD52 monoclonal antibody, was the first of this class of drugs to receive U.S. Food and Drug Administration (FDA) approval for the treatment of patients with CLL relapsed or refractory to fludarabine; it is currently under review for approval in Canada. Although the function of CD52 is not known, this antigen is expressed on a variety of hematopoietic cells, including normal and malignant T-and B-lymphocytes; CD52 is not expressed on hematopoietic stem cells. Once bound to CD52, alemtuzumab induces cell death by one or more of three mechanisms: (i) complementdependent cellular cytotoxicity (CDCC), (ii) antibody-dependent cellular cytotoxicity (ADCC), and (iii) induction of apoptosis. Clinical activity has been demonstrated in heavily pre-treated patients, including those with disease progression following treatment with fludarabine. However, the benefits of alemtuzumab are offset by potential toxicities, including infection-related morbidity and mortality. As licensing approval may precede the publication of phase III studies, the Hematology Disease Site Group (DSG) felt a systematic overview of the current literature was needed. This systematic review will inform further recommendations on this topic when updated with relevant, highquality evidence in the future. This systematic review was developed by Cancer Care Ontario's Program in Evidence-based Care (PEBC). Evidence was selected and reviewed by one member of the PEBC Hematology DSG and methodologists. This systematic review is a convenient and up-to-date source of the best available evidence on alemtuzumab in CLL. The body of evidence in this review is primarily comprised of mature RCT data, where available. This evidence is the basis for clinical recommendations developed by the Hematology DSG and presented in a practice guideline as part of this evidence-based series (Section 1). The systematic review and companion practice guideline are intended to promote evidencebased practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. # Literature Search Strategy A systematic search of the published literature identified all reports relating to the use of alemtuzumab for the treatment of patients with CLL. The MEDLINE (1966 databases were searched according to the strategy shown in Appendix A. In addition, abstracts from the American Society of Hematology (ASH) (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004) and the American Society of Clinical Oncology (ASCO) (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005) annual conference proceedings were searched. Our search strategy included only studies published in English. Publications evaluating alemtuzumab in non-human subjects and those that were categorized as "published comments," "letters," and "editorials" were excluded. The United Kingdom Coordinating Committee on Cancer Research (UKCCCCR) Register, Physician Data Query (PDQ), National Institute of Health (NIH) Clinical Trials, and the European Organization for Research and Treatment of Cancer (EORTC) databases were searched to identify ongoing clinical trials. The National Guidelines Clearinghouse was searched for clinical practice guidelines. The references for each selected article were also reviewed. Where it was deemed necessary, the authors of included publications were contacted to obtain missing or additional data. It should be noted that a preliminary literature search was performed in November 2002 and subsequently updated in November 2004 and July 2005. After the preliminary literature search, the study selection criteria were amended to exclude studies with fewer than 20 evaluable patients. As a result, studies in the preliminary literature search that had fewer than 20 evaluable patients were later removed from the report. The data from those small studies, had they been included, would not have significantly affected the results or the DSG recommendations. For the sake of clarity, results from the preliminary and updated searches for this systematic review are presented together. # Study Inclusion Criteria Articles were selected for inclusion in this systematic review if they met the following criteria: 1. Studies included patients with CLL. 2. Studies tested the role of alemtuzumab as either induction or consolidation therapy, and either as a single agent or in combination with other therapy. 3. Results were reported for any of the following outcomes: survival, quality of life, time-toprogression, response duration, response rate, or adverse effects. 4. Trials had a minimum sample size of 20 evaluable patients. Two independent observers reviewed the title and abstract of each citation. They were blinded to author name, institution, name of journal, nature of the paper (full paper or abstract), and results. The blinded observers scored each abstract as follows: "yes" if it met inclusion criteria, "no" if it did not meet inclusion criteria, or "maybe" if there was uncertainty. If both observers agreed that the abstract met the inclusion criteria, the complete document, if available, was retrieved for further analysis. In cases of disagreement, both observers reassessed the blinded abstracts together to achieve consensus. Where consensus could not be reached, or in cases where both observers gave a score of "maybe," the full document was retrieved and assessed by both reviewers to achieve consensus regarding eligibility. The reasons for excluding retrieved articles were documented. # Synthesizing the Evidence Due to a lack of adequately designed RCTs in our sample, a formal meta-analysis was deemed inappropriate. Where possible, response rates from single-arm studies evaluating similar patient groups were calculated. Data were pooled using intention-to-treat groups, and response proportions computed. # Literature Search Results A total of 527 citations were found with the original and updated searches; 40 citations met the inclusion criteria. Eighteen of the 40 citations were subsequently excluded from analysis for the following reasons: One publication was a duplicate, Three were anecdotal case reports (one report of severe immune thrombocytopenic purpura following a 10-week course of alemtuzumab, one report of gas gangrene six weeks after an eightweek course of alemtuzumab, and one report of a patient with CLL treated with three courses of alemtuzumab over a three-year period), One evaluated patients with Sezary syndrome, One evaluated non-clinical outcomes (T-cell subset recovery post-treatment with alemtuzumabthe clinical outcomes were reported in a separate publication that was included in this systematic review), and Eleven were abstracts subsequently published as full papers (all met the inclusion criteria for this systematic review). The 22 publications eligible for review (Table 1) are summarized below: Nine single-arm studies (four full papers, five abstracts) evaluated alemtuzumab as a single agent in patients with relapsed or refractory CLL. Three studies (two full papers, one abstract) evaluated alemtuzumab as a single agent in newly diagnosed patients with previously untreated CLL. One abstract publication reported only preliminary toxicity data from a RCT comparing alemtuzumab with chlorambucil as a first-line treatment of CLL. Three single-arm studies (two full papers, one abstract) evaluated alemtuzumab in combination with additional agents for patients with refractory CLL. Six studies (one full paper, five abstracts) evaluated alemtuzumab as consolidation therapy in CLL patients with a 'response' to previous-line therapy. One citation, published as a full paper, reported results from an RCT comparing alemtuzumab maintenance therapy to observation alone in patients with a response to first-line fludarabine. The trial was stopped early due to severe infection-related complications in patients randomized to the alemtuzumab arm. The remaining citations reported results from single-arm studies. One publication reported a pooled analysis for the risk of cytomegalovirus (CMV) reactivation, CMV pneumonia, and CMV-related deaths in patients with lymphoid malignancies treated with alemtuzumab. # Practice Guidelines for CLL Seven published practice guidelines on the management of CLL were retrieved. Two of those were excluded from our report because they were not published in English. The European Society for Medical Oncology (ESMO), the German CLL Study Group, and the Guidelines Working Group of the UK CLL Forum published separate guidelines for the diagnosis, staging, and treatment of patients with CLL that included reference to alemtuzumab therapy. One practice guideline was published specifically on the use of alemtuzumab in CLL by Keating et al. (2004). The ESMO guideline did not include a description of the methods used to develop its recommendations; did not provide response rates, response durations, or associated toxicities of the studies included; and did not indicate explicitly which studies informed which recommendations. The guideline published by German CLL group was described as a review article that stated it was a consensus document of the German CLL Study Group (with the membership listed). No description of the methods used to produce the guidelines were provided. Two studies on the outcomes of alemtuzumab therapy were cited as evidence for the German CLL group's recommendations, and were also retrieved in the literature search for our report (one was excluded because of our sample size criteria). The UK CLL Forum guideline described the methods used to develop their recommendations and indicated explicitly which studies informed which recommendations. Outcome data, including response rates, durations of response, and median survival rates observed in trials were reported. Nine single-arm studies of alemtuzumab in patients with CLL informed their guideline. Of those studies, six are included in our report, and three were excluded in our search strategy because they did not meet our minimum sample-size criteria. The practice guideline that addressed alemtuzumab use specifically indicated that it was developed out of an expert-opinion roundtable on the topic (held August 8-9, 2004). No description of methods are provided beyond that information. The Keating et al. guideline was informed by evidence from eight trials of alemtuzumab in CLL, all of which were included in our report. The recommendations of these practice guidelines, which concern alemtuzumab use in patients with CLL, are addressed in the discussion. Outcomes Question 1: Is alemtuzumab a beneficial treatment option, with respect to outcomes such as survival, response rate, response duration, time-to-progression, and quality of life, for patients with B-cell chronic lymphocytic leukemia? For this question, no studies reported quality-of-life outcome data. # (i) Single agent alemtuzumab for relapsed/refractory CLL Response Rates The overall response (RR), complete response (CR), and partial response (PR) rates associated with single-agent alemtuzumab for patients with relapsed or refractory CLL are summarized in Table 2 and include data from nine single-arm studies; there were no comparative or randomized studies available for analysis. Six trials each evaluated a standard 12-week course of alemtuzumab in patients with relapsed or refractory disease post-fludarabine therapy (5)(6)(7)(8)(9)(10). The combined RR rate across those six trials was 38% (range 31-41%); combined CR and PR rates were 6% (range 1-10%) and 32% (range 26-38%), respectively. One study (8) evaluated alemtuzumab administered subcutaneously and reported RR and CR rates similar to studies with intravenous administration; no trials directly compared subcutaneous with intravenous administration. Three studies administered alemtuzumab for longer than 12 weeks. A single-arm study by Moreton et al. (11) evaluated the treatment with alemtuzumab until a maximal clinical response was achieved in patients with relapsed or refractory disease post-fludarabine therapy. RR, CR, and PR rates of 54%, 35%, and 19%, respectively, were reported for 91 patients treated for a median of nine weeks (range 1-16 weeks). Peripheral blood and bone marrow samples were obtained from all patients before, during, and after alemtuzumab therapy to evaluate minimal residual disease (MRD) status. A highly sensitive and validated four-colour flow cytometry-based assay was used to define MRD status; the limit of detection for that assay was approximately one CLL cell in 104 to 105 leukocytes (12). Twenty percent of patients achieved an MRD-negative remission in the bone marrow and peripheral blood. However, those patients had a median treatment-free period, prior to initiating alemtuzumab, of 10 months (range 4-43 months), and most patients (72%) had no evidence of lymphadenopathy or splenomegaly prior to alemtuzumab treatment. No trials have directly compared different alemtuzumab regimens. The remaining two studies (13,14) administered therapy to 16 and 30 weeks, respectively, had smaller sample sizes (24 and 27 patients), and reported response rates similar to the other studies in that group. 1 Unless indicated otherwise, intervention was 30 mg Alemtuzumab administered intravenously three times per week for 12 weeks. 2 Evaluable patients are given in parenthesis, if less than total number of patients. 3 Only 3 patients received prior treatment (fludarabine). 4 Complete remission not reached in MRD-ve pts. Numbers are for MRD+ve patients with complete remission. 5 Regimen details not reported. 6 Alemtuzumab administered intravenously bi-weekly for 8 weeks + rituximab (375mg/m 2 administered weekly for 4 weeks. # Response Duration Data on median time-to-progression (TTP) were reported in five single-arm studies evaluating alemtuzumab in patients with disease that had relapsed after or was refractory to fludarabine (Table 2) (5,6,8,11,13). Fludarabine-refractory disease was usually defined as either no response to fludarabine or relapse within six months following a response to fludarabine. The median TTP ranged from four to 10 months. Moreton et al. ( 11) compared the median treatment-free-survival (TFS) according to the response to alemtuzumab (MRD-negative CR, MRD-positive CR, PR, or non-responders). Patients achieving MRD-negative CR had a significantly prolonged TFS compared to MRD-positive CR, PR, or non-responders (median TFS not reached, 20 months, 13 months, and six months, respectively, p<0.0001). The median TFS for the entire cohort was not reported. Survival data were reported in 4 single-arm studies evaluating alemtuzumab in patients with relapsed or refractory disease post-fludarabine (Table 2) (5,6,8,13). Median overall survival (OS) ranged from 8 months to more than 2 years. Moreton et al. ( 11) compared OS according to response to alemtuzumab. Patients achieving MRD-negative CR had a significantly prolonged OS compared to MRD-positive CR, PR, or nonresponders (median OS not reached, 60 months, 70 months, and 15 months respectively, p<0.0007). Median OS for the entire cohort was not reported. # (ii) Single-agent alemtuzumab for previously untreated CLL Response Rates Two studies investigated the RR, CR, and PR rates associated with a trial of single-agent alemtuzumab for patients with previously untreated CLL (15,16). Lundin et al. (15) reported an RR rate of 87% for 38 evaluable patients treated with subcutaneous alemtuzumab for 18 weeks; the CR and PR rates were 19% and 68%, respectively. Most patients were at the advanced disease stage (69% Rai III/IV). # Response Duration In the trial by Lundin et al. (15), median time-to-treatment-failure (TTF) had not been reached at 18 months. In an update of that trial, reported in abstract form, median TTF in responders had not been reached at 35 months (16). No other trials reported data pertaining to response duration. No studies reported OS rates associated with alemtuzumab therapy for previously untreated patients with CLL. # (iii) Alemtuzumab in combination with additional agents for relapsed/refractory CLL Response Rates Three single-arm studies evaluated alemtuzumab-containing combination regimens for the treatment of relapsed or refractory CLL (Table 2) (17)(18)(19). No trials directly compared different combination regimens. One trial (19) evaluated alemtuzumab in combination with fludarabine. Elter et al. (19) reported an RR rate of 83% for 36 evaluable patients; the CR and PR rates were 31% and 53%, respectively. Faderl et al. (17) reported a 63% RR rate (6% CR, 57% PR) for 32 patients treated with alemtuzumab in combination with rituximab. Wierda et al. (18) evaluated a regimen consisting of cyclophosphamide, fludarabine, alemtuzumab, and rituximab administered over six 28-day cycles; the overall response rate was 52% (14% CR, 38% PR). # Response Duration Elter et al. (19) reported a median TTP of 13.0 months for the entire patient cohort; for patients who achieved a CR, median TTP was 21.9 months. No other studies reported data for response duration associated with alemtuzumab-containing combination regimens for patients with relapsed/refractory CLL. Elter et al. (19) reported a median OS of 35.6 months; for patients who achieved CR, median OS was not reached. No other studies reported survival data. # (iv) Alemtuzumab consolidation for patients with a response to previous-line therapy Response Rates One RCT ( 20) and four single-arm studies (32,33,35,37) reported response rates for alemtuzumab consolidation therapy; results are summarized in Table 3. The German CLL Study Group (Wendtner et al.) published results from an open-label, multicentre, randomized phase III trial comparing 12 weeks of alemtuzumab consolidation with observation in patients achieving at least a PR following six cycles of first-line fludarabine-containing chemotherapy (20). The study's sample size of 90 patients was designed to have an 80% statistical power to detect a 25% improvement in progression-free survival (PFS) at two years. The trial was stopped after the accrual of 21 patients due to the occurrence of the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2.0 grade III/IV infections in seven of the first 11 patients randomized to alemtuzumab consolidation. Two of eleven patients (18%) randomized to alemtuzumab consolidation improved upon their response to first-line therapy; both patients achieved a PR following first-line fludarabine-containing chemotherapy and improved to CR following consolidation with alemtuzumab. The four single-arm studies evaluating alemtuzumab-consolidation therapy were reported in abstract form only (21)(22)(23)(24). All studies evaluated a four-to eight-week course of alemtuzumab in patients who had stable disease (SD) or better following first-or second-line chemotherapy. Response to alemtuzumab consolidation was generally defined as an improvement in 'post-induction' response status according to National Cancer Institute-Working Group (NCI-WG) criteria. Overall, response status improved following alemtuzumab consolidation. Two studies (21,23) documented an MRD-negative remission status in 38% to 51% of patients, based on clonality of the IgH gene rearrangement by polymerase chain reaction (PCR) analysis of peripheral blood and/or bone marrow samples. Note: a = abstract; A = alemtuzumab; C = cyclophosphamide; chemo = chemotherapy; CR = complete remission; fl = first-line; mc = monoclonal; med = median; mo = median months; n = near; N = number; nr = no response; NR = not reported; OS = overall survival; pc = polyclonal; PR = partial remission; PR+ = partial remission or better; ref = reference; resp = response to; RR = response rate; SD+ = stable disease or better; TTP = time-to-progression; vs. = versus, w = with; wks = weeks. # Response Duration Two studies reported data for response duration associated with alemtuzumab consolidation following a response to first-or second-line chemotherapy (20,23). In the RCT published by the German CLL Study Group (20), no progression occurred in the 11 patients randomized to alemtuzumab consolidation compared with a 24.7 months mean PFS in the 10 patients randomized to observation (p=0.036). O'Brien et al. (23) reported a median TTP of greater than 24 months in patients who demonstrated a response to alemtuzumab consolidation. Survival data associated with the use of alemtuzumab-consolidation therapy were reported in the RCT published by the German CLL Study Group (20); median OS had not been reached in either the alemtuzumab arm or the observation arm. No other studies reported survival data. # Question 2: What toxicities are associated with the use of alemtuzumab? Toxicities associated with the administration of alemtuzumab were reported in most studies (Table 4). The most common adverse events can be broadly grouped into: (i) infusion-related side effects, (ii) myelosuppression, and (iii) infection-related toxicities. # (i) Infusion-related side effects Infusion-related side effects were reported in 17 studies (5)(6)(7)9,11,13,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). They occurred in most patients treated with intravenous alemtuzumab, were usually grade I/II in severity, and were manageable with appropriate supportive care. The prophylactic use of pre-medications was reported in about one third of the studies and usually consisted of orally administered acetaminophen and antihistamines; corticosteroids were generally reserved for more severe reactions. Grade III/IV fever, rigor, and nausea were reported in up to 20% of patients, while other serious infusion-related toxicities were less common. The incidence of infusion-related side effects was similar regardless of the population evaluated, tended to be higher and more severe with the first infusion, and improved with subsequent courses of treatment. The subcutaneous administration of alemtuzumab was reported in three trials (8,15,21) and was generally much better tolerated compared to similar patients treated intravenously (Table 4). Grade I/II fever (68%) and local injection site reactions (88%) were reported; grade III/IV reactions of any kind were rarely reported (≥ 2% of patients) (15). # (ii) Myelosuppression Data regarding myelosuppression associated with the use of alemtuzumab were reported in 10 trials (6)(7)(8)(9)11,13,15,(18)(19)(20). Results for studies evaluating different disease populations were analyzed separately. Grade III/IV myelosuppression was common in studies evaluating alemtuzumab monotherapy for patients with relapsed/refractory disease (6-9,11,13); the pooled estimates (range) for grade III/IV neutropenia, thrombocytopenia, and anemia were 39% (22-66%), 31% (23-46%), and 8% (0-28%), respectively. Similar rates of grade III/IV myelosuppression were reported for studies evaluating alemtuzumab in combination and maintenance/consolidation regimens. Data regarding the coadministration of hematopoietic growth factors were not well reported. # (iii) Infection-related toxicity Data regarding the incidence of infections in patients treated with alemtuzumab were reported in 21 publications (5)(6)(7)(8)(9)(10)(11)(13)(14)(15)(16)(17)(18)(19)(20)(22)(23)(24)(25)(26)(27). In 13 studies, antimicrobial prophylaxis was administered during alemtuzumab therapy; cotrimoxazole in combination with antiviral therapy (acyclovir, valacyclovir, famciclovir), for the prevention of pneumocystis carinii pneumonia (PCP) and herpes virus infections, respectively, were most frequently cited. For this systematic review, data relating to infection-related toxicity were analyzed and reported separately for different study populations. # (a) Single agent alemtuzumab for relapsed/refractory CLL Data pertaining to infection-related morbidity in that patient population were reported in eight studies (5)(6)(7)(8)(9)11,13,14). The per capita incidence of all infections ranged from 30 to 93 per 100 patients (46 per 100 patients across studies). The incidence of Grade III/IV infections was 7 to 36 per 100 patients (18 per 100 across), and infection-related mortality ranged from 0 to 10 per 100 patients (4.5 per 100 across). Grade III/IV infections included disseminated viral infections (e.g., Varicella zoster virus and herpes simplex virus, systemic candidal infections, mycobacterial reactivation, and invasive fungal infections (e.g., pulmonary aspergillosis, rhinocerebral mucormycosis, and cryptococcal meningitis/pneumonia). PCP was reported but generally occurred in patients not receiving prophylaxis. The incidence of CMV reactivation was reported in seven of the above-mentioned trials (5-8,10,11,14) and ranged from 1% to 29% (9% across); CMV pneumonitis was reported in four patients (0.8% across). The actual risk of CMV reactivation in that patient population was not clear because most studies did not prospectively screen all patients. Williams et al. (27) retrospectively reported pooled safety data-3.6% of patients experienced 'symptomatic' CMV reactivation, CMV pneumonitis (0.8%), and CMV related-deaths (0.2%) in 1,538 patients with lymphoid malignancies treated with alemtuzumab in five single-arm trials-the routine screening of all patients for CMV reactivation was not performed in those studies. Patients who developed CMV reactivation were usually treated with intravenous ganciclovir until evidence of viremia resolved. Ganciclovir therapy was highly effective for treating CMV reactivation, but, because ganciclovir-induced neutropenia was common, treatment with myeloid growth factors (G-CSF) was often co-administered. Rates of adverse events ranged from 11 to 82% in those studies. Overall, alemtuzumab therapy was prematurely discontinued in approximately 20% of patients due to an adverse event, most often due to infection-related complications and/or myelosuppression. # (b) Single-agent alemtuzumab for previously untreated CLL In an RCT comparing alemtuzumab to chlorambucil for newly diagnosed patients with CLL, Hillmen et al. (25) reported a CMV-reactivation rate of 15% for all patients randomized to receive alemtuzumab. All patients with detectable CMV reactivation were treated with ganciclovir; no cases of CMV pneumonitis occurred. Other infection-related toxicities have not yet been reported. Lundin et al. (15) reported CMV reactivation in four (11%) patients treated with subcutaneous alemtuzumab. One case of PCP occurred in a patient not receiving prophylaxis. An update describing the long-term follow-up for that patient cohort documented one episode of symptomatic Epstein-Barr virus (EBV infection 21 months post-alemtuzumab therapy (16). No other serious infections occurred. # (c) Alemtuzumab in combination with additional agents for relapsed/refractory CLL Faderl et al. (17) documented infections in 52% of patients with lymphoid malignancies treated with alemtuzumab in combination with rituximab; CMV reactivation occurred in 27%. Infections in CLL patients were not reported separately. Elter (19) reported data on 36 patients treated with alemtuzumab in combination with fludarabine; fungal pneumonia (n=2), CMV reactivation (n=2), and one infection-related death (E. coli sepsis) were the only reported infection-related complications. Wierda et al. (18) reported CMV reactivation in 24% of patients (n=21) treated with alemtuzumab in combination with cyclophosphamide, rituximab, and fludarabine. # (d) Alemtuzumab consolidation for patients with a response to previous-line therapy Wendtner et al. randomized patients with a response to first-line fludarabine containing chemotherapy to consolidation with alemtuzumab (30mg intravenously three times per week for 12 weeks) or observation (20). Explicit stopping rules were determined a priori and included grade III/IV infections occurring in five of the first 10 patients accrued to the alemtuzumab arm. The study was stopped early due to severe infections in seven of 11 patients randomized to alemtuzumab consolidation. Grade III/IV infections included CMV reactivation (n=2), CMV pneumonitis (n=2), pulmonary aspergillosis and HSV/human herpes virus (HHV)-6 (n=1), pulmonary tuberculosis (n=1), and herpes zoster reactivation (n=1). An additional two patients developed grade II CMV reactivation. Overall, nine of 11 patients (82%) randomized to alemtuzumab consolidation discontinued therapy due to an adverse event (severe infection in five patients and severe myelosuppression in four patients). Four additional single-arm studies reported infection-related toxicity for alemtuzumab consolidation therapy (22)(23)(24)26). CMV reactivation was common, occurring in 21-57% of patients; the one reported case of CMV pneumonitis (22) contributed to patient death. The studies evaluated either 10mg or 30mg doses of alemtuzumab administered over six to eight weeks; there was no apparent difference in the rate or severity of infections according to treatment regimen. # Question 3: Which patients are more likely, or less likely, to benefit from treatment with alemtuzumab? Statistical evaluations for independent predictors of response, response duration, or survival were not reported in any study included in this systematic review. However, several publications reported subgroup analyses and clinical observations for patients who were more or less likely to respond to alemtuzumab. Several authors noted that patients with lymphadenopathy, particularly bulky lymph nodes (> 5cm), were less likely to achieve a clinical response to alemtuzumab-containing therapy (5,9,11,13,15,20,23). Keating et al. (5) reported that patients less likely to respond included those with Rai stage IV disease, at least one lymph node greater than 5cm in diameter, or a World Health Organization (WHO) performance status of two. Moreton et al. (11) evaluated alemtuzumab monotherapy administered to maximal response in patients relapsed or refractory to fludarabine and reported that patients were significantly less likely to respond if they had lymph nodes larger than 5cm (p<0.0001), had received three or more previous lines of therapy (p=0.0005), or had a pre-treatment WHO performance status greater than one. The RCT published by the German CLL study group (20) failed to find a correlation between response status and age, disease stage, response to previous-line fludarabine-containing chemotherapy, cumulative alemtuzumab dose, duration of alemtuzumab therapy, IgH mutational status, or cytogenetic aberrations; however, the analysis was limited to only 11 patients, because the trial was stopped early due to excessive severe infections in the alemtuzumab-consolidation arm. In its deliberations, the Hematology DSG places particular emphasis on the following: (a) results from published RCTs (where available), (b) the recognition of a hierarchy of outcomes that should influence treatment decisions, with priority given to therapies found to extend life or improve quality of life, and (c) the potential toxicities associated with treatment, with particular emphasis on those toxicities seen in the patients most likely to make up the eventual population treated. The members of the Hematology DSG had considerable difficulty reaching consensus on the appropriate wording of the recommendation for a potential indication for alemtuzumab in patients with CLL; the recommendation went through multiple iterations (see section 3, Guideline Development and External Review-Methods and Results). Based on their review of the evidence provided in this systematic review, the DSG considered several interpretations for the use of alemtuzumab in patients with CLL. The DSG regards alemtuzumab as an active agent for the treatment of patients with relapsed or chemotherapy-refractory CLL. This conclusion is based on response data from single-arm studies that report partial responses in approximately one third of patients and recognizes that complete remissions are uncommon. From a perspective of drug and/or multi-agent regimen development, these data are extremely promising and warrant further testing of alemtuzumab. In their deliberations, the DSG cited the following factors leading to the above recommendation: (a) a lack of data from properly designed RCTs, (b) a paucity of comparative data suggesting improved response duration, quality of life, or improved overall survival compared with alternative treatment approaches, and (c) significant potential toxicity, particularly infection-related morbidity and mortality. Given the anticipated toxicity, data from RCTs demonstrating improvement in clinically meaningful outcome measures (e.g., time-to-progression, quality of life, or overall survival) are required before recommendations permitting the routine use of alemtuzumab in this patient population can be made. The practice guidelines published by ESMO ( 28) and the UK CLL Forum ( 29) made recommendations regarding the use of alemtuzumab in previously treated patients. The ESMO guideline recommended alemtuzumab as an option for patients with refractory disease following firstline therapy, based on the lowest level evidence (ASCO level V evidence: small case-series). In addition, the UK CLL Forum guideline recommended alemtuzumab for use in patients without bulky lymphadenopathy (<5cm), who were previously treated with alkylating agents and refractory to fludarabine. The evidence informing the UK CLL Forum recommendation was similar to the evidence contained in this report and was comprised of data from a smaller selection of single-arm studies. The German CLL Study Group determined that definitive recommendations could not be made regarding alemtuzumab use and indicated that further testing in clinical trials would be preferred (30). The Keating et al. guideline (31) did not make explicit recommendations regarding the appropriateness of alemtuzumab use in CLL patients, but implied that alemtuzumab is appropriate in fludarabinerefractory patients. Keating et al. also stated that advanced age should not be a contraindication for alemtuzumab use. The DSG considered the above recommendations to be based on low levels of evidence and, initially, was not convinced that these recommendations would inform the basis of a best clinical practice. Instead, the DSG initially concluded that potential benefits (response rates in a minority of patients, uncertain benefit in terms of response duration, overall survival, and quality of life) were offset by the potential for significant toxicity. Therefore, an initial recommendation was developed to indicate that there were insufficient data to support the routine use of alemtuzumab in patients with CLL. The DSG acknowledged the potential controversy that could result from issuing a "nonpermissive" recommendation regarding alemtuzumab use and the potential implications such a recommendation might have for drug availability. The DSG was aware that its recommendations differed from those of other existing practice recommendations, including those published by ESMO and the UK CLL Forum. The DSG was also aware that within the response data described from the literature reviewed were responses of a magnitude that reporting authors, and members of the DSG, considered to be clinically important. While the precise frequency of these responses were uncertain, and the best estimate was that they would be infrequent, the DSG acknowledged that an opportunity for such a response, even with substantial risks of toxicity, may be highly desired by some patients. The DSG attempted to reflect this sentiment by indicating that, after balancing the benefits and risks of treatment, certain patients may wish to consider a trial of therapy. While the DSG had concerns with issuing an unclear and potentially conflicting set of recommendations, it initially considered this option to represent the best available alternative and offered the following guidance: For patients with CLL, there is insufficient evidence to recommend the use of alemtuzumab outside of clinical trials. The DSG recognizes that, in highly selected cases, after thorough consideration of the risks and benefits, a trial of alemtuzumab might be considered. Section 3 details the subsequent Practitioner Feedback and notes that responding clinicians were generally in agreement with the synthesis and interpretation of the available literature and the resulting recommendation. However, a small number of respondents commented on the lack of clarity associated with the recommendations. As a result, the DSG continued its consensus process in an effort to develop a clearer statement and issued a new set of recommendations. The redeveloped recommendation states, "Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens." In order to account for the continued concern about the level of evidence supporting this recommendation and the potential adverse risk-benefit profiles of this therapy, a detailed set of Qualifying Statements were also developed. # ONGOING TRIALS The NCI, UKCCCCR, PDQ, NIH Clinical Trials, and EORTC databases were searched for any ongoing clinical trials. Alemtuzumab in combination with fludarabine is being compared with fludarabine alone for patients with relapsed CLL in one large, multicentre, phase III industrysponsored study. Alemtuzumab continues to be investigated in phase II studies as consolidation therapy for both newly diagnosed patients (fludarabine/rituximab/alemtuzumab) and patients with relapsed/refractory CLL (Pentostatin/cyclophosphamide/rituximab/alemtuzumab). Alemtuzumab is also being compared with chlorambucil in a large, multicentre RCT of the first-line treatment of newly diagnosed patients with CLL (25). Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens. The evidence supporting treatment with alemtuzumab comes principally from case-series studies that evaluate disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and remain speculative at this time. Treatment with alemtuzumab is associated with significant and potentially serious adverse treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Given the potential toxicities associated with alemtuzumab, and given the limited nature of the clinical trials testing its use in broad populations of patients with CLL, the use of alemtuzumab in patients with important co-morbidities may be associated with excessive risks. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# QUESTIONS Overall Question In patients presenting to primary care services with signs and/or symptoms of lung cancer, what should the referral process include? The following questions are the factors considered in answering the overall question: # TARGET POPULATION Patients presenting in primary care settings comprise the target population. This guideline does not provide recommendations for patients in a screening program. # INTENDED USERS This guideline is targeted to family physicians (FPs), general practitioners, emergency room physicians, other primary care providers (PCPs) (nurse practitioners, registered nurses, and physician assistants), respirologists, thoracic surgeons, and radiologists. For the purposes of this document, we have referred to FPs, general practitioners, emergency room physicians, and other PCPs as 'FPs and other PCPs. The guidelines are also intended for policymakers to help ensure that resources are in place so that target wait times are achieved. They are also intended to help guide referrals to Diagnostic Assessment Programs (DAPS) in Ontario. DAPs provide a single point of referral, coordination of care using a clinical navigator, fast tracking of diagnostic tests and a multidisciplinary team approach. They are an Ontario-wide strategic priority designed to improve patient access and outcomes, and are outlined in the Ontario Cancer Plan since 2005-2011 and 2011-2014 (1). Added in February 2021: Formal Cancer Care Ontario DAPs no longer exist in Ontario, but many hospitals provide ongoing multidisciplinary team approaches to diagnosing colorectal cancer. The following recommendations were adapted from the New Zealand Guidelines Group (NZGG) guideline Suspected cancer in primary care: guidelines for investigation, referral and reducing ethnic disparities and the National Institute for Health and Clinical Excellence (NICE 2005), Referral guidelines for suspected cancer (2,3). The recommendations below reflect the 2019 endorsement by the PEBC Lung Cancer Referral Expert Panel, the integration of the NZGG 2009 and NICE 2005 recommendations, and the updated systematic review of the research evidence of those guidelines and consensus by the PEBC Lung Cancer Referral Working Group (see Section 2: Appendix 1) (2,3). Modifications made in 2019 to the content of this recommendations section are shown in highlighted text. # Special consideration for these recommendations: Factors that Increase the Risk of Lung Cancer The following factors have been shown to increase the risk of lung cancer and will be referred to in the recommendations below: - Tobacco exposure by means of: current or previous smoking of tobacco using cigarettes, vaping, cigars, dry pipe or water pipe (bong); second hand exposure to tobacco smoke - Previous exposure to asbestos or other known carcinogens (e.g., radon, chromium, nickel) - Occupational exposure to dust or microscopic particles (e.g., wood dust, silica, diesel engine emissions, or chlorinated solvents) - Personal or family history of cancer (especially lung, head and neck cancer) - Lung Diseases (chronic obstructive pulmonary disease, asthma, pulmonary fibrosis) - Infections (tuberculosis, HPV 16/18 of the respiratory tract, previous pneumonia, HIV) - Occupations (miners, painters, iron and steel workers, bricklayers, welders) - Environmental (in-home burning of coal and/or biomass, unventilated cooking over high heat, air pollution, low socioeconomic status, high caffeine intake) - Other underlying health issues (lupus, rheumatoid arthritis, systemic sclerosis , diabetes, periodontal disease, increased abdominal obesity, dyslipidemia) Indications for Referral to the Emergency Department A person should be referred to the Emergency Department for the following: - Stridor - Massive hemoptysis - New neurological signs suggestive of brain metastases or cord compression Indications for Urgent Chest CT and/or Urgent Referral to DAP or Thoracic Surgeon A person should be referred if presenting with any of the following: - Persistent non-massive hemoptysis (Multiple episodes of coughing blood or bloodstreaked sputum) - Superior vena cava syndrome/obstruction The ordering physician (i.e., FP or other PCPs, specialist, radiologist, or clinicians in the DAP) will depend on locally available resources and processes for expedited CT scans. Indications for Chest X-ray A person should have a chest X-ray within two working days if they present with any of the following: - The requisition for a chest X-ray should include the presenting history, including signs and symptoms suspicious of lung cancer and whether risk factors exist. Chest X-rays should be completed, reviewed, and reported by the radiologist, and the report received by the FP or other PCPs within one week of being ordered. If the chest Xray is suspicious for lung cancer, this must be clearly noted on the X-ray report. Radiologists should consider using two or more mechanisms to directly inform the FP or other PCPs of the suspicion of lung cancer. (e.g., fax, flagging, telephone call, email) Indications for Chest CT scan A person should have a chest CT scan within two weeks if they have any of the following: - An abnormal chest X-ray that reports suspicion of lung cancer - A normal chest X-ray, but there is a high suspicion of lung cancer, based on clinical judgement The ordering physician (i.e., FP or other PCPs, specialist, radiologist, or clinicians in the DAP) will depend on locally available resources and processes for expedited CT scans. # Sputum Cytology Sputum cytology is not recommended for the investigation of suspected lung cancer. # Follow-up to diagnostic investigations A person who has consolidation or unexplained pleural effusion on an initial chest X-ray should be treated and have a chest X-ray repeated within four weeks to confirm complete resolution. Indications for Referral to a Specialist (Respirologist or Thoracic Surgeon) or DAP Patients should be referred and expect a consultation to a specialist or where locally available to a DAP within one to two weeks if they have any of the following: - Persistent hemoptysis If promptly accessible, a chest CT scan can be simultaneously ordered with the referral while waiting for the DAP or the specialist's consultation. This will depend on locally available resources. If the CT scan is entirely negative, then further referral to a DAP or specialist may no longer be required. - A chest X- To expedite the diagnosis and avoid duplication of investigations, at a minimum, the following information should be provided to the specialist: - History of the patient, including all risk factors and signs or symptoms suspicious of lung cancer - All efforts should be made to provide all pre-existing imaging results, including chest X-rays and CT scans (films and digital images should be available at the time of consultation) - All relevant other medical conditions and medications taken by patient - All recent blood work Recommendations to Reduce Diagnostic Delay There should be appropriate educational tools developed and disseminated that highlight the signs and symptoms of lung cancer for FPs and other PCPs and for patients. FPs and other PCPs should have a high index of suspicion with a low threshold for investigation of suspected lung cancer in ordering chest x-rays and referral to lung cancer specialists or the DAP. Decision support tools should be readily available to assist FPs and other PCPs. FPs and other PCPs should include as much information as possible in their referral letters and should ask patients to help retrieve electronic copies of their imaging tests to bring to specialist appointments. # Counselling of patients should occur to address common fears and concerns. Public health and other health agencies should work with local community leaders to address challenges, such as lower levels of education or demographic discrepancies in communities with high rates of lung cancer or known delays in lung cancer diagnosis. There is a lack of awareness of changing epidemiology; with increasing numbers of young people and lifelong non-smokers being diagnosed with lung cancer. Therefore, a young age (<40 years) or being a lifelong non-smoker should not preclude investigation or referral if there is high suspicion of lung cancer, based on clinical judgement. # KEY EVIDENCE - Many of these recommendations were adapted or endorsed from the NZGG 2009 or NICE 2005 recommendations (2,3). Signs and symptoms listed in the NZGG 2009 or NICE 2005 recommendations were derived from their systematic reviews, which mainly included case-series studies (2,3). The development of the recommendations in this guideline can be found in Section 3 of this report. - There was no evidence found on wait times and their effects on patient outcomes. One study found that wait times to referral for specialist consultation for patients with signs or symptoms suspicious for lung cancer can be reduced from 20 days to six days with the implementation of a DAP (4). For this guideline, the wait times for diagnostic investigations and referral developed by the Lung Cancer Referral Working Group were chosen because they considered them to be achievable targets in the Ontario health care system, especially with the introduction of DAPs across the province. - The list of risk factors was broadened to include all risk factors summarized by NZGG 2009 based on the review by NICE 2005 (2,3). # Indications for Referral to Emergency Department - This recommendation was adapted from the NICE 2005 guidelines for immediate referral. New neurological signs suggestive of brain metastases or cord compression were included based on common practice in Ontario and massive hemoptysis was included based on the Time-to-Treat Program (4). # Indications for Chest X-ray - This recommendation was adapted from the NZGG 2009 guidelines for urgent referral for a chest X-ray (3). Based on expert opinion, it was felt that, for new finger clubbing, features suggestive of lung cancer that has metastasized elsewhere or other cancers that have metastasized to the lung, and suspicious lymphadenopathy, the three-week time frame was not required for referral for a chest X-ray. The Working Group chose to include dysphagia as an indicator for a chest X-ray, because it was reported in the NICE 2005 review as a symptom of lung cancer and was found to be a major clinical symptom among lung cancer patients in a tertiary care setting (2,5). Furthermore, paraneoplastic syndromes were included as indications for chest X-ray based on the review by Spiro et al (2007) that reported that paraneoplastic syndromes may occur in 10% of patients with lung cancer (6). - For patients with underlying chronic respiratory problems, the Working Group chose to adapt the recommendation from NICE 2005 (2). # Indications for CT Scan - There was little evidence to inform these recommendations; therefore, the Working Group decided to develop their own recommendations based on experiences within their own practices. # Sputum Cytology - The updated literature search found high specificity but variable sensitivity of sputum cytology in detecting lung cancer (7)(8)(9)(10)(11). Therefore, this recommendation was endorsed from the NZGG 2009 referral guidelines (3). # Follow-up to Diagnostic Investigations - The recommendation for follow-up to consolidation on a chest X-ray was adapted from the NZGG 2009 referral guideline, which was based on the experience of their guideline development team (3). The Working Group chose to modify the NZGG's 2009 recommendation by including all patients rather than specifying only patients with risk factors for lung cancer. In addition to consolidation, the Working Group also included unexplained pleural effusion based on their experience in their practices. Indications for Referral to a Specialist (Respirologist or Thoracic Surgeon) or the DAP - These recommendations were adapted from the NZGG 2009 and NICE 2005 referral guidelines, which were based on expert opinion (2,3). Additional abnormal chest X-ray results were included from the Time-to-Treat Program (4). Unexplained elevated diaphragm was included based on the suggestion of an expert panel member. # Recommendations to Reduce Diagnostic Delay - There is evidence to suggest that the following may delay the diagnosis of lung cancer (2,3,5,12,13): § Patient-Related Delay: -patient's lack of appreciation regarding the association of symptoms with lung cancer fear of cancer diagnosis § Family Physician related delay: -not recognizing signs and symptoms suggestive of lung cancer co-morbidity of conditions increased delay multiple consecutive investigations in primary care over-reliance on chest X-ray results to diagnose lung cancer imaging follow-up failure initial referral to a non-respiratory physician - The process used to develop this algorithm can be found in Section 3. # FUTURE RESEARCH Further studies could be designed to investigate the diagnostic performance of signs, symptoms, or tests for lung cancer in the primary care setting. In addition, studies are needed to determine which educational initiatives would be best at decreasing practitioner-or patientrelated delay. # Diagnostic Assessment Programs Diagnostic Assessment Programs, provide a single point of referral, coordination of care using a clerical navigator, fast tracking of diagnostic tests and a multidisciplinary team approach, thereby improving the quality of care and the patient experience. They are an Ontario-wide strategic priority designed to improve patient access and outcomes and outlined in the Ontario Cancer Plan since 2005-2011 and 2011-2014 (1). Abnormal Chest Signs e.g., crackles or wheezes Abnormal Chest X-ray that Reports Suspicion of Lung Cancer e.g., nodule(s), infiltrates, non-resolving consolidation or effusion despite treatment Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Although the incidence and mortality of gastric cancer has been steadily decreasing in Canadian men and women, this disease remains a global health problem, accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide (1). In Canada, the annual percent change in age-standardized incidence between 1996 and 2005 is -2.3% and -1.9% in males and females, respectively. The corresponding numbers for the change in agestandardized mortality between 1995 and 2004 is -3.6% and -3.1% for males and females, respectively (2). In Ontario in 2009, there will be an estimated 1090 new incident cases of stomach cancer (38% of new incident stomach cancer cases in Canada) and 670 deaths from stomach cancer (36% of stomach cancer deaths in Canada). The five-year relative survival ratio is 23% (95%CI: 21-24%) for males and females combined (2). However, the 5-year survival rate is much higher (about 75%) for patients with localized disease without regional lymph node involvement in whom the cancer is managed with surgery alone (3). Because the prognosis worsens with progressive lymph node involvement, there is interest in finding ways to improve the treatment results for this group of patients. Although many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer, these studies have produced conflicting results (4)(5)(6), making the role of neoadjuvant and adjuvant therapy controversial. Results of gastric cancer treatment have tended to be better for studies carried out in Asian countries, possibly because of etiologic or biologic differences in the disease or different practices such as screening for early stage cancer, the use of extended lymph node dissection, and the commencement of chemotherapy immediately after surgery. This guideline is an update of Evidence-based Series (EBS) #2-14, which was originally developed in 2000 and then updated in 2003. The Gastrointestinal DSG believed that this further update was warranted, given the existence of new evidence published that could change the recommendations provided in the previous guideline. The EBS guidelines developed by Cancer Care Ontario's Program in Evidence-Based Care (PEBC) use the methods of the Practice Guidelines Development Cycle (7). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by one member of the PEBC Gastrointestinal DSG and a methodologist. The systematic review is a convenient and up-to-date source of the best available evidence on neoadjuvant or adjuvant therapy for resectable gastric cancer. The body of evidence in this review is primarily comprised of mature randomized controlled trial (RCT) data and meta-analyses of RCTs. That evidence forms the basis of the recommendations developed by the Gastrointestinal DSG. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. # Literature Search Strategy The MEDLINE (January 2002 to June week 3 2010), EMBASE (2002 to 2010 week 25), and Cochrane Library (February 2010), databases were systematically searched using revised literature search strategies (Appendix 1). In MEDLINE, the Medical Subject Heading (MeSH) "stomach neoplasms" and associated text words were combined with treatment-related terms, including the MeSH terms "chemotherapy, adjuvant," "radiotherapy, adjuvant," and "neoadjuvant therapy" and the text words "adjuvant," "neoadjuvant," "preoperative," and "postoperative." These terms were then combined with a search filter designed to identify randomized trials, systematic reviews, and meta-analyses adapted from a strategy developed by the Scottish Intercollegiate Guidelines Network (SIGN), available at www.sign.ac.uk. Modifications were made to the search terms, where appropriate, for use in EMBASE. The proceedings of the 2002 to 2010 American Society of Clinical Oncology (ASCO) and the 2002 to 2009 American Society for Therapeutic Radiology and Oncology (ASTRO) annual meetings were also searched for abstract reports of relevant studies. Reference lists of relevant reviews were searched for additional relevant reports. # Study Selection Criteria The study inclusion and exclusion criteria used in the original systematic review (Section 2B) were modified for the updated review. Articles were selected for inclusion if they: - were published abstracts or fully published reports of RCTs comparing preoperative or postoperative chemotherapy and/or radiotherapy versus potentially curative surgery alone or another preoperative or postoperative therapy approach. Syntheses of RCTs in the form of systematic reviews or meta-analyses were also included. were studies of adults with resectable gastric cancer. Trials of gastric cancer that also including patients with tumours of the gastroesophageal junction were included. included reports of OS data. Articles were excluded if they: - were studies of immunotherapy, immunochemotherapy, intraperitoneal chemotherapy, or intra-arterial chemotherapy. were published in a language other than English, due to unavailability of translation services. were abstract reports of preliminary or interim data only. were abstract reports of studies that were subsequently fully published. reported results of RCTs or meta-analyses in the form of a letter or editorial. included a majority of patients with esophageal tumours and did not report data separately for patients with gastric or GEJ tumours. # Study Quality Appraisal The quality of the systematic reviews and meta-analyses was assessed using the AMSTAR tool (8). Randomized trials were assessed for key methodological characteristics, using information provided in the trial reports. The following elements were assessed: generation of allocation sequence, allocation concealment, blinding, intention-to-treat analysis, withdrawals, loss to follow-up, funding source, statistical power calculations, length of follow-up, differences in baseline patient characteristics, and early termination. # Synthesizing the Evidence No data pooling was conducted in this review due to the availability of published meta-analyses comparing postoperative chemotherapy to surgery alone, postoperative CRT to either surgery alone or postoperative chemotherapy, and preoperative radiotherapy to surgery alone. # Literature Search Results The updated search of MEDLINE and EMBASE yielded 1129 articles, of which 149 were retrieved for full-text review following title and abstract screening (Appendix 2). One hundred nineteen of the 149 articles were subsequently excluded because they were either duplicate citations or did not meet the inclusion criteria. One further meta-analysis conducted in Japan and that only included oral fluoropyrimidine trials was also excluded (9). Thirty-three abstracts from the ASCO annual meeting proceedings and six abstracts from the ASTRO proceedings were retrieved for review; 14 initially met the inclusion criteria. However, five of these 14 abstracts were reports of RCTs or meta-analyses that were subsequently fully published and are not discussed further. Two were meta-analyses conducted in Japan and that only included studies of oral fluoropyrimidines are not discussed further (10,11). No additional relevant studies were identified in a search of the Cochrane Library. Overall, 22 RCTs (12-33), 13 meta-analyses (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), and two secondary analyses that report survival data (47,48) are included in this systematic review. One article reported the results of two RCTs (17). Six systematic reviews without meta-analyses were identified, but none were included in this report as meta-analytic data was available. Table 1 provides a summary of the original evidence and new evidence used in this guidance document. # Randomized Controlled Trials Postoperative Chemotherapy vs. Surgery alone vs. Other postoperative Chemotherapy 30 # Postoperative Chemotherapy (a) Study/Trial Design and Quality Five of the 17 RCTs identified were terminated early before reaching target accrual, four for poor accrual (16,17,19) (Nitti (17) reports on two trials) and one for early evidence of benefit after an unplanned interim analysis (26). An additional RCT was discontinued after evidence of benefit at a planned interim analysis, and the results were reported before the planned follow-up was completed (20). Target accrual was met for this trial. Randomization methods appeared adequate in most trials; however, some did not report allocation concealment. None of the trials reported that patients or healthcare providers were blinded to treatment allocation, although one trial reported blinded outcome adjudication (20) (Appendix 3). The GASTRIC group (41) meta-analysis was an individual patient data (IPD) metaanalysis. Well-conducted IPD meta-analyses are superior to well-conducted published literature meta-analyses, and this meta-analysis scored well on the AMSTAR scale. It included most of the items deemed necessary for a well-conducted meta-analysis except a list of excluded studies, which few meta-analyses provide, and an assessment of the likelihood of publication bias (Appendix 4). # (b) Outcomes Seven published literature meta-analyses were identified that compared postoperative chemotherapy versus surgery alone for patients with resected gastric cancer (34)(35)(36)(37)(38)(39)(40). Study inclusion criteria, literature search periods, and statistical methods differed between the seven meta-analyses although the basic research question was the same. There was considerable overlap in the studies included in each of these meta-analyses (Appendix 5). These seven meta-analyses will not be discussed further, owing to the availability of a recent IPD meta-analysis (41). These authors identified 31 eligible trials from 1970-2009 and were able to obtain IPD from 17 of them. An examination of the eligible studies does not indicate any bias with respect to studies for which the authors were and were not able to obtain the IPD. These authors used a fixed-effects model and determined that there is a modest advantage for postoperative chemotherapy for OS (HR, 0.82; 95% CI, 0.76 to 0.90; p<0.001) based on 17 trials and for DFS (HR, 0.82; 95% CI, 0.75 to 0.90; p<0.001) based on 14 trials. No heterogeneity was detected for either outcome measure. The GASTRIC group (41) subsequently conducted a sensitivity analysis for OS using IPD where available (17 trials) and published summary statistics for the other studies, where available (11 trials). The results of the sensitivity analysis were consistent with the main analysis for OS (HR, 0.82; 95% CI, 0.77 to 0.88; p<0.001). The GASTRIC group report (41) does not include information about adverse events. However, searching through the individual studies demonstrates that the most common grade 3 and 4 hematologic toxicities are leucopenia, thrombocytopenia, and neutropenia, depending on the chemotherapy regimen. The most common grade 3 and 4 non-hematologic toxicities, other than alopecia, are nausea and/or vomiting, diarrhea, mucositis, and stomatitis, depending on the chemotherapy regimen. Not all of the studies reported toxicity or graded the toxicity if they did report it; this was especially apparent in the older trials. The updated literature search identified 11 trial reports, representing 12 RCTs that compared postoperative chemotherapy with surgery alone (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). All of these studies, except one very recently published trial (22), were part of the meta-analyses described above and will not be discussed further. Kulig et al. (22) compared postoperative chemotherapy (etoposide, adriamycin, and cisplatin) to surgery alone. They report no survival advantage in the chemotherapy arm. Grade 3 or 4 toxicities were reported in 22% of patients, with leucopenia being the most common toxicity reported (6%). Five RCTs compared postoperative chemotherapy versus another postoperative chemotherapy regimen (23)(24)(25)(26)(27). Study characteristics and results are summarized in Tables 2 and 3 below. Three trials did not demonstrate a difference in OS, DFS, or local recurrence between treatment arms 1 : one compared FAM vs. FM vs. 5-FU (23); one compared PELF vs. 5-FU (25); and one compared MfP vs. Mf (27). A small trial comparing PELF vs. EtLF for completely resected advanced gastric cancer (clinical stage 3 or 4, M0) reported a significant benefit for PELF in OS and DFS (24). Another trial comparing FOLFIRI/docetaxel/cisplatin vs. MMC was stopped early for evidence of a DFS benefit favouring FOLFIRI/docetaxel/cisplatin at an unplanned interim analysis. Therefore, the results should be interpreted with caution (26). Other than alopecia, hematologic toxicities (leucopenia, thrombocytopenia, and neutropenia) and nausea and vomiting were the most often reported grade 3 and 4 toxicities, especially for regimens involving cisplatin, etoposide, or epirubicin. # Postoperative Radiotherapy No meta-analyses or RCTs solely comparing postoperative radiotherapy vs. surgery alone for resectable gastric cancer were identified in the updated literature search. # Postoperative Chemoradiotherapy (a) Study/Trial Design and Quality The one RCT found was terminated early for poor accrual, before reaching its target (28). These authors did conduct an ITT analysis and had less than 1% loss to follow-up (Appendix 3). One published literature meta-analysis was identified (44) that included most of the items deemed necessary by AMSTAR for a well-conducted meta-analysis except a list of excluded studies and an assessment of the quality of the included studies (Appendix 4). # (b) Outcomes One Phase III RCT comparing postoperative CRT vs. postoperative chemotherapy was identified (28). Initially, the chemotherapy regimen consisted of docetaxel and cisplatin. However, the cisplatin was subsequently changed to carboplatin, owing to high rates of nausea and vomiting. The arms did not differ significantly with respect to median and 3-year OS or median and 3-year PFS. This was not surprising as the trial did not meet its accrual target and was, therefore, underpowered to detect a survival difference. The most common grade 3 and 4 toxicities reported, other than alopecia, were non-febrile neutropenia, febrile neutropenia, and diarrhea. However, the difference between the two arms was not statistically significant for any of these toxicities. One meta-analysis of RCTs of postoperative CRT was identified (44). Five RCTs were included, three of which compared postoperative CRT vs. surgery alone, and two of which compared postoperative CRT vs. postoperative chemotherapy. Meta-analysis of the five trials indicated no significant benefit for postoperative chemoradiotherapy over control in 3-year mortality (OR, 0.79; 95% CI, 0.59 to 1.05; p=0.10); however, a meta-analysis of three trials that provided 5-year mortality data indicated a significant benefit for postoperative CRT over surgery (OR, 0.45; 95% CI, 0.32 to 0.64; p<.00001). No significant statistical heterogeneity between trials was reported. Fiorica et al. (44) report that 52% of patients did not complete the CRT protocol as planned. Grades 3 and 4 hematologic and gastrointestinal toxicities as well as mucositis were significantly greater in the CRT arms compared to controls in this meta-analysis. Two secondary analyses of the SWOG/Intergroup trial (49) were identified that also reported updated survival data (47,48). The results from Hundahl (47) are consistent with earlier data reported in Section 2B of this report. Updated results indicated a median survival of 36 months for patients who received postoperative CRT (5-FU/leucovorin vs. 27 months for patients who underwent surgery alone (p=0.003). Relapse-free survival was 30 vs. 19 months (p<0.001), respectively. Further updates of the SWOG/Intergroup trial were presented at ASCO in 2009 (48). The abstract based on 10 years of follow-up demonstrated continued benefit for the chemoradiotherapy group for both survival (HR, 0.76; p=0.004) and DFS (HR, 0.66; p<0.001). The presentation of this abstract was based on 11 years of follow-up and demonstrated similar results for both OS (HR, 0.76; 95% CI, 0.63 to 0.92; p=0.005) and DFS (HR, 0.66; 95% CI, 0.55 to 0.80; p<0.001). The original publication on the SWOG/Intergroup trial (49) reported that 33% and 54% of patients in the CRT arm had Grade 3 or higher hematologic and gastrointestinal toxicities, respectively. # Preoperative or Perioperative Chemotherapy (a) Study/Trial Quality and Design Two of the four RCTs identified were terminated early for poor accrual before reaching target (29,32). Neither of these trials reported whether their analyses were intention-to-treat (ITT). Both the Cunningham (30) and Boige (31) trials achieved their accrual targets, and both conducted ITT analyses. Only Hartgrink (29) reported on the loss to follow-up, which was 0% (Appendix 3). Two published literature meta-analyses were identified comparing preoperative chemotherapy to surgery alone. Neither of these meta-analyses scored well on the AMSTAR instrument, likely owing to the fact that they were only available in abstract form (Appendix 4). # (b) Outcomes Two meta-analyses were identified that compared preoperative chemotherapy vs. surgery alone (42,43). Both of these meta-analyses were only available in abstract form, providing only a limited amount of methodological information, and for this reason will not be discussed further. No meta-analyses were identified that compared perioperative chemotherapy vs. surgery alone. Four RCT reports, comparing preoperative or perioperative chemotherapy vs. surgery alone, have been published since 2002 (29-32) (Table 4, Table 5). One of the reports (29) presents long-term results of the Dutch trial by Songun et al. (50) included in Section 2B of this report. This trial was stopped after accrual of 59 of a planned 450 patients, owing to the slow recruitment and poor interim results. No benefit for preoperative fluorouracil-doxorubicin-methotrexate (FAMTX) over surgery alone could be demonstrated. Another trial compared preoperative chemotherapy with folinic acid and cisplatin followed by surgery to surgery alone in patients with locally advanced adenocarcinoma of the stomach and cardia. This trial was stopped early owing to poor accrual. Only 144 of an expected 360 patients (40%) were accrued during more than four years of the study. No survival benefit for the addition of preoperative chemotherapy was demonstrated (32). The Fédération Nationale des Centres de Lutte Contre le Cancer (FNLCC) ACCORD07 (31) trial of 224 patients comparing preoperative 5-FU/cisplatin vs. surgery alone in resectable gastric and lower esophageal cancer is available only in abstract form. A significant improvement in OS and DFS with preoperative 5-FU/cisplatin was reported (Table 5). The MAGIC trial reported by Cunningham et al. in 2006 (30) is the largest trial incorporating preoperative therapy to date and the only randomized trial with a perioperative approach. A total of 503 patients were randomized to preoperative and postoperative ECF or surgery alone. Patients with adenocarcinoma of the stomach or lower third of the esophagus who had stage II or higher (M0) disease or locally advanced inoperable disease were included. It should be noted that only 68% of patients underwent curative surgery, while the remaining patients had palliative surgery, no surgery, or surgery of unknown intent. Of the patients assigned to perioperative ECF, 41.6% completed all six cycles of chemotherapy, and 49.5% of patients who completed preoperative ECF also completed postoperative therapy. A significant benefit for perioperative ECF was reported for OS and PFS (Table 5). Although results for patients with gastric and GEJ tumours were not reported separately from results for tumours of the lower esophagus, no heterogeneity of treatment effect according to disease site was demonstrated (interaction p=0.25). Overall, preoperative and perioperative chemotherapy approaches resulted in greater hematologic toxicities as well as nausea and vomiting compared to surgery alone (Table 5). # Preoperative Radiotherapy (a) Study/Trial Quality and Design One RCT was identified (33), but it provided very little information with respect to methodological quality (Appendix 3). Three meta-analyses were identified (44)(45)(46) 46) study scored poorly as it was only available in abstract form (Appendix 4). # (b) Outcomes Three published literature meta-analyses of trials comparing preoperative radiotherapy vs. surgery alone were identified in the updated literature search (44)(45)(46), as well as a full publication of a trial by Skoropad et al included in abstract form in the original systematic review (Section 2B) (33). The Skoropad trial ( 33) is included in the Fiorica et al. (44) meta-analysis and will not be discussed separately. The meta-analysis by Fiorica et al. (44) included four RCTs of preoperative radiotherapy vs. surgery alone, one of which combined preoperative radiotherapy with local hyperthermia. Results indicated a significant survival benefit for preoperative radiotherapy at both three years (OR, 0.57; 95% CI, 0.43 to 0.76; p=0.0001) and five years (OR, 0.62; 95% CI, 0.46 to 0.84; p<0.00001), and no significant statistical heterogeneity between trials was demonstrated. All patients in the studies of this meta-analysis were able to complete the preoperative radiation without dose reductions. The meta-analysis by Valentini et al. (45) included studies of preoperative, postoperative, and intraoperative radiation as well as radiation combined with chemotherapy all combined into one analysis. Because of this clinical heterogeneity, this meta-analysis will not be discussed further. The meta-analysis by Lu et al. (46) was only available in abstract form, and because only a limited amount of methodological information was provided, it will not be discussed further. # Ongoing Trials The NCI® database of ongoing clinical trials (/) was searched on April 7, 2010. Twelve relevant phase III trials were identified and are described in Table 6. Many trials and meta-analyses of trials have investigated the value of neoadjuvant and adjuvant treatment in gastric cancer. These efforts have produced conflicting results. The Gastrointestinal DSG decided that an update of EBS #2-14, which was first developed in 2000 and updated in 2003, was justified, given the availability of new evidence that could change the recommendations made in the last version of this guidance document. # Postoperative Chemotherapy The IPD meta-analysis by the GASTRIC group (41) demonstrated that there is a modest but significant survival advantage for postoperative chemotherapy, based on the 17 trials for which they could get IPD. This conclusion was maintained when a sensitivity analysis, which added in summary statistics for another 11 trials, was carried out. # Postoperative Radiation No trials solely comparing postoperative radiation therapy to surgery alone were identified in the updated literature search. # Preoperative Radiation A published literature meta-analysis by Fiorica et al. (44) included four RCTs of preoperative radiotherapy vs. surgery alone, one of which combined preoperative radiotherapy with local hyperthermia. Results indicated a significant survival benefit for preoperative radiotherapy at both three years (OR, 0.57; 95% CI, 0.43 to 0.76; p=0.0001) and five years (OR, 0.62; 95% CI, 0.46 to 0.84; p<0.00001), and no significant statistical heterogeneity between trials was demonstrated. A preoperative radiotherapy approach seems to provide a superior outcome with respect to 3-year and 5-year OS. However, this treatment has not been taken up in the North American oncology community. There are four main reasons for this. First, the evidence for preoperative radiation originated predominantly from China and Russia. The generalizability of the results to Canadian/North America practice cannot be assumed. There was significant heterogeneity in the way the preoperative therapy was delivered. The radiotherapy used in three of the four studies used large dose per fraction (20 Gy in 5 fractions) (51,52) although one study did employ a standard 2 Gy dose per fraction (40 Gy in 20 fractions) (53). Similarly, the target volume included for radiotherapy varied across the studies. These differences create challenges toward understanding how to implement these findings into practice. The magnitude of benefit as demonstrated through meta-analysis ( 44) is potentially smaller compared with a postoperative CRT approach (Number Needed to Treat for RT =10 and for CRT = 6) (44). Finally, the high probability of both local and distant recurrence in gastric cancer has led to a preference towards strategies that incorporated both radiotherapy and chemotherapy. The preference towards incorporating chemotherapy into adjuvant or neoadjuvant approaches is reflected by the fact that none of the clinical trials currently ongoing evaluate the use of preoperative radiation therapy alone, although the evaluation of preoperative CRT, perioperative chemotherapy, and postoperative CRT approaches continue to be actively pursued. # Postoperative Chemoradiation The meta-analysis by Fiorica et al. (44) of RCTs comparing postoperative chemoradiation to surgery alone did demonstrate a significant benefit with respect to 5-year mortality (OR, 0.45; 95% CI, 0.32 to 0.64; p<0.00001), although it is interesting to note that the results for 3-year mortality were not significant. This might be an indication that the 5-year results are spurious, though it is not possible to determine this. It should also be noted that one of the trials included in this meta-analysis is the Macdonald et al. (49) SWOG/Intergroup trial. Updated survival data from this specific trial was identified (47) and indicate superior median survival for patients receiving postoperative chemoradiation over surgery alone (36 vs. 27 months; p=0.003). Similarly, relapse-free survival was superior in the chemoradiation arm (30 vs. 19 months; p<0.001). A further update of SWOG/Intergroup trial demonstrates the robustness of these findings even after 11 years of follow-up for both OS (HR, 0.76; 95% CI, 0.63 to 0.92; p=0.005) and DFS (HR, 0.66; 95% CI, 0.55to 0.80; p<0.001) (48). In the Macdonald et al. SWOG/Intergroup trial (49), the protocol recommended that a D2 (more extensive) lymph node dissection be performed, but as many of the referrals to the trial occurred postoperatively, this could not be mandated. Upon final analysis, only 10% of patients had a D2 lymph node dissection, 36% had a D1 lymph node dissection, and 54% had a D0 lymph node dissection (i.e., not all of the N1 nodes were removed). The lack of adequate lymph node dissection in over half of the SWOG/Intergroup patients has lead to criticism of the trial, with suggestions that the addition of adjuvant chemoradiation may be compensating for inadequate surgical resection (54,55). However, subsequent trials, in which a D2 lymph node dissection occurred in the majority of patients, have upheld a survival benefit for adjuvant chemoradiation in patients who underwent more aggressive surgery (56). Furthermore, the MAGIC (30) and the S-1 (20) trials had 68% and 100% of patients with a D2 resection, respectively, demonstrating a significant benefit to adjunct chemotherapy, even with cohorts of patients who have had a D2 lymph node dissection. # Preoperative or Perioperative Chemotherapy The MAGIC trial (30) was a large trial of over 500 patients comparing perioperative chemotherapy (ECF) to surgery alone. This trial demonstrated significant improvement in 5year OS (HR, 0.75; 95% CI, 0.60 to 0.93; p=0.009) and 5-year PFS (HR, 0.66; 95% CI, 0.53 to 0.81; p<0.001). # Considerations for Choice of Therapy The Macdonald et al. (47)(48)(49) and the Cunningham et al./MAGIC (30) trials have provided strong support for either a postoperative chemotherapy/radiotherapy approach to treatment or a perioperative approach, respectively. Summaries of these protocols are provided in Appendix 6. The decision to initiate a perioperative chemotherapy approach vs. the postoperative chemoradiation approach should be based on a number of patient and tumour-specific factors and ideally be made preoperatively. Diagnostic laparoscopy is reasonable to consider prior to initiation of perioperative chemotherapy to determine if there is peritoneal spread of metastatic disease not detected on CT imaging, as this assessment may be less accurate following the administration of chemotherapy. While down-staging is not considered an indication for the MAGIC protocol, a perioperative approach does allow for assessment of biologic response to systemic chemotherapy, which may be important in clinical decision-making for patients with bulky tumours, or radiologically positive lymph nodes. Patients who are undergoing a total gastrectomy, as opposed to a sub-total gastrectomy, may have difficulty with nutrition postoperatively especially when additional therapy is introduced as described in the SWOG/Intergroup clinical trials (49). A feeding tube should be considered for patients undergoing a total gastrectomy with plans for post-operative therapies if there are doubts that the patient will be able to complete postoperative treatment because of poor caloric intake. Some factors can be associated with increased or escalated risk of radiotherapy toxicities specifically. The anastomosis is typically included in the radiotherapy portal. For patients where the esophagogastric anastomosis or planned location is above the carina, the inclusion of this region that is required would predict for excessive lung and cardiac radiotherapy toxicities. The nodal regions and the blind loop post resection are frequently immediately adjacent to the kidneys. For patients with borderline renal function, radiation is expected to be associated with an increased risk of chronic renal impairment. In these patients, consideration for the Cunningham approach (30) using chemotherapy alone should be considered. Similarly, there are factors that need to be made for the use of perioperative chemotherapy. The presence of cardiac or renal dysfunction would contraindicate the use of epirubicin and cisplatin, respectively. During the combined modality treatment of radiation and chemotherapy used during the Macdonald (49) protocol, some centres used a low-dose continuous 5-FU infusion or alternatively used oral capecitabine as a radiosensitizer. This would seem to be reasonable from a biologic perspective and is considered acceptable. Clearly, all patients would benefit from a multidisciplinary care assessment prior to surgery in order to determine the best plan of care for each individual patient. Clinicians must tailor the decision to recommend postoperative CRT according to a patient's nutritional and performance status. Unless obviously contraindicated owing to poor performance status, all patients undergoing gastric surgery with curative intent should be considered for adjuncts to resection. # TECHNICAL CONSIDERATIONS FOR RADIATION THERAPY Many technical issues for the provision of radiation therapy have been introduced to refine and enhance the quality of the radiotherapy plan. The target volume is in the upper abdomen targeting the tumour bed and regional nodes, 2 cm beyond the proximal and distal margin of resection. The extent of regional node irradiation is further modified based on the location of the primary tumour: for example, for T3 lesions in the proximal stomach and the medial left hemidiaphragm was also included. The regional nodes were defined (based on the Japanese Research Society for Gastric Cancer) as perigastric, celiac, local para-aortic, splenic, hepatoduodenal or hepatic portal, and pancreaticodudenal. In addition, for GEJ tumours, the regional nodes included paracardial and para-esophageal lymph node beds but excluded the pancreatic duodenal and splenic nodal beds. The latter were also excluded in antral tumours. Guidelines for more specific tailoring of nodal regions based on tumour location as well as T and N stage are provided in Tepper and Gunderson (57) and a recent guideline for preoperative radiation treatments of the stomach published by the EORTC (58). Strategies to incorporate internal organ motion into treatment planning allows for further individualization of treatment plans. Respiratory motion can be incorporated through the use of four-dimensional computerized tomography (4-D CT) (59), and gastric volume variation can be reduced through instructions for 'standardized meals' prior to treatment planning and each treatment (60). The use of renal perfusion scans allow for refinement of radiotherapy beam geometry based on risk and organ function. The use of conformal radiotherapy has generally superseded the techniques described in the original MacDonald study. IMRT techniques may provide further incremental benefit with lower doses to normal structures being achieved, although the optimal way of adopting this continues to be investigated (61,62). Permissible radiation dose limits for organs at risk (OAR) may affect the expected and observed long-term risks. More conservative parameters than described in the original Macdonald (49) study have been recommended (58) and adopted into clinical practice. OS in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation implementing the Macdonald protocol (47-49) or perioperative ECF implementing the MAGIC protocol (30). The choice of which option to utilize should be based on individual patient factors affecting their ability to tolerate either the radiation used in the Macdonald protocol or the epirubicin/cisplatin used in the MAGIC protocol. If neither of these approaches is appropriate for a given patient, then postoperative chemotherapy is a reasonable alternative. All patients with resectable gastric cancer should undergo a multidisciplinary assessment to determine the best plan of care. # CONFLICT OF INTEREST GI DSG members involved in the development of the systematic review and clinical practice guideline were polled for potential conflicts of interest. All authors declared no conflicts of interest. # JOURNAL REFERENCE The following systematic review and practice guideline have been published in Gastric Cancer (© The International Gastric Cancer Association and The Japanese Gastric Cancer Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

To improve the quality and consistency of the management of depression for patients with cancer in Ontario.Adult patients with cancer who are diagnosed with a major depressive disorder based on a structured diagnostic interview, or who have a suspected depressive disorder based on meeting a threshold on a validated depression rating scale.This guideline is intended to be used by mental health care providers (psychiatrists, psychologists), palliative care professionals, oncologists, oncology nurses, nurse practitioners, psychosocial intervention providers, primary care providers, and community nurses.# INTRODUCTION Knowing of the significant prevalence of depressive disorders in patients with cancer and of the clinical relevance of depression to health outcomes, the Program in Evidencebased Care (PEBC) developed an initial guideline for the management of depression in patients with cancer, which was published in 2007. The recommendations contained in this section are an update of the 2007 recommendations, based on the results of an updated systematic review (Section 2) and the consensus opinion of the members of the project Working Group. While this guideline summarizes the best available evidence to guide the management of depression in patients with cancer, members of the Working Group acknowledge the challenge of conducting research in an area of diagnostic complexity across the depression severity continuum. Clinicians must distinguish physical symptoms of cancer from neurovegetative symptoms of depression, functional impairment from decreased activities due to anhedonia, and rational thoughts of death from suicidality. Treatment complexity is further compounded by medical and psychosocial factors, such as pain or inadequate social supports, that contribute to depression and often need to be addressed prior to or concurrently with depressive symptoms. Clinicians must also consider potential detrimental pharmacotherapy side effects, drug interactions, and treatment compliance issues unique to the cancer context. The eight recommendations developed in this guideline have been synthesized into a quick reference guide for the initial management of depression in patients with cancer (Figure 1). This management algorithm provides a general approach and practical guidance tool for health care providers treating patients with cancer who present with a depressive disorder. Most of the steps in the tool are described in more detail within the recommendations. Recommendations and Practical Tools can be found at the following locations within Section 1: # Recommendations Page Quick reference management algorithm (Figure 1) 5 Delivery of intervention according to the stepped care model (Figure 2) 6 Recommendation 1: Screening of patients 7 Recommendation 2: General management principles 7 Depressive disorders consist of a continuum of symptoms that mental health researchers have classified into categories. This remains an area of ongoing debate and modifications, as evidenced by revisions in the International Classification of Diseases, 10th edition (ICD-10) Classification of Mental and Behavioural Disorders and the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) of the American Psychiatric Association classification systems. Also, various guidelines have adopted pragmatic subdivisions of dimensions that may not be perfectly aligned with each other. While the target population of this systematic review is interview diagnosed major depression or depression severity above threshold on depression rating scales, the recommendations have been adapted 1 Complex depression includes depression that shows an inadequate response to multiple treatments, is complicated by psychotic symptoms, and/or is associated with significant psychiatric comorbidity or psychosocial factors. Stepped care algorithm adapted from NICE CG91, p.110. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION Recommendation 1. Screening of patients with cancer for distress or depression Patients with cancer should be screened for depression. Many cancer programs incorporate depression screening into Screening for Distress programs. A clear diagnosis of depression is required to guide treatment. See Appendix 3 for psychological features that distinguish the continuum of depressive symptoms. To improve health outcomes, screening must be linked to effective interventions. # Summary of Key Evidence for Recommendation 1 Screening for Distress, the 6 th Vital Sign is a standard of care in multiple cancer care guidelines. This recommendation is the suggestion of the members of the Working Group, based on recommendations contained within these publications: the NICE Guidance on Cancer Services . # Qualifying Statements for Recommendation 1 It is recognized that the evidence base for the effectiveness of depression screening in reducing depression outcomes in cancer is lacking and is a topic of much recent debate in the field of distress screening. Review of this literature is beyond the scope of this guideline; however, it is the opinion of the members of the Working Group that lack of evidence is not equivalent to lack of effectiveness. These guidelines apply to patients who are in the moderate to severe care pathways according to A Pan-Canadian Practice Guideline: Screening, Assessment and Care of Psychosocial Distress (Depression, Anxiety) in Adults with Cancer. # Recommendation 2. General management principles The following general management principles are recommended: - Provide psychoeducation about the nature of depression in patients with cancer and consider providing handouts such as those published by the National Cancer Institute. 2. Inform patients about the impact of depression on cancer outcomes, including reduced quality of life, intensification of physical symptoms, longer hospital stays, and reduced survival rates. 3. Destigmatize clinical depression in cancer by framing it as a serious problem requiring treatment, rather than as a personal weakness or failure to cope. 4. Investigate medical contributors to depression such as hypothyroidism, or vitamin B12, folate, or iron deficiency. 5. Assess and optimize cancer-related physical symptom control. 6. Encourage family members' involvement and education, communication with family members regarding prognosis, and resolution of problems within the support network. 7. Discuss treatment options, attending to patients' preferences and previous treatment experiences. 8. Consider use of a validated depression rating scale to monitor change over time (Appendix 2). # Summary of Key Evidence for Recommendation 2 Recommendations for general management are the consensus-based opinion of the members of the Working Group and are adapted from the NICE Clinical Guideline 91 (CG91), Depression in Adults with a Chronic Physical Health Problem and from the European Palliative Care Research Collaborative (EPCRC) guideline The Management of Depression in Palliative Care. # Recommendation 3. Pharmacological or psychological/psychosocial interventions Patients with cancer who are diagnosed with major depression may benefit from pharmacological or psychosocial interventions either alone or in combination. # Summary of Key Evidence for Recommendation 3 Insufficient new evidence was found in this updated systematic review to alter the conclusions of the previous version of this guideline regarding pharmacological therapies for patients with both cancer and depression. The evidence derived from the small number of placebo-controlled randomized trials conducted in patients with cancer demonstrates a significant overall beneficial effect of antidepressants on depression (odds ratio, 1.91; 95% confidence interval, 1.09 to 3.36). In the absence of a strong cancer-specific evidence base, this recommendation is the consensus of the members of the Working Group, and is consistent with NICE CG91 and EPCRC guidelines on the management of depression in patients with medical comorbidity and palliative care, respectively. A significant difference was found between means for psychological interventions evaluated after two to 13 weeks (standardized mean difference -1.40, but the difference did not remain statistically significant when the effects were evaluated after longer time periods, ranging from six to 12 months (SMD -0.55,. The level of heterogeneity in these analyses was high, with I 2 values of 96% and 80%, respectively. # Qualifying Statements for Recommendation 3 - The effectiveness of psychosocial and pharmacological interventions for moderate depression is equal. - Pharmacologic interventions are most effective for more severe depression. - Combined psychosocial and pharmacologic interventions should be considered for severe depression in patients with cancer. # Recommendation 4. Depression severity and a stepped care approach Interventions for depression in patients with cancer should be delivered according to a stepped care model. This involves assessment of the severity of depression for each patient (Appendix 3), provision of support and psychoeducation to all patients, delivery of lowerintensity interventions for persistent subthreshold and mild to moderate depression, followed by progression to higher intensity interventions for nonresponsive or moderate to severe depression (Figure 2). Low-intensity psychosocial interventions include structured group physical activity programs, group-based peer support or self-help programs, and guided selfhelp programs based on cognitive behavioural therapy (CBT), behavioural activation, or problem-solving techniques. High-intensity psychosocial interventions include individual or group CBT, behavioural couples' therapy, and individual or group supportive-expressive psychotherapies. # Summary of Key Evidence for Recommendation 4 This recommendation is based on NICE CG91. For more information on stepped care models for treatment of depression in patients with a physical illness, see NICE CG91, Chapter 6. # Qualifying Statement for Recommendation 4 Antidepressant medication should be reserved for moderate to severe depression, but can be considered for subthreshold or mild depressive symptoms persisting after initial interventions or that interfere with engagement in cancer treatment. # Recommendation 5. Collaborative care interventions Collaborative care interventions should be considered for patients with cancer who are diagnosed with major depression. Collaborative care involves active collaboration between the oncologist or primary care provider and a patient care manager (nurse, social worker, psychologist), with pharmacological treatment supervised by a consulting psychiatrist as needed. The care manager provides psychoeducation, delivers structured psychosocial interventions such as behavioural activation or problem-solving therapy, and monitors progress. Weekly case review meetings are held to adjust treatment plans for inadequate improvement. These are multi-component interventions, which can be offered at a range of intensity levels, depending on the presentation of the patient and local resources. They typically include measurement-based care, and involve increases in the level or intensity of intervention as needed according to the principles of stepped care. # Summary of Key Evidence for Recommendation 5 A meta-analysis of six reports of four randomized trials of collaborative care interventions in patients with major depression and cancer found that patients receiving the collaborative care intervention (compared with usual care or enhanced usual care) were significantly more likely to experience a 50% reduction in score on a validated depression rating scale, had lower mean scores, and were significantly more likely to experience remission of depression at time periods ranging from three to 24 months (Section 2, Figures 4 to 6, Section 2, Appendix 7, Figures 1 to 14). Most of the patients in these studies had at least moderately severe depression at baseline. # Qualifying Statements for Recommendation 5 - Within a stepped care approach, collaborative care interventions may be most appropriate for patients with cancer and with subthreshold/mild depression persisting after other interventions, or with moderate to severe depression. - Implementation of a collaborative care model may require significant reorganization of mental health care service delivery in cancer treatment facilities. Details regarding implementation of a collaborative care model of service delivery are outside the scope of this guideline, but information can be obtained at / or / # Recommendation 6. Specialist referral In a stepped care model, referral to psychosocial specialists, including mental health specialists, should occur in the following instances: When there is risk of harm, 2. In complex psychosocial cases, 3. Where the patient experiences persistent symptoms after initial intervention, When diagnosis is unclear, 5. For delivery of specific psychotherapies requiring specialized training. # Summary of Key Evidence for Recommendation 6 This recommendation was adapted by the Working Group from EPCRC recommendation 2.6 (Refer to a mental health specialist if) and NICE CG91 recommendation 5.6.1.12 (Risk assessment and monitoring). # Recommendation 7. Selection of psychological therapies Because there is insufficient evidence for superiority of one modality over another, selection of psychological therapy should be based on patient factors and local resource availability. - Among patients with cancer presenting with depressive symptoms, most are mild to moderate. The stepped care model recommends that psychological interventions be considered first for mild to moderate depression. - Psychological therapies should be delivered by health care professionals competent in the modality, but non-mental health specialists can be trained in basic psychosocial interventions. # Summary of Key Evidence for Recommendation 7 This recommendation is the consensus-based opinion of the members of the Working Group. Examples of psychological therapies are provided in Appendix 4. # Qualifying Statements for Recommendation 7 - Delivery of therapy: - Empathic communication, psychoeducation, problem-solving, and behavioural activation are therapeutic techniques that may be delivered by trained health care professionals. o Supportive-expressive and structured psychotherapies (e.g., CBT, interpersonal therapy, psychodynamic therapy) require specially trained therapists. # - Patient factors guiding selection: - CBT may be useful for patients wanting a symptom-based approach. - Supportive-expressive therapies may be of value with more psychologically minded patients (i.e. patients with the capacity for self-reflection and introspection, and the ability to gain insight into their motivations and behaviours). o Individual therapies may be more practical in patients who are in the palliative phase. # Recommendation 8. Use of antidepressant medication Do not use antidepressants routinely to treat subthreshold depressive symptoms or mild depression, due to the higher risk-benefit ratio at this level of depression severity. Antidepressant medication should be considered first for severe depression. Table 1 provides practical guidance on selecting commonly used antidepressants for patients with cancer (see Appendix 5, Appendix 6, and Appendix 7 for further guidance on antidepressant prescribing practices, classes of antidepressants for use in cancer patients, and information on antidepressant drug interactions, respectively). In clinical practice, a selective serotonin reuptake inhibitor (SSRI) such as citalopram/escitalopram should be the first resort due to best tolerability and the least potential for drug interactions. # Summary of Key Evidence for Recommendation 8 This recommendation is based on the consensus opinion of the members of the Working Group, supported by NICE CG91 and other guidelines and reviews on pharmacotherapy in medical and cancer populations. Despite the limitations of the evidence-base, the members of the Working Group recognize that both antidepressants and antipsychotic agents are widely prescribed for patients with cancer ; this is most particularly the case for patients with advanced illness. Only case series and open trials have been published for newer antidepressants, such as escitalopram, citalopram, venlafaxine, desvenlafaxine, mirtazapine, bupropion, and duloxetine, which are routinely used in cancer patients. Indications for these agents include not only depression but also anxiety and hot flashes in the case of SSRIs and serotonin-norepinephrine reuptake inhibitors neuropathic pain with serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants and nausea, sleep disturbances, and appetite enhancement in the case of mirtazapine and atypical antipsychotics. # Qualifying Statement for Recommendation 8 Some studies have raised concerns about interactions between tamoxifen and antidepressants that inhibit cytochrome P450 2D6 (CYP2D6), reducing the conversion of tamoxifen to the active metabolite endoxifen and, thereby, increasing the risks of recurrence and mortality. However, meta-analyses have suggested that the reductions in endoxifen do not translate into increased breast cancer recurrence rates or mortality rates, possibly because the therapeutic dosing of tamoxifen fully saturates the estrogen receptor. Existing recommendations have been conservative, cautioning avoidance of potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, high-dose sertraline, bupropion) with tamoxifen. Although these antidepressants are not recommended as first-line agents, clinical judgement can be exercised in their use with patients for whom safer alternatives are not an option, after discussion with the treating oncologist has occurred and informed consent been obtained. More potent CYP2D6 inhibitors may be safer to use in postmenopausal women or women with a known extensive metabolizer CYP2D6 genotype. When possible, it is prudent to prefer antidepressants with low CYP2D6 inhibition (e.g., citalopram/escitalopram, venlafaxine/desvenlafaxine, or mirtazapine) as first-line agents. This guideline does not include recommendations for the management of depressive symptoms in the normative or nonpathological range of severity. Studies addressing this level of depression have been highly heterogeneous, group-as-a-whole studies, and were beyond the scope of this systematic review. Such studies have been extensively reviewed in previous publications with management recommendations provided in other guidelines. Recommendations for the management of threshold depressive disorders are integrated into the quick reference guide provided in Figure 1. This management algorithm includes steps not fully articulated in these recommendations, because they represent accepted standard of care and have been extensively reviewed elsewhere. For example, assessment for suicidality requires either direct inquiry, or the use of depression rating scales that contain items assessing suicidal ideation (e.g., Patient Health Questionnaire 9, Beck Depression Inventory II). Further guidance on the management of suicidal ideation in patients with cancer is available through the International Psycho-Oncology Society's core curriculum webcast series. Empathic communication by health care providers is an important component of management at all levels of depression severity in patients with cancer. The significance of good patient-provider communication has been extensively reviewed in other guidelines and excellent online training resources for cancer care providers are available. More specific management tools, including strategies for the management of depression in patients who do not respond to initial treatments, are provided in Appendices 1 to 7 accompanying this guideline. These tools were developed by consensus by the members of the Working Group. There has been a dearth of new and high-quality individual pharmacotherapy or psychotherapy research in this field since the previous version of this guideline was published. Investigators conducting antidepressant trials in patients with cancer have reported lack of success in recruiting subjects and report numerous potential barriers to study completion, including patient and clinician refusal to consider placebo trials for medications that are already in widespread clinical use. As a result, the literature continues to accumulate modestly powered open-label nonrandomized pilot studies, such as a 2014 study of citalopram and mirtazapine. Psychological intervention studies are similarly hampered by difficulties establishing appropriate nonintervention control groups in a population with both depression and cancer and strong placebo effects in comparative control groups. Despite the decades-long history of psychosocial oncology research, little has changed over the past decade and high-quality pharmacotherapy or psychotherapy studies on the treatment of depression in patients with cancer are still lacking. As a result, clinical practice must be guided by the existing evidence base and must be extrapolated from evidence of treatment efficacy in primary psychiatric and other medical populations. Recent research in this field has shifted to the study of more effective models of interprofessional collaborative care delivery. Effective management of depression in cancer is required to optimize patient quality of life, improve cancer outcomes, and support a person-centred model of cancer care delivery. # PRACTICAL TOOLS (APPENDICES 1-7) Appendix 1. DSM-5 Diagnostic Criteria for Major Depressive Episode. # I. DSM-5 diagnostic criteria for a major depressive episode (A and B criteria only) A. At least five of the following symptoms, present during the same two-week period, representing a change from previous functioning, each present nearly every day; and at least one of the symptoms is either ( 1 The following are selected examples and definitions of psychological interventions frequently used for depression in cancer. Not all modalities are currently supported by a research evidence-base in cancer patients, but their use is extrapolated from the treatment of depression in psychiatric and other medical populations. In practice, various components of different models may be used. For a more complete list, and levels of evidence for the interventions, refer to sources: NICE CP91 and Canadian Network for Mood and Anxiety (CANMAT) clinical guidelines for management of depressive disorder in adults. - Group-based peer support (self-help) programs for patients with cancer and mild to moderate depression, and for patients with subthreshold depressive symptoms that complicate cancer care should: o be delivered to groups of patients with a common cancer type; o focus on sharing experiences and feelings associated with having cancer; o be supported by practitioners who should facilitate attendance at the meetings, have knowledge of the patients' cancer and its relationship to depression, and review the outcomes of the intervention with the individual patients; and o consist typically of one session per week delivered over a period of eight to 12 weeks. - Structured group physical activity programs for patients with mild to moderate depression and cancer, and for patients with subthreshold depressive symptoms that complicate care of the cancer, should: o be modified (in terms of duration of the program, and frequency and length of the sessions) for different levels of physical ability as a result of the cancer in liaison with the team providing care for the cancer; o be delivered in groups with support from a competent practitioner; o consist typically of two or three sessions per week of moderate duration (45 minutes to one hour) over 10 to 14 weeks (average 12 weeks); and o Be coordinated or integrated with any rehabilitation program for the cancer. - Mindfulness Based Stress Reduction and Mindfulness Based Cognitive Therapy : Mindfulness has roots in Buddhist meditation and is based on adopting a moment-to-moment, nonjudgmental awareness. Thoughts, feelings and behaviours are observed with gentle curiosity, rather than analysis. Mindfulness Based Stress Reduction combines stress reduction with mindfulness meditation techniques. Mindfulness Based Cognitive Therapy combines mindfulness meditation with cognitive therapy techniques. - Cognitive Behavioural Therapy (CBT) : CBT is a discrete, time-limited, structured psychological intervention, derived from the cognitive behavioural model of affective disorders and in which the patient: - works collaboratively with the therapist to identify the types and effects of thoughts, beliefs, and interpretations on current symptoms, feeling states and/or problem areas; o develops skills to identify, monitor and then counteract problematic thoughts, beliefs, and interpretations related to the target symptoms/problems; and o learns a repertoire of coping skills appropriate to the target thoughts, beliefs and/or problem areas (i.e., cognitive restructuring and behavioural exposure). - Behavioural activation therapy (BAT) : BAT is based on the premise that depression is a consequence of compromised environmental sources of positive reinforcement. Treatment involves increasing patient activity and access to rewarding experiences, evaluating the consequences of depressive versus nondepressive behaviours, and de-emphasizing particular cognitions or mood states as necessary for re-engaging with one's environment. - Problem solving therapy (PST) : PST is a discrete, time-limited, structured psychological intervention, which focuses on learning to cope with specific problem areas and in which therapist and patient work collaboratively to identify and prioritize key problem areas, to break problems down into specific, manageable tasks, to problem-solve, and to develop appropriate coping behaviours. - Interpersonal therapy (IPT) : IPT is a discrete, time-limited, structured psychological intervention, derived from the interpersonal model of affective disorders that focuses on interpersonal issues and in which the therapist and patient: o work collaboratively to identify the effects of key problematic areas related to interpersonal conflicts, role transitions, grief and loss, and social skills, and their effects on current symptoms, feeling states and/or problems; o seek to reduce symptoms by learning to cope with or resolve these interpersonal problem areas. - Behavioural couples' therapy: Consider for patients with a regular partner when the relationship may contribute to the depression. Therapy is based on behavioural principles, and an adequate course should be 15 to 20 sessions over five to six months. Therapy is based on a model of interactional processes in relationships where: o the intervention aims to help participants understand the effects of their interactions on each other as factors in the development and/or maintenance of symptoms and problems o the aim is to change the nature of the interactions so that the participants may develop more supportive and less conflictual relationships. - Supportive-expressive therapy : Supportive-expressive therapy in the context of oncology patients involves the creation of a supportive environment in which participants are encouraged to confront their problems, strengthen their relationships, and find enhanced meaning in their lives. Emotionally expressive, rather than didactic, discussion regarding shared experiences is facilitated around themes such as fears of dying and death, reordering life priorities, improving support from and communication with family and friends, integrating a changing self and body image, and improving communication with physicians. Coping strategies and psychoeducation are provided in a nondidactic manner. - Core conflictual relationship theme (CCRT) : CCRT is a 16-week structured short-term psychodynamic psychotherapy focusing on a central pattern of intrapsychic and interpersonal conflicts. The initial phase identifies a recurrent maladaptive wish, the expected response of the other, and the response of the self in relationships (the CCRT). Middle sessions focus on exploring the CCRT in current relationships and the relationship to the therapist, with a termination phase focusing on separation. Booster sessions are included to consolidate treatment progress. o CCRT has been adapted specifically for depression in cancer populations by Zwerenz et al. - Dignity Therapy : An individual, legacy project intervention for palliative patients using a tape recorded interview and based on a nine-question interview protocol. The dignity interview focuses on issues that matter most to the patient or that the patient would most want remembered. Edited transcripts of the interview are given to patients to share with family. - Meaning-Centred Psychotherapy : A brief intervention focusing on historical, attitudinal, creative, and experiential sources of meaning developed for patients with advanced cancer. Developed as either an eight-week group or sevenweek individual intervention. - Managing Cancer and Living Meaningfully (CALM) : A brief, manualized, semistructured individual and couple-based psychotherapy designed to alleviate distress in patients with advanced cancer. CALM consists of three to eight sessions delivered over six months that address four broad domains: symptom management and communication with health care providers, changes in self and relations with close others, sense of meaning and purpose, and thoughts about the future and mortality. It has been shown to alleviate depression and anxiety about death, and to improve the patient's sense of meaning and peace (spiritual well-being). -verall suicide risk is decreased by treatment of depression - Inquire separately about suicidal ideation, intent, and plan - Distinguish suicidal ideation from rational thoughts of death, and desire for hastened death - Reassess adherence and mood after one week if suicidal ideation is present - Refer to mental health specialist if considerable imminent risk # Maintaining an Antidepressant - Provide support in first week when risk of nonadherence is greatest; follow up every two to four weeks until remission - Monitor agitation, increased anxiety, and insomnia. Consider short-term benzodiazepine for initial symptoms, if required - Assess response after three to four weeks at a therapeutic dose; increase dose if no response; switch medication if no response after six weeks - Regularly monitor for changes in medical status and cancer treatments and adjust accordingly - Continue at effective dose for at least six months after full remission - Patients with a history of recurrent depression should be advised to continue maintenance treatment for at least two years or indefinitely # Discontinuing an Antidepressant - Be aware that discontinuation syndromes (malaise, dizziness, agitation, headache, nausea, paresthesia) may occur with abrupt termination or missed doses at high dosage levels - Understand that discontinuation syndromes are more common with antidepressants with a shorter half-life (i.e., venlafaxine, paroxetine); they do not occur with fluoxetine - Taper gradually over four weeks to minimize discontinuation syndromes; symptoms may be more prominent toward the end of the taper - Advise that symptoms are usually mild and self-limiting over approximately one week - If symptoms are severe, taper more slowly or consider switching to longer half-life SSRIs such as fluoxetine and then stopping - Monitor for possible depression relapse over the next few months # Drugs Common Side Effects Cautions Tricyclic Antidepressants (TCAs) # Selecting an Antidepressant - Past psychiatric history (e.g., past positive treatment responses to an antidepressant) - Family psychiatric history (e.g., past positive treatment responses to an antidepressant) - Concurrent medications (e.g., potential drug-drug interactions) - Somatic symptom profile (e.g., sedating antidepressant for those with prominent insomnia; weight gaining antidepressant for cachectic patients) - Potential for dual benefit (e.g., duloxetine and TCAs for neuropathic pain, venlafaxine for hot flashes) - Type of cancer (e.g., avoid bupropion in those with central nervous system cancers) - Comorbidities (e.g., avoid psychostimulants or TCAs in cardiac disease) - Cancer prognosis (e.g., consider psychostimulants if very short life expectancy) # Initiating an Antidepressant - Screen for possible medical contributors to presenting conditions (e.g., TSH, vitamin B12), as well as substance use - Start on lowest dose to minimize detrimental side effects and titrate up to therapeutic dose after first week - Discuss potential detrimental side effects (particularly initial gastrointestinal (GI) upset, headache, or anxiety) which should resolve within the first week - Explain that detrimental side effects occur before therapeutic benefit, which can take four to six weeks to reach full beneficial effect - Advise of need to take medications daily and continue even after remission of depressive symptoms - Counsel about potential discontinuation symptoms if medications are stopped abruptly - Reassure patients that dependence or tolerance does not occur - Discuss concerns related to antidepressants and potential increased suicidality # Managing Risk of Suicide - Advise risk of increased suicidality from antidepressants is small, most often associated with adolescents, and occurs early in the course of treatment - Explain that increased risk may arise from improved motivational activation, occurring before improvement in the depressed mood which underlies the suicidal thoughts - Provide guidance on how to seek help - Note that suicidal thoughts can be common, but completed suicide accounts for <0.02% of cancer deaths (this is 1.5 times the general population's risk), and Updating All PEBC documents are maintained and updated through an annual assessment and subsequent review process. This is described in the PEBC Document Assessment and Review Protocol, available on the CCO website at:

# GUIDELINE OBJECTIVES The primary objective of this guideline is to develop recommendations related to the frequency by which prostate-specific antigen (PSA) levels should be tested in men after curative-intent treatment for prostate cancer and to define the most appropriate diagnostic testing if biochemical (BC) recurrence occurs. The secondary objective is to develop recommendations that address psychosocial issues, sexual health, fatigue, urinary health, and bowel heath outcomes associated with treatment for prostate cancer. # TARGET POPULATION Prostate cancer patients who have undergone curative-intent treatment are the target population for this guideline. For prostate cancer patients who are on active surveillance, please refer to PEBC Guideline 17-9. # INTENDED USERS This guideline is targeted for radiation oncologists specializing in prostate cancer, family physicians, urologists, nurses, allied health professionals, and any other care provider involved in follow-up care of prostate cancer. # RECOMMENDATIONS RECOMMENDATION 1 No evidence-based recommendation can be made with respect to follow-up schedule of PSA testing for prostate cancer survivors following curative-intent treatment with surgery. However, if PSA levels remain undetectable, the Prostate Cancer Follow-up Expert Panel suggests the following as a reasonable schedule. This schedule for PSA testing is in line with PSA kinetics following therapy, other guidelines, and their clinical experience: - Every three months in year 1 - Every six months in year 2 - Annually thereafter # Qualifying Statements for Recommendation 1 - If PSA levels become detectable, a more frequent PSA surveillance schedule may be appropriate. - Even though PSA follow-up is recommended annually until end of life, healthcare professionals should use their own discretion in determining the applicability of annual surveillance in patients who are unlikely to benefit from salvage therapy. # RECOMMENDATION 2 No evidence-based recommendation can be made with respect to follow-up schedule of PSA testing for prostate cancer survivors following curative-intent treatment with non-surgery primary therapy, including any form of radiation therapy, cryotherapy, or high-intensity focused ultrasound. # Not usually appropriate - Use of NaF and choline PET should be considered experimental Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NaF, sodium fluoride; PET, positron emission tomography; PSA, prostate-specific antigen; RT, radiation therapy. Note: Salvage therapy refers to follow-up treatment provided after biochemical recurrence. # Qualifying Statements for Recommendation 3 - Diagnostic imaging should only be ordered if that test will result in management decisions; consideration should be given to the appropriateness of the test, coupled with available salvage options. - Salvage therapies following radiation therapy or ablation therapies need to be performed at specialized centres, with imaging decisions dependent on the local evaluation process. # RECOMMENDATION 4 In men who are not being evaluated through regularly scheduled clinical visits, a PSA test should be performed if the following symptoms develop. Additionally, diagnostic imaging specific to the patient's symptom(s) may be indicated. # RECOMMENDATION 5 Men experience very specific and oftentimes long-lasting effects after their primary therapy, usually occurring more than three months after surgery or radiation, or during/after androgen deprivation therapy (ADT). Follow-up healthcare providers should be aware of the domains of quality of life potentially affected by treatment for prostate cancer and the management options available to combat them. Research surrounding management options is lacking. Included management options that are based on the clinical standard in Ontario or expert opinion of the Prostate Cancer Follow-up Expert Panel have been denoted with an asterisk (). The symptoms listed are based on known profiles; however, individual men respond differently to treatments, resulting in individual side-effect profiles. To ensure optimal quality of life in these men, individual patient-reported outcomes should be measured. # Side-Effect Primary Treatment # Side-Effect Primary Treatment # Management Options - Referral to applicable support groups for coping training for couples, as well as social and emotional QoL well-being, may be considered Abbreviations: ADT, androgen deprivation therapy; PDE5, phosphodiesterase type 5; QoL, quality of life; rP, radical prostatectomy; RT, radiation therapy. # RECOMMENDATION 6 No diet plan can be recommended because no diet plan or food supplement has been associated with improved cancer outcomes. # RECOMMENDATION 7 For prostate cancer survivors who have completed curative-intent therapy, surveillance is required and may be provided by the treating oncologist, urologist, family physician, nurse practitioner, or hospital-based nurses. Models of care are described more thoroughly in PEBC Guideline 26-1. # Qualifying Statements for Recommendation 7 - All healthcare practitioners that provide PSA surveillance should manage PSA as per the current CCO Prostate Cancer Pathway. - Although the identified literature only evaluated hospital-based nurse-led care and shared care within the hospital setting, expert opinion supports family physicians being involved in all survivorship care models. - With the greater emphasis on a person-centred approach to care, a multidisciplinary approach to survivorship, which includes a psychosocial focus to recovery, is recommended. Although the shared care model identified by the literature did not include a psychosocial intervention focus, in order to provide person-centred care, expert opinion supports multiple disciplines being involved in shared care models.

What benefit to clinical management does 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) contribute to the initial diagnosis or staging of lymphoma?What benefit to clinical management does FDG PET/CT contribute after conventional imaging is performed, in patients with suspected or proven recurrence of lymphoma? What benefit to clinical management does FDG PET/CT contribute to routine follow-up at the time of documented recurrence for lymphoma?What benefit to clinical management does FDG PET/CT contribute to the interim assessment of treatment response and assessment of residual mass for lymphoma?# TARGET POPULATION The target population for these recommendations is adult patients suspected of, with a diagnosis of, or recurrence of lymphoma including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). # INTENDED USERS - This recommendation report is intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. - This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation of one high-quality United Kingdom (UK) Health Technology Assessment (HTA) that included systematic review and primary study literature for the period from 2000 to August 2005 (1). An update of this systematic review was undertaken by the New Zealand Guidelines Group (NZGG) to retrieve the evidence from the period from August 2005 to November 2011 (2). The Program in Evidence-Based Care (PEBC) has endorsed and adapted this evidentiary base for the purpose of this recommendation report; however, 17 additional studies were added post hoc by the PEBC team due to differences in the research objectives of the NZGG and the PEBC. In the NZGG report, systematic reviews were included. This PEBC review did not include these systematic reviews due to overlap in the studies between the reviews; however, the references lists of these systematic reviews were checked to ensure that no primary studies were missed. From this point forward in this document, reference will only be made to the UK HTA (primary studies prior to August 2005) and the primary studies included in this recommendation report (primary studies from August 2005 to November 2011). Pediatric studies were included in the systematic review and qualitatively summarized in Section 2 of this report; however, they were not utilized as part of the evidentiary base for these recommendations. # RECOMMENDATIONS AND KEY EVIDENCE Diagnosis Recommendation(s): A recommendation cannot be made for or against the use of FDG PET/CT for the diagnosis of lymphoma due to insufficient evidence. # Key Evidence: UK HTA (studies published prior to August 2005) The UK HTA (1) included one primary study that evaluated the use of PET in eight patients with gastric NHL. Due to its small population, the authors concluded that PET is unlikely to be used routinely for the diagnosis of lymphoma because histological confirmation is always required. # Studies published after August 2005 In adult patients, one study (3) evaluated the utility of FDG PET (no co-registered CT component) in primary central nervous system lymphoma diagnosis. Forty-two scans were performed for the purpose of initial diagnosis and staging. FDG PET scans were abnormal in eight of 42 patients. Biopsies were obtained in six of the patients, of which five revealed malignancy. In three patients, FDG PET revealed systematic NHL. Three patients had falsepositive results. # Qualifying Statements: - FDG PET may disclose higher rates of systemic disease; however, due to false-positive results, FDG PET scans should be subject to clinical follow-up or biopsy. # Staging Recommendation(s): When functional imaging is considered to be important in situations where anatomical imaging is equivocal, and/or in potentially curable cases, a FDG PET/CT scan is recommended. When functional imaging is considered to be important in situations where anatomical imaging is equivocal and treatment choices may be affected in limited stage indolent lymphomas, a FDG PET/CT scan is recommended. # Key Evidence: UK HTA (studies prior to August 2005) The UK HTA (1) evaluated several studies relating to the initial staging of HL and NHL. PET was consistently shown to be of superior sensitivity to Gallium ( 67 Ga) scanning, and was more accurate than or comparable with CT for staging. # Studies published after August 2005 In terms of patient management, the addition of FDG PET/CT modified the management of 8% to 32% of patients across included studies, with the majority of patients being upstaged as a result of the identification of distant disease. Studies evaluating the utility of FDG PET or PET/CT for initial staging in patients with both HL and NHL showed similar results (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In most studies, the specificity was high for both conventional imaging and FDG PET (often >90%); however, the sensitivities varied widely across studies and were generally low due to a prevalence of false-negative cases. In patients with mucosa-associated lymphoid tissue lymphoma, PET scans at baseline were reported to pick up more sites of disease than conventional staging tests (15)(16)(17)(18). In the detection of bone marrow involvement, FDG PET/CT correctly identified bone marrow involvement in approximately 95% of cases and patients were staged appropriately (5,19). FDG PET/CT was also shown to be useful in the planning of directed bone marrow biopsy. # Qualifying Statements: - There was some evidence to suggest that FDG PET/CT may miss small disease foci; however, in studies that compared FDG PET/CT with 67 Ga scanning, the diagnostic accuracy of FDG PET/CT was shown to be superior. - In most cases, FDG PET/CT changed the management of several patients. Most patients were upstaged due to the identification of advanced disease stage; however, due to poor reporting and short follow-up, the clinical relevance and whether the change resulted in a better clinical outcome of the upstaging was unclear. # Response Evaluation (interim and at completion of therapy) Recommendation(s): An FDG PET/CT scan is recommended for the assessment of early response in early stage (I or II) HL following two or three cycles of chemotherapy when chemotherapy is being considered as the definitive single-modality therapy, to inform completion of therapy or if more therapy is warranted. # Key Evidence: UK HTA (studies prior to August 2005) The UK HTA (1) included nine primary studies and concluded that there was some weak evidence, consisting mainly of small-scale observational studies, suggesting that FDG PET/CT may be predictive of therapeutic response following two to three cycles of chemotherapy. There was no evidence to suggest that the addition of interim FDG PET/CT changed patient management (such as intensification or change in therapy). # Studies published after August 2005 Evidence suggests that FDG PET/CT scans are superior to conventional anatomical imaging in assessing response to treatment both interim and at completion (10,11,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Interim PET scan results appear to carry powerful prognostic information that can be predictive for treatment failure in patients with NHL and HL undergoing primary therapy. The available evidence indicates that a PET-positive scan at the completion of therapy is associated with poorer prognosis. Also, in patients with relapsed lymphoma who are undergoing salvage chemotherapy and autologous stem cell transplantation, PET scan results appear to be an independent predictive factor for progression-free survival, but are not as strong for overall survival. # Qualifying Statements: - For interim response to treatment, data around the role of PET in this population are continuing to evolve and patients should be involved in prospective clinical trials conducted in a multidisciplinary setting. # Diagnosis of Suspected Recurrence and Routine Follow-up Recommendation(s): In potentially curable cases, when functional imaging is considered to be important and conventional imaging is equivocal, a FDG PET/CT scan is recommended to investigate recurrence of HL or NHL. An FDG PET/CT scan is recommended for the evaluation of residual mass(es) following chemotherapy in a patient with HL or NHL when further, potentially curative, therapy (such as radiation or stem cell transplantation) is being considered and when biopsy cannot be safely or readily performed. # Key Evidence: UK HTA (studies prior to August 2005) The UK HTA (1) included five primary studies that demonstrated that FDG PET/CT was a better predictor of relapse after therapy than CT. When compared with 67 Ga scanning and CT scanning, post-therapy FDG PET/CT had a similar sensitivity and better specificity. # Studies published after August 2005 In regard to recurrence, the current recommendation report included six studies evaluating adult patients (11,20,(32)(33)(34)(35) and three studies evaluating pediatric patients (21,36,37). FDG PET/CT showed a good concordance with conventional imaging in the detection of recurrence; however, due to a prevalence of false-positive results in these studies, PETpositive patients may benefit from clinical follow-up. In this recommendation report, 11 primary studies (3,7,9,11,14,(38)(39)(40)(41)(42)(43) investigating FDG PET/CT in the routine follow-up of patients with lymphoma showed similar results with no significant differences between HL and NHL or adult and pediatric patients. Both specificity and sensitivities were high and were in good concordance with conventional imaging. Several studies also provided evidence that a pretransplant FDG PET/CT scan contained predictive information on the long-term clinical outcome of patients (7,(44)(45)(46). # Qualifying Statements: - In cases where FDG PET/CT scans have a positive result, patients may benefit from close clinical follow-up or confirmatory biopsy due to a prevalence of false positives in the literature. # Routine Surveillance Recommendation(s): An FDG PET/CT scan is not recommended for the routine monitoring and surveillance of lymphoma. # Key Evidence: Studies published after August 2005 Three studies evaluated the efficacy of FDG PET/CT in the routine surveillance of lymphoma patients (20,32,33). All studies noted increased false positives as well as a lack of evidence of cost effectiveness compared with conventional imaging. The costs incurred as a result of the false positive results were unacceptably high. # Qualifying Statements: - The current standard of practice in Ontario is to follow patients clinically with history, physical examination, and routine blood work. # Qualifying Statements Applicable to all Recommendations: - In cases where FDG PET/CT scans have a positive result, patients may benefit from close clinical follow-up or confirmatory biopsy due to a prevalence of false positives in the literature. - Although most individual studies outlined the technical aspects of how the FDG PET or PET/CT scan was performed and reported, in most studies, the scans were not read by blinded readers and it is unclear whether technical differences may make studies more difficult to compare with one another. - PET scans are not assumed to be perfect tests and they are associated with variable rates of false-positive and false-negative rates. Practitioners should keep this in mind when interpreting the results of a PET scan. - With respect to HIV-positive lymphoma patients, only small studies that did not meet the inclusion criteria were found in the systematic literature search; however, the authors are aware of a higher prevalence of false-positive FDG PET/CT results due to higher standardized uptake values in areas of inflammation. # FUTURE RESEARCH Future research should focus on conducting randomized controlled trials with larger sample sizes focusing on clinically and histologically more homogeneous populations using standardized FDG PET/CT protocols and interpretation criteria. Better standardization of diagnostic criteria with the involvement of well-trained assessors should also be emphasized due to the potential of inter-reader variability. It should also be a priority to incorporate FDG PET/CT scan results in the design of randomized clinical trials to better direct patient management. It is suggested, where possible, that patients be enrolled in clinical trials of PET-directed therapy. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

There are various definitions for palliative care, but most people would agree that "it focuses on care that addresses both physical and non-physical symptoms. It can be delivered throughout the course of the disease. It involves a team of healthcare providers and supports patients as well as their families." This evidence summary on palliative care guidelines was requested by the Ontario Palliative Care Network (OPCN). The purpose of this evidence summary is to identify existing palliative care guidelines that could potentially be endorsed or adapted for use in Ontario. # RESEARCH QUESTIONS These research questions were developed to direct the search for available evidence on any palliative guidelines in the public domain. # TARGET POPULATION The target population of the guideline search is any individual requiring palliative care. # INTENDED PURPOSE To determine the breadth and scope of palliative care guidelines that are available in the public domain. # INTENDED USERS Clinicians and staff involved in the delivery of palliative care. This evidence summary was developed by a Working Group consisting of a palliative care physician, a clinical nurse manager, a palliative care specialist, a quality standards lead, and a health research methodologist. The Working Group was responsible for reviewing the identified evidence and drafting the summary. Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. # Search for Existing Guidelines A search was conducted for existing guidelines. The search was undertaken in the following databases: Medline, EMBASE, and HeathSTAR. The databases were searched from January 1, 2000 to March 10, 2016. The search terms used included: guideline, consensus, palliative care, palliative medicine, terminal care, hospice, and palliative therapy. A complete literature search strategy is available in Appendix 2. The websites of major international as well as national guideline developers were also searched using the terms "palliative care". These include the National Institute for Health Care and Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), The BC Cancer Agency, Alberta Health Services, National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), National Guideline Clearinghouse, New Zealand Guidelines Group, Australian Clinical Practice Guidelines. # Study Selection Criteria and Process Papers were included if they provided any recommendations on palliative care. Papers were excluded if they only provided guideline or consensus methods and no recommendations. A review of the titles and abstracts that resulted from the search was conducted independently by one reviewer (NC). For items that warranted full-text review, one reviewer (NC) reviewed each item independently. # Data Extraction and Assessment of Study Quality and Potential for Bias For the selected guidelines, one reviewer (NC) assessed each guideline for quality using the "Rigour of Development" scale from the AGREE instrument. # Search for Existing Guidelines A total of 4943 potential guidelines were found; 4915 were identified through the electronic search and 28 from searching the websites of major guideline development groups. Articles were chosen for full-text review if they contained any recommendations. The flow diagram can be seen in Appendix 3. Of the 266 potential guidelines chosen for full-text review, 172 were retained after the full-text review. The guidelines were then sorted into three groups. The first contains guidelines on general aspects of palliative care; the second group contains guidelines that are disease specific (i.e. cancer, diabetes, or amyotrophic lateral sclerosis); and the third contains palliative care guidelines that pertain to children from newborn to 18 years of age. There were 88 guidelines on general aspects of palliative care, 69 disease-specific guidelines, and 15 for children. Due to the large number of guidelines, the Working Group decided to restrict the review to include only guidelines published in the past five years (2011 to 2016). To identify the best-quality guidelines, the AGREE Instrument Rigour of Development scale was used and only guidelines that scored 28 or above were included in this review. The AGREE Rigour of Development scale is scored out of seven for each of eight questions for a total possible score of 56. Guidelines that scored 28 or above were considered to have higher AGREE scores and will be discussed below. The Working Group chose this section to use as a screening tool because it shows how rigorous the reported guideline methods were. It was also faster to do this one section than completing the whole AGREE scale for all the large number of identified guidelines. # General Palliative Care Guidelines This section contains guidelines that pertain to palliative care but are not disease or patient specific. This section is the most detailed of the three sections, and the most relevant because it focuses on the whole pathway of palliative care and is related to the guideline objective. Some of the guidelines are broad and cover the entire palliative care path that a patient would follow, while others are narrow in scope and only pertain to a single aspect of palliative care. Of the 172 potential guidelines selected for full-text review, 88 were classified as general palliative care. Of these, 66 guidelines were published before 2011 and, thus, excluded (see Appendix 4). Fifteen guidelines had AGREE Rigour of Development subsection scores lower than 28 and seven had high AGREE scores that were 28 or higher. The guidelines that could be assessed using the AGREE tool are presented in Table 1. Due to the low scores, the guidelines that scored in the bottom half of the range in the AGREE, Rigour of Development scale will not be discussed in detail. It should be noted that many of these guidelines scored low because they were lacking details in several of the guideline development methods, such as: no systematic methods were used to search for evidence, there was no criteria for selecting the evidence, and no method for formulating the recommendations was provided. The seven guidelines with highest AGREE Rigour of Development subsection scores ranged in topics from specific aspects of palliative care to the general organization of palliative services. The "Palliative Care for Adults" guideline by McCusker et al. from the Institute for Clinical Symptoms Improvement covers the palliative care path from the patient's first diagnosis of a serious illness to death. This guideline had an AGREE Rigour of Development subsection score of 37. It provided few details on the systematic review methods, including how the evidence was selected and how the recommendations were developed. This guideline used GRADE to evaluate the evidence but did not provide much information on how the guidelines were chosen for review. Since this is the only broad palliative care guideline, the recommendations are listed below: The guideline from the Registered Nurses Association of Ontario scored highly in the AGREE Rigour of Development subsection (48 of 56). This is a Canadian guideline about patient care in the last days and hours of life, and the recommendations in this guideline were specific to nurses. The guideline makes recommendations in the following areas: - Assessment for end of life, Decision support at end of life, Care and management at end of life, Education, and Organization and policy recommendations. Another guideline from the Registered Nurses Association of Ontario was also found. The topic of this guideline was the assessment and prevention of pressure ulcers. This guideline does not focus solely on palliative care, but the treatment and assessment of pressure ulcers in palliative care is a part of the guideline. This guideline is Canadian and is specific to nurses. The guideline makes recommendations in the following areas: - Assessment, Planning, Interventions, Discharge or transfer or the care arrangements, and Education and organization/policy. The guideline by Wee et al. discusses chronic cough in patients receiving palliative care. This guideline scored 37 using the AGREE Rigour of Development subsection. The systematic review in this guideline was conducted well; however, much of the evidence was from small studies or cohort studies, case reports, and expert opinion pieces. The small studies were randomized but had high heterogeneity and could not be easily compared to each other. The recommendations include use of simple linctus, therapeutic trial of sodium cromoglycate, and then prescription of an opioid or opioid derivative (dextromethorphan, morphine, or codeine). Two of the guidelines came from NICE. They both scored high on the AGREE Rigour of Development subsection (52 of 56, respectively). One focused on strong opioids for pain relief in patients receiving palliative care and the other on care of dying adults in the last days of life. The guideline on strong opioids for pain relief made recommendations in the following areas : - Communication, Starting strong opioids -titrating the dose, First-line maintenance treatment, First-line treatment if oral opioids are not suitable -transdermal patches, First-line treatment if oral opioids are not suitable -subcutaneous delivery, Management of constipation, Management of nausea, and Management of drowsiness. The care of dying adults in the last days of life guideline made recommendations in the following areas : - Recognizing when a person may be in the last days of life, Communication, Shared decision-making, Providing individualized care, Maintaining hydration, Pharmacological interventions, and Anticipatory prescribing. # Disease-Specific Guidelines This section contains guidelines that are specific to a group of patients with a disease or condition. The majority of the guidelines pertain to cancer or patients with dementia. Of the 172 papers that were selected for full-text review, 69 were classified as disease-specific palliative care. Of these, 46 guidelines were published before 2011 and excluded (see Appendix 4). Six had AGREE Rigour of Development subsection scores lower than 28 and will not be discussed further and 17 had AGREE scores that were 28 or higher. The results of the AGREE Rigour of Development assessment can be seen in the table below. There are 12 guidelines specific to cancer 39,42,. The NCCN guideline by Levy et al. is a comprehensive guideline about the palliative care path in cancer patients. It scored highly on the AGREE Rigour of Development subsection scale (40 of 56). This guideline includes recommendations on screening, assessment, palliative interventions, reassessment, and after-death interventions. It does not begin the palliative assessment with the onset of disease, but further along during disease progression or when the patients inquire about it. The ASCO guideline has a provisional clinical opinion that relates to integrating palliative care services into standard cancer care. This guideline scored 39 on the AGREE Rigour of Development subsection scale and states that palliative care services should begin when patients are diagnosed with metastatic or advanced cancer. The other higher AGREE Rigour of Development scoring cancer-related guidelines focused on a single aspect of palliative care. There were four guidelines on the use of radiotherapy, two for palliative radiotherapy for bone metastases and two for palliative radiotherapy for lung cancer. There was one guideline each on depression terminal hemorrhage in cancer palliative care patients being treated at home cancer pain and dyspnea. There was an additional guideline on cancer fatigue ; this NCCN guideline was not exclusively on palliative care, but had sections pertaining to palliative care fatigue. The other large group of disease-specific guidelines pertained to dementia. The guideline by van Riet Paap et al. is a consensus guideline that centres on quality indicators to assess the organization of palliative cancer and dementia care. This guideline scored 30 on the AGREE Rigour of Development subsection scale. This guideline identified 23 quality indicators covering the following areas: the availability of palliative care teams; the availability of special facilities to provide palliative care for patients and their relatives; and the presence of educational interventions for professionals, such as documentation of pain and other symptoms, communication with patients in need of palliative care and their relatives, and end-of-life decisions. An additional two guidelines were found that focused on dementia or delirium. The first is a Canadian guideline by Brajtman et al. which pertained to delirium in older adults at the end of life in various healthcare settings. The guideline by van der Maaden et al. focused on reliving symptoms of pneumonia and dementia in patients in nursing homes. Two guidelines centred on treating diabetes in the palliative setting. The first is a Canadian guideline by Mallery et al. for the Diabetes Care Program of Nova Scotia (DCPNS) and the Palliative and Therapeutic Harmonization (PATH), and focuses on frail older adults with type 2 diabetes. This guideline scored a 36 on the AGREE Rigour of Development subsection scale. The goal of this guideline was to create a more appropriate standard of care regimen for frail patients and makes clinical recommendations for care. The second diabetes guideline is by Dunning et al. This guideline scored 31 on the AGREE Rigour of Development subsection scale and describes the process used to develop a clinical practice guideline for managing diabetes at the end of life. The recommendations are guiding philosophies and not clinical recommendations. # Pediatric Guidelines This section contains guidelines that pertain to palliative care and are specific to children. This group includes children from newborns to 18 years of age. Of the 172 papers that were selected for full-text review, 15 pertained to children. Six guidelines were published before 2011 and therefore excluded (see Appendix 4). Six had lower AGREE Rigour of Development subsection scores (lower than 28) and will not be discussed further and three had higher AGREE Rigour of Development subsection scores. The assessed guidelines can be seen in Table 3 below. There were three guidelines that had AGREE Rigour of Development subsection scores that were 28 or over. The first guideline by Berger et al. focused on palliative care of preterm infants delivered between 22 and 23 weeks' gestation. The second guideline by Coccia at al. was an NCCN guideline that focused on adolescent and young adults through their cancer journey and had a section on palliative care. The third guideline by Knops et al. was a thorough guideline on palliative care for children. # DISCUSSION AND CONCLUSION The goal of this evidence summary was to determine the breadth and scope of available, recent, palliative care guidelines to see if there were any that could potentially be endorsed or adapted. The 172 guidelines found in this review ranged in topic and quality. Comparison among guidelines was challenging due to marked heterogeneity. Many of the guidelines included in this review scored low on the Rigour of Development AGREE scale. This was only one subsection of the AGREE scale and the guidelines that scored low in this area may have scored higher in other areas. # INTERNAL REVIEW The evidence summary was reviewed by the Director of the PEBC. The Working Group is responsible for ensuring the necessary changes are made. After internal review, the report was presented to the working group. The working group reviewed the document at a meeting on June 16 th 2016, and formally approved the document. The Working Group would like to thank the following individuals for their assistance in developing this report: - Sheila McNair, and Hans Messersmith, for providing feedback on draft versions. for copyediting.

# GUIDELINE OBJECTIVES The objective of this guideline is to update a previous guideline on chemotherapy options for women with recurrent, metastatic, or persistent cervical cancer. The primary outcomes of interest are overall survival rate and quality of life. Other outcomes of interest include response rate, progression-free survival rate, and adverse effects. Second-line or higher therapy options are outside the scope of this guideline. # TARGET POPULATION These recommendations apply to women with metastatic, recurrent, or persistent cervical cancer for whom systemic therapy is indicated. This includes women with squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix. # INTENDED USERS The intended users of this guideline are gynecologic oncologists or oncologists treating gynecologic cancers in the province of Ontario. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION RECOMMENDATION 1 It is recommended that all patients with recurrent, metastatic or persistent cervical cancer be offered the opportunity to participate in randomized clinical trials, if available, that evaluate the efficacy of and adverse effects of systemic therapy regimens. # Summary of Key Evidence and Justification for Recommendation 1 This recommendation is the opinion of the Working Group and was adopted from the previous version of this guideline. # RECOMMENDATION 2 Cisplatin with paclitaxel is recommended for this patient population, and cisplatin in other combinations, including cisplatin-vinorelbine, cisplatin-gemcitabine, and cisplatin-topotecan may also be considered. The substitution of carboplatin for cisplatin in these combinations is also recommended for this target population because carboplatin is associated with fewer adverse effects and greater ease of administration. The selection of combination chemotherapy will depend on toxicity profile, patient preference, and other factors; for example, cisplatin combinations may be preferred in cases of allergic reaction or of difficulty with bone marrow suppression. # Summary of Key Evidence and Justification for Recommendation 2 GOG-0204 which included patients with a performance status ≤1 (meaning that they were restricted in physically strenuous activities but ambulatory) compared the combinations cisplatin-vinorelbine, cisplatin-gemcitabine, and cisplatin-topotecan with the reference arm cisplatin-paclitaxel, with OS as the primary endpoint. This study was terminated early because the comparator groups were unlikely to demonstrate any of the combinations statistically superior to the reference arm, thus justifying the recommendation that each of these combinations could be considered options for the target population. Paclitaxel (175 mg/m 2 of body surface area for 3 hours on day 1 in combination with carboplatin (area under the curve 5 1h d1) has been tested as an alternative to the standard, but more toxic, paclitaxel (135 mg/m 2 24h d1) and cisplatin (50 mg/m 2 2h d2) in a Japan Clinical Oncology Group phase III noninferiority trial in stage IVB, persistent, or recurrent cervical cancer (JCOG-0505). This study, published as an abstract, followed 253 patients for 17.4 months and demonstrated the noninferiority of carboplatinpaclitaxel compared with cisplatin-paclitaxel (overall survival rate 17.5 versus 18.3 months; hazard ratio 0.99; adjusted 90% confidence interval 0.79 to 1.25; noninferiority p=0.032). Lower rates of neutropenia, febrile neutropenia, creatinine levels, and early treatment discontinuation due to adverse effects were experienced by patients in the carboplatin combination group, as well as higher rates of thrombocytopenia and neuropathy. There was a significantly higher nonhospitalization period, a proxy for quality of life, for patients in the carboplatin-paclitaxel arm. Based on these results, and on the feasibility of administration, carboplatin-paclitaxel is recommended as a treatment option for recurrent, metastatic, or persistent cervical cancer. # RECOMMENDATION 3 Bevacizumab in combination with cisplatin-paclitaxel is recommended for a specific subset of the target population, which includes only patients that match the characteristics of the GOG-0240 study population. Carboplatin may be substituted for cisplatin in this patient population, based on the justification given under Key Evidence and Justification below. The subset includes patients with primary stage IVB (has spread to parts of the body away from the cervix, such as the liver, intestines, lungs, or bones) recurrent, or persistent disease not amenable to curative treatment with surgery and/or radiotherapy, who have performance status scores of ≤1, adequate renal, hepatic, and bone marrow function, and not including those patients previously treated with chemotherapy for recurrence or those with nonhealing wounds, active bleeding conditions or inadequately anticoagulated thromboembolism. In addition, GOG-0240 did not include patients with stage IIIB cancer (local extension to pelvic sidewall) or IVA cancer (invasion into bladder or rectum). For more details on the GOG-0240 patient population, see the study details provided at clinicaltrials.gov. Contraindications to bevacizumab include: # Summary of Key Evidence and Justification for Recommendation 3 Results detected a significant overall survival rate advantage of chemotherapy with cisplatin (50 mg/m 2 and paclitaxel (135 or 175 mg/m 2 d1) or topotecan (0.75 mg/m 2 d1 to d3) and paclitaxel (175 mg/m 2 d1) with bevacizumab (15 mg/kg of body weight d1) (HR], 0.71; 98% CI, 0.54-0.95; p=0.004, one-sided) versus these chemotherapy options without bevacizumab. Cycles were repeated at 21-day intervals. There was also a significant difference in OS for cisplatin-paclitaxel with bevacizumab compared with cisplatin-paclitaxel without bevacizumab (median OS: 17.5 versus 14.3 months, HR, 0.68; 95% CI, 0.48-0.97; p=0.04, one-sided). Patients in the bevacizumab arm experienced more hypertension of grade 2 or higher, thromboembolitic events of grade 3 or higher, and gastrointestinal fistula of grade 3 or higher; however, no significant differences in quality of life were detected. As in GOG-0204, patients in this trial had a performance status of ≤1. The discontinuation rate was 25% with patients in the bevacizumab group versus 16% of patients in the group that did not receive bevacizumab. Although GOG-0240 tested bevacizumab with cisplatin and paclitaxel, the noninferiority of carboplatin-paclitaxel demonstrated in JCOG-0505, its more favourable toxicity profile and ease of administration, as well as its demonstrated efficacy in other disease sites provide support for the recommendation for carboplatin. # Qualifying Statement for Recommendation 3 There may be a risk of thrombocytopenia with the combination of carboplatin and bevacizumab. However, estimates of the level of risk for this adverse event are not available, as the combination was not tested in the patient population for this guideline. Updating All PEBC documents are maintained and updated through an annual assessment and subsequent review process. This is described in the PEBC Document Assessment and Review Protocol, available on the CCO website at: Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

What benefit to clinical management does positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) contribute to the diagnosis or staging of melanoma? What benefit to clinical management does PET or PET/CT contribute to the assessment of treatment response for melanoma? What benefit to clinical management does PET or PET/CT contribute when recurrence of melanoma is suspected but not proven? What benefit to clinical management does PET or PET/CT contribute to restaging at the time of documented recurrence for melanoma? What is the role of PET when a solitary metastasis is identified at the time of recurrence and a metastectomy is being contemplated? # TARGET POPULATION Patients with melanoma. # INTENDED PURPOSE - This recommendation report is primarily intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality U.K. Health Technology Assessment (HTA) systematic review (1) that included systematic review and primary study literature for the period from 2000 to August 2005 and an update of that systematic review undertaken to retrieve the same level of evidence for the period from August 2005 to June 2008. # Diagnosis/Staging PET is recommended for staging of high-risk patients with potentially resectable disease. One study (Brady et al evaluated the additive benefit of PET to CT as a preoperative imaging technique. The combination of PET and CT had higher sensitivity than either technique alone. Information from the preoperative imaging results of PET plus CT led to treatment change in 35% of patients. Another study (Strobel et al showed a sensitivity, specificity, and accuracy of 85%, 96%, and 91%, respectively, for the depiction of metastases in high-risk melanoma. Qualifying Statement Criteria for high risk include lymph node metastases, deep head and neck melanoma, and evidence of satellitosis or in-transit metastases. These include patients with American Joint Committee on Cancer (AJCC) stage IIC and III disease. PET is not recommended for the diagnosis of sentinel lymph node micrometastatic disease or for staging of I, IIa, or IIb melanoma. Nine primary studies in the HTA review (1) and three primary studies from the 2005-2008 update (Kell et al Maubec et al Cordova et al evaluated PET or PET/CT as a useful adjunct to lymphatic staging in patients with primary melanoma. The sensitivity of PET was too low to detect sentinel node metastases in early-stage melanoma (sensitivity range 0% to 22%). # Qualifying Statement # The routine use of PET or PET/CT is not recommended for the diagnosis of brain metastases. A limitation of PET is the normal uptake of fleurodeoxyglucose (FDG) into the brain, leading to uncertainty in the detection of cerebral metastases. Several small studies have confirmed this, showing low sensitivity of PET for the detection of brain metastases. One study (Pfannenberg et al showed that MRI was superior to PET in detecting brain metastases. # Qualifying Statement The routine use of PET is not recommended for the detection of primary uveal malignant melanoma. One primary study (Kato et al showed that single photon emission computed tomography (SPECT) was superior to PET for detection of uveal melanoma. The sensitivity of PET was 11%. # Qualifying Statement # Assessment of Treatment Response A recommendation cannot be made for or against the use of PET for the assessment of treatment response in malignant melanoma due to insufficient evidence. No prospective studies exist that examine PET or PET/CT in the assessment of treatment response for melanoma. # Qualifying Statement A recommendation cannot be made for or against the use of PET for routine surveillance due to insufficient evidence. No prospective studies exist that examine PET in the assessment of recurrence. # Qualifying Statement Solitary Metastasis Identified at Time of Recurrence PET is recommended for isolated metastases at time of recurrence or when contemplating metastectomy. There is some evidence showing change in patient management with the use of PET or PET/CT prior to metastectomy (HTA review Koskivuo et al. However, prospective studies assessing isolated metastases alone have not been conducted. # Qualifying Statement Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Peer review publication. # TARGET POPULATION - Patients of any age diagnosed with localized Ewing's sarcoma of bone who have completed neoadjuvant chemotherapy for the first objective - Patients of any age diagnosed with localized Ewing's sarcoma of bone who will undergo surgical management following neoadjuvant chemotherapy for the second objective # INTENDED USERS General surgeons, orthopaedic oncology surgeons, medical oncologists, radiation oncologists, pathologists, radiologists, and other clinicians who are involved in the treatment of the target patients in the province of Ontario. # RECOMMENDATIONS Recommendation 1 In patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy: - Either surgery alone or RT alone is a reasonable treatment option; the combination of surgery plus RT is not recommended as an initial treatment option. - The local treatment for an individual patient should be decided by a multidisciplinary tumour board together with the patient after consideration of the following: 1) patient characteristics (e.g., age, tumour location, tumour size, response to neoadjuvant chemotherapy, and existing comorbidities), 2) the potential benefit compared with the potential complications from surgery and/or toxicities associated with RT, and 3) patient preference. # Qualifying Statements for Recommendation 1 - If complete tumour resection is impossible, RT alone may be the optimal choice. - RT may be a treatment option postoperatively in patients who have residual tumours or positive margins. - The optimal RT dose has not been determined. The reported RT doses in this document ranged from 55 to 60 Gray for RT alone (except one study published in 1999) and from 35 to 60 Gray for RT as an adjuvant to surgery. # Added to the 2022 Endorsement: - One retrospective data analysis of patients in the Euro-EWING99 trial treated with induction chemotherapy reported that a combination of RT and surgery decreased local recurrence more than RT alone in patients with non-sacral tumours of the pelvis. This evidence requires corroboration from further studies to warrant a review of or change to the current recommendation. See Section 6 for details. # Recommendation 2 In patients with localized Ewing's sarcoma who will undergo surgery: - Both pre-chemotherapy and post-chemotherapy MRI scans should be taken into consideration for surgical planning. In certain anatomic locations with good chemotherapy response, the post-chemotherapy MRI may be the appropriate imaging modality to plan surgical resection margins.

These recommendations apply to adult patients (≥18 years old) with unresectable metastatic colorectal cancer. The cytotoxic agents covered in this guideline include initial fluoropyrimidine (5-FU or capecitabine) either alone or in combination, irinotecan and oxaliplatin. # INTENDED USERS This guideline is intended for use by clinicians and healthcare providers involved in the management of patients with unresectable, metastatic colorectal cancer treated with palliative intent. # RECOMMENDATIONS AND KEY EVIDENCE A meta-analysis of five trials (1-5) demonstrates a survival advantage for combination chemotherapy (HR, 0.92; 95%CI, 0.86-0.99, p=0.02). Median survival advantage in most trials is 3 to 6 weeks (range <1 week to 12 weeks). Therefore, any survival advantage that exists is likely to be very small and not clinically significant. First-line toxicities are reported by three trials (1,2,4). Hematological toxicities include significantly more neutropenia (1,4), febrile neutropenia (1) and thrombocytopenia (4) with upfront combination chemotherapy. Nonhematological toxicities include significantly more diarrhea (1), nausea (1,4), vomiting (1,4) and sensory neuropathy (4) in the upfront combination chemotherapy arm, and significantly more hand-foot syndrome in the sequential chemotherapy arm (1). # QUALIFYING STATEMENTS - The FOCUS (2) trial is the largest trial of the five included trials. The individual hazard ratio for the FOCUS (2) trial only includes two arms of this trial. Therefore, one third of the data from this trial is missing from the overall meta-analysis of the five trials. - Based on the results of this systematic review, patients should have access to all effective cytotoxic drugs using a sequential strategy. - Combination chemotherapy may be more appropriate for patients with rapidly progressing, very symptomatic or bulky life-threatening visceral disease given their higher overall response rates. - The studies included in this systematic review were done in an era prior to the use of biologics in the treatment of mCRC. Definitive statements about the integration of biologics into a sequential strategy cannot be made at this time. # FUTURE RESEARCH Future research of strategies of care should also include biologically targeted therapies. Planned sequential chemotherapy and upfront combination chemotherapy are both acceptable standards of care. While there is a statistically significant difference in overall survival in favour of combination chemotherapy, the magnitude of the difference between the two strategies may not be clinically significant. Furthermore, sequential therapies may reduce upfront toxicities. Therefore, choice of treatment should be made on a caseby-case basis based on considerations that include patient and tumour characteristics, toxicity of each strategy and patient preference. Sequential chemotherapy consists of a fluoropyrimidine monotherapy followed by either: a. another monotherapy with irinotecan OR b. combination chemotherapy consists of a doublet of a fluoropyrimidine with irinotecan or oxaliplatin Combination chemotherapy consists of an upfront doublet of a fluoropyrimidine with irinotecan or oxaliplatin. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED GUIDELINES

# Acute Myeloid Leukemia (AML) What is the role of SCT in the treatment of AML? # TARGET POPULATION All adult patients with MDS or AML being considered for treatment that includes either blood or bone marrow transplantation. # RECOMMENDATIONS AND SUPPORTING EVIDENCE MYELODYSPLASTIC SYNDROME (MDS) Allogeneic transplantation is an option for patients with MDS. This is the only potentially curative therapy for MDS. # Evidence One systematic review comprising a total of 22 studies demonstrated a long-term curative outcome for related, unrelated, either or unspecified allogeneic SCT (alloSCT) (1). Autologous stem cell transplantation is not recommended for patients with MDS. # Evidence One systematic review comprising a total of 22 studies did not detect any benefit associated with autologous SCT (ASCT), and does not recommend it outside of a clinical trial (1). # ACUTE MYELOID LEUKEMIA (AML) First complete remission Allogeneic transplantation is a treatment option for patients with AML in first complete remission (CR1), with high-risk features including intermediate or high-risk cytogenetic or molecular phenotypes, high-risk clinical features at presentation, and secondary or treatmentrelated AML. Evidence One systematic review (2), comprising 24 clinical studies involving 6,007 patients with AML in CR1 comparing alloSCT, ASCT, chemotherapy (CT), or any combination of the three, found a significant RFS and OS benefit associated with allogeneic SCT. That review performed subgroup analyses for both recurrence or relapse-free survival (RFS) and overall survival (OS) according to patient risk (good, intermediate, or poor risk). Significant benefits in favour of alloSCT for both intermediate and poor risk patients (p<0.01) were detected, but no difference was detected with good risk patients. The OS subgroup analysis also detected significant benefits in favour of alloSCT for intermediate and poor risk patients (p<0.01) but not for good risk patients. One meta-analysis ( 3), that pooled data from two trials (AML 96 and AML 02) that compared alloSCT with ASCT with CT, including a total of 708 patients, detected significant differences in favour of alloSCT for both OS and leukemia-free survival (LFS) at two years. In a multivariate analysis, factors associated with better OS and longer LFS were being younger (p=0.008) and receiving an allogeneic transplant. One prospective cohort study (4) found significant benefits in favour of alloSCT compared with ASCT in the relative risk for eight-year disease-free survival (DFS). ASCT is not recommended for patients with AML in first complete remission. Evidence While associated with more favourable treatment-related mortality (TRM) rates, if longterm survival is the primary outcome of interest, then there is no evidence to support the use of ASCT in first complete remission. # Beyond first complete remission Allogeneic transplantation is the recommended option for patients with AML who achieve a second or subsequent remission. Evidence Evidence from one clinical practice guideline (5) demonstrated that if CR only occurs after a second course of induction therapy, myeloablative alloSCT from a fully-matched sibling donor is recommended, regardless of the risk, if the patient is under 55 years of age and has no other co-morbidities There is insufficient evidence to support the use of ASCT for patients with AML in second or subsequent remission. Evidence If long-term survival is the primary outcome of interest, then there is no evidence to support the use of ASCT in second or subsequent remission. Autologous transplantation is recommended for acute promyelocytic leukemia (APL) in a molecularly-negative second remission. # Evidence No evidence was obtained in this update of the 2009 report (6), and the Expert Panel continues to support this recommendation. Select patients with AML not in remission may derive benefit from allogeneic transplant. Evidence Evidence from one clinical practice guideline (7) demonstrated that, when a patient does not experience a CR, then that patient should be offered entry into a clinical trial, or reduced intensity alloSCT within a clinical trial setting, or best supportive care (BSC). # QUALIFYING STATEMENT The patient selection process and the ultimate decision to perform an SCT should take into account not only disease-related characteristics, but also comorbidities and patient preferences. Patients with MDS or AML should be referred to a transplant centre for transplant assessment. # FUTURE RESEARCH Ongoing studies in MDS and AML testing newer agents may or may not impact on the number of patients potentially requiring SCT. Reduced intensity transplant and newer methods of preventing or treating graft versus host disease may expand the eligible transplant population. In addition, stem cell procurement from alternative donors such as cord blood and haploidentical donors may also allow SCT to be an option for a greater number of patients. # IMPLICATIONS FOR POLICY Given the potential increase in the numbers of patients with MDS and AML over time, and the possibility of new transplant methodologies resulting in better outcomes and more donors available thru newer sources, the number of patients eligible for SCT will likely increase. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED PROGRAM IN EVIDENCE-BASED CARE REPORTS

# GUIDELINE OBJECTIVES The objective of this guideline is to determine the most effective therapy for patients with thymic epithelial tumours. # TARGET POPULATION The target population are adult patients with thymic epithelial tumours, including thymoma, thymic carcinoma, and thymic neuroendocrine tumours (NETs). # INTENDED USERS The intended users of this guideline are all healthcare professionals managing patients with thymic epithelial tumours. Complete resection -refers to an R0 resection of the tumour or resection with negative margins Total resection -refers to resection of the entire thymus (including all mediastinal tissues anterior to the pericardium, aorta, and superior vena cava from phrenic nerve to phrenic nerve laterally and from the diaphragm inferiorly to the level of the thyroid gland superiorly, including the upper poles of the thymus), the tumour, and any involved structures Partial resection -refers to resection of less than the entire thymus, but includes the tumour and any involved structures The staging system for patients with thymic epithelial tumours has recently changed to a TNM staging system. The evidence used to support these recommendations was mainly from observational studies that used the prior Masaoka and Masaoka-Koga staging systems. Given the lack of randomized trials, the Working Group endorsed most of the consensus-based recommendations from the previous version of this guideline (see Appendix 1). For patients with thymic NETS, recommendations were endorsed from the National Comprehensive Cancer Network (NCCN) Version 1.2021 Neuroendocrine and Adrenal Tumors Guideline. General Principles 1. The aim of surgery in all cases is to achieve a complete resection. 2. The TNM staging system should be used for all patients. 3. Discussion of all patients at multidisciplinary cancer conference (MCC) is strongly recommended, not just at local MCC but also with higher-volume centres. Presentation at the International Thymic Malignancies Interest Group tumour board should be considered. # PATIENTS WITH # IMPLEMENTATION CONSIDERATIONS The Working Group members believed that patients in rural areas or patients who are disadvantaged may find it more challenging to attend daily PORT treatments or treatments in high-volume centres since they may live further away from these centres in Ontario or may have difficulty in acquiring transportation for daily treatments than patients in urban areas or patients who are less disadvantaged. Also, peptide receptor radionuclide therapy has not been approved for patients with thymic epithelial tumours in Ontario. # FURTHER RESEARCH Larger, collaborative, international prospective trials that control for confounders are needed to provide a greater degree of certainty in the evidence to inform recommendations. # GUIDELINE LIMITATIONS The Working Group for this guideline did not include patient representatives. Thus, when developing recommendations, input from patients about their values and preferences was not sought and a systematic review for this information was not performed. Working Group members used their prior clinical experiences with patients with thymic epithelial tumours to assume their relevant values and preferences.

Is there a role for high dose rate endobronchial brachytherapy (HDREB) in the palliation of respiratory symptoms in patients with non-small cell lung cancer? 2. If so, what is the optimal dose of HDREB in this setting? # Target Population The recommendations apply to adult patients with symptomatic endobronchial disease in non-small cell lung cancer. - For patients with previously untreated, symptomatic, endobronchial non-small cell lung cancer: o External beam radiation therapy (EBRT) alone is more effective for palliation of respiratory symptoms than HDREB alone. June 2018: "Respiratory symptoms" is indicated in the research question and systematic review, and has been added here for clarification. - The evidence does not provide conclusive results to suggest that routine use of HDREB and EBRT would provide improved symptom relief over EBRT alone. June 2018: It is the opinion of the Lung Cancer Disease Site Group that HDREB and EBRT might be suitable in selected patients. o December 2022: the recommendation "For patients with complete collapse of the lung due to endobronchial obstruction, a surgical core out procedure may be needed before EBRT or EBRT with HDREB" is no longer endorsed because the updated evidence does not show a benefit of this procedure (See Section 4 for details). - For patients previously treated by EBRT who are symptomatic with endobronchial obstruction due to recurrent disease, HDREB is recommended, providing that endobronchial brachytherapy is technically feasible. # Related Evidence Summary - Evidence Summary Report #7-15: The Role of Photodynamic Therapy (PDT) in Patients with Non-small Cell Lung Cancer. The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This guideline is copyrighted by Cancer Care Ontario; the guideline and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# GUIDELINE OBJECTIVES To make recommendations regarding the use of adjuvant systemic therapy in adult patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence. # TARGET POPULATION Adult patients with cutaneous or mucosal melanoma with high risk of recurrence who are rendered disease-free following resection (including resection of all locoregional or distant metastases, if present). Patients with unresected primary disease or metastases fall outside the scope of this document. # INTENDED USERS Medical oncologists, surgical oncologists, and other health care providers involved in the management and referral of patients with resected melanoma at high risk for recurrence. # A. Cutaneous Melanoma Recommendation 1 - Nivolumab or pembrolizumab is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma without BRAF V600E or V600K mutations with high risk of recurrence (stage IIIA to IIID, IV). - Nivolumab, pembrolizumab, or dabrafenib plus trametinib is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with BRAF V600E or V600K mutations and high risk of recurrence (stage IIIA to IIID, IV). - Molecular testing of high-risk melanoma patients to characterize mutations should be conducted to help guide appropriate treatment decisions. # Qualifying Statements for Recommendation 1 - Nivolumab, pembrolizumab, or the combination dabrafenib plus trametinib (for BRAF V600E/K mutated melanoma) are all appropriate treatments; there is currently insufficient evidence to suggest which of these is more effective. These agents were evaluated in different trials (see Table 4-4) and have not been directly compared in the adjuvant setting. For nivolumab and pembrolizumab, treatment-related adverse events (AEs) tended to be mild and manageable, and occurred in 85% and 78% of patients, respectively, with the most common being fatigue, skin reactions (rash, pruritus), diarrhea, nausea, and endocrine disorders. Rates of grade 3+ treatmentrelated AEs (14.4% and 14.7%) resulting in treatment discontinuation (9.7% vs. 13.8%) were similar. The combination dabrafenib plus trametinib resulted in a higher rate of serious AEs (36%), including pyrexia, hypertension, and hepatic effects, and higher rate of discontinuation due to AEs (25%). The spectrum of adverse effects and contraindications for immunotherapy with nivolumab or pembrolizumab compared with that for dabrafenib plus trametinib should be discussed with the patient when deciding on adjuvant treatment. - These treatments were evaluated in trials requiring patients to have complete regional lymphadenectomy. The Multicenter Selective Lymphadenectomy Trial-II (MSLT-II) and the Dermatologic Cooperative Oncology Group (DeCOG)-SLT trial found that in patients with clinically localized cutaneous melanoma (no satellite, in-transit, regional, or distant metastases) with positive sentinel lymph nodes, immediate completion lymph node dissection compared with nodal observation with ultrasonography and completion lymphadenectomy only upon recurrence did not improve melanoma-specific survival but led to higher morbidity (lymphedema). Based on these results, routine immediate completion lymphadenectomy is no longer standard practice for patients with pathologically node-positive disease by sentinel lymph node biopsy (see guidelines by the Program in Evidence-Based Care/Cancer Care Ontario and the American Society of Clinical Oncology/Society of Surgical Oncology. In the absence of complete lymphadectomy, some patients with positive sentinel lymph nodes assigned as stage IIIA or IIIB may be understaged. These trials and recommendations regarding axillary resection do not apply to patients with clinically positive lymph nodes (by palpation or radiologic investigation), and the standard of care is dissection of lymph nodes in that area (axillary, groin, or head and neck) prior to adjuvant therapy or adjuvant radiotherapy. In the case of unresectable disease, up-front systemic therapy should be considered. - Patient inclusion in these trials was based on the American Joint Committee on Cancer (AJCC) 7 th edition, which subdivides stage III into IIIA, IIIB, and IIIC groups. The AJCC 8 th edition now in effect has an additional IIID category; with revised criteria for stage III substages there will be stage migration. For example, using data from the COMBI-AD trial 38% of stage III patients were reclassified to a different subgroup. - Stage IV patients with completely resected disease were only included in the Eastern Cooperative Oncology Group (ECOG) E1609 trial (abstract only, not reported separately) and the CheckMate 238 trial (see key evidence). Data are therefore more limited for this population. - High-risk stage II patients were not included in the key trials, and some trials excluded all (Checkmate 238) or a portion of stage IIIA patients (Keynote 054, COMBI-AD). For stage IIIA diseases, Keynote 054 excluded N1a melanomas with nodal metastasis <1mm, and the COMBI-AD trial excluded any nodal metastases <1 mm. The absolute benefit in patients with stage II or IIIA with <1 mm of nodal disease is unknown. The patient and physician should discuss benefits and risks (adverse effects) and these patients should be enrolled in a clinical trial when possible. Such clinical trials are currently ongoing. - The role of radiotherapy was outside the scope of the literature review; adjuvant radiotherapy is the subject of a separate guideline. Patients who received adjuvant radiotherapy were excluded from the trials of immune checkpoint inhibitors and targeted therapy, except for the E1609 trial comparing ipilimumab doses. - The recommendations from the immunotherapy trials are based on interim results for disease-free survival (DFS); most overall survival (OS) results are not yet available but are forthcoming. A recent review by Suciu et al. supports the view that recurrence-free survival is a suitable surrogate for OS. Recommendations should be reevaluated once final results for the relevant studies are reported. - Data on targeted therapy for BRAF mutations other than V600E/K are not available, and therefore adjuvant therapy with nivolumab or pembrolizumab should be considered. # Recommendation 2 - Ipilimumab is not recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with high risk of recurrence. # Qualifying Statements for Recommendation 2 - While ipilimumab may be effective in reducing the risk of melanoma recurrence, this agent has lower efficacy and higher rates of serious adverse effects than nivolumab and is not recommended. # Recommendation 3 - Use of interferon alpha (IFN-α) for adjuvant treatment of cutaneous melanoma outside of a clinical trial is no longer recommended. # Qualifying Statements for Recommendation 3 - The EORTC 18081 trial (NCT01502696) comparing pegylated IFN-α2b for two years to observation in ulcerated stage II melanoma has an estimated completion of April 2019. This trial may confirm results of the individual patient meta-analysis by the International Melanoma Meta-Analysis Collaborative Group which suggested IFN-α is of benefit in ulcerated melanoma. - IFN may have a limited role in high-risk patients not eligible for other treatments. # Recommendation 4 - Chemotherapy regimens, vaccines, levamisole, bevacizumab, Bacillus Calmette-Guerin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial. # B. Mucosal Melanoma - Immune checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapy (in patients with identified mutations) are recommended for adjuvant therapy of mucosal melanoma with high risk of recurrence. # Qualifying Statements for Recommendation - Mutation characterization is required prior to consideration of targeted agents. Mucosal melanoma has a different origin and spectrum of mutations than cutaneous melanoma. BRAF mutations are less common than in cutaneous melanoma, and therefore inhibitors are of little value in unselected patients. KIT mutations are more prevalent in mucosal melanoma, and inhibitors such as imatinib appear to be of value in advanced melanoma with KIT mutations ; however, no trials on adjuvant use of KIT inhibitors were found. - The trials forming the key evidence for cutaneous melanoma (see Recommendations 1-2) excluded mucosal melanoma, with the exception of the CheckMate 238 trial, which included 29 patients (3.2% of total). This small number is insufficient to allow any conclusions specifically for this subgroup. - There may be a role for chemotherapy, but evidence is not sufficient at this time to make a recommendation. Adjuvant treatment of mucosal melanoma with high-dose IFN-α2b compared with temozolomide plus cisplatin was studied in a phase II trial of patients with stage II/III mucosal melanoma and a subsequent phase III trial in stage I-III mucosal melanoma that has been reported only in abstract form. The phase II study found temozolomide plus cisplatin to result in better OS and DFS than IFN-α2b or placebo. A follow-up phase III study confirmed benefit of temozolomide plus cisplatin compared with IFN-α2b. The available evidence is limited due to lack of full publication and inconsistency with studies in metastatic melanoma. # FURTHER QUALIFYING STATEMENTS The recommended adjuvant therapies have potential for adverse effects (see above key evidence and qualifying statements). While usually manageable and reversible, they may be severe. It was outside the scope of the accompanying systematic review to deal with the management of these adverse effects. The user may refer to other guidelines such as those by the Multinational Association of Supportive Care in Cancer ECOG the American Society of Clinical Oncology/National Comprehensive Cancer Network ( Cancer Care Ontario and others. There are several ongoing trials, and the above recommendations may need to be revisited upon their completion.

# Questions Considered Does treatment with imatinib mesylate (Gleevec TM have palliative benefit, in terms of tumour response, disease progression, survival or quality of life, for patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing the KIT tyrosine kinase receptor (identified by CD117 immunohistochemical staining)? # Literature Search and New Evidence The new search (2006 to March 2011) yielded six relevant new publications from one meta-analysis and four randomized controlled trials (RCTs). One RCT was already included in the existing guideline. Brief results of these publications are shown in the Document Assessment and Review Tool at the end of this report. # Impact on Guidelines and Its Recommendations The new data supports existing recommendations for EBS 11-7 (imatinib mesylate in adult patients with unresectable or metastatic GIST). Hence, the Sarcoma DSG ENDORSED the 2006 recommendations on imatinib mesylate in adult patients with unresectable or metastatic GIST. Does treatment with imatinib mesylate (Gleevec TM have palliative benefit, in terms of tumour response, disease progression, survival or quality of life, for patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing the KIT tyrosine kinase receptor (identified by CD117 immunohistochemical staining)? # Target Population These recommendations apply to adult patients with unresectable or metastatic GIST expressing KIT (CD117+). - In patients with KIT-expressing (CD117+) unresectable or metastatic GIST, treatment with imatinib is a recommended therapy. Until additional data become available, the initial dose of imatinib should be prescribed at a dose of 400 mg daily. A dose of 400 mg twice daily may be considered in patients who demonstrate progression on the lower dose. - The optimal duration of therapy in responding patients or in those patients who achieve a complete clinical and/or radiologic remission has not yet been defined. Phase III trials have demonstrated benefit for up to two years of continued therapy. Eligible patients with GIST who do not respond adequately to optimum doses of imatinib should be considered for entry into a clinical trial. Qualifying Statements It is acknowledged that there are no randomized controlled trials (RCTs) comparing imatinib to no treatment or best supportive care thereby making it difficult to statistically quantify the benefits for progression free survival and overall survival conferred by imatinib. The Sarcoma DSG has concluded that such trials will never be performed in the future in patients with unresectable or metastatic GISTs. In framing its recommendations, the DSG has also borne in mind the fact that treatment with imatinib in such patients has already gained wide acceptance among oncologists internationally. The recommendations for an initial dose of 400 mg daily is based on analyses of two randomized phase III trials that have compared two doses (400 mg versus 800 mg/day) of imatinib. A higher dose has not been shown to increase overall survival. There is a discrepancy in two-year progression-free survival, with one trial reporting a significant advantage in progression-free survival with the higher dose and one trial finding no significant difference. The treatment duration in responding patients, particularly those who achieve a clinical complete response is as yet undefined. For practical purposes, until further studies are done: Patients with stable disease should be treated until disease progression. Phase III data beyond two years of continued therapy are not available. Treatment should be discontinued if serious toxicity develops. The dose may be reduced or interrupted to allow side effects to resolve, then may be re-started. For patients who achieve a complete clinical response and radiologic remission with imatinib, treatment should be continued indefinitely until further data is available regarding the optimum duration of therapy in such patients. This is based on the observation that the majority of patients relapse following cessation of therapy with imatinib. At present, there is insufficient evidence to support the use of imatinib as an adjuvant therapy in patients who have undergone initial complete resection of disease. Surgery may be considered for patients whose disease is rendered resectable following imatinib therapy or to remove residual disease in selected patients. At present, the use of neoadjuvant imatinib is not recommended. # Key Evidence - Evidence was available from two parallel phase III randomized trials (one in abstract form) that compared two doses of imatinib. None of the trials compared imatinib with a control. Across trials, response rates ranged from 41 to 65%, with an additional 32 to 36% of patients achieving stable disease. No quality-of-life data were reported from clinical trials of imatinib. Phase III trials comparing 400 mg and 800 mg of imatinib daily detected no survival advantage with the higher dose but a significant increase in side effects. Data on progression-free survival are mixed, with one trial reporting a significant improvement with the higher dose and a second trial finding no significant difference.

The 2012 recommendations have been ENDORSED. This means that the recommendations are still current and relevant for decision making. Please see Section 3: Document Assessment and Review for a summary of updated evidence published between 2010 and 2019, and for details on how this Recommendation Report was ENDORSED. # CLINICAL QUESTION What is the role of stem cell transplantation (SCT) in the treatment of primary systemic (AL, amyloid light-chain) amyloidosis? # TARGET POPULATION All adult patients with primary (AL) amyloidosis who are being considered for treatment that includes either bone marrow or SCT. # RECOMMENDATIONS AND KEY EVIDENCE High-dose chemotherapy (CT) and autologous SCT is an option for selected patients with primary systemic amyloidosis, preferably within an investigative setting. A single meta-analysis (1) met the inclusion criteria for this review, and that meta-analysis found no significant difference between autologous stem cell transplantation (ASCT) and CT for AL patients in survival outcomes. An RCT included in that meta-analysis (Jaccard et al, 2007) found treatment with ASCT to be associated with a significant increase in treatment-related mortality (TRM). This meta-analysis has some limitations that must be considered when making evidencebased recommendations. The quality of the included evidence was low and consisted of a small RCT and non-RCTs with likely patient selection bias. The single included RCT needed 340 patients to detect a 15% survival difference at µ=0.05, but only 100 were accrued. Secondly, AL patients typically also have significant co-morbidities precluding them from study enrolment. In consideration of the lack of curative treatment options and the limitations of the evidence reviewed, the Expert Panel believes that offering ASCT may be a reasonable option for some patients, depending on performance status, co-morbidities, patient preferences, and ultimate treatment goals. There is no evidence supporting the use of allogeneic SCT for patients with AL. # QUALIFYING STATEMENT The patient selection process and the ultimate decision to perform an SCT should take into account not only disease-related characteristics, but also comorbidities and patient preferences. # Added to the 2019 Endorsement: Careful patient selection based on degree of light chain amyloidosis involvement and organ function is an emerging concept in amyloidosis that should be considered to reduce transplant-related mortality. Transplantation in amyloidosis is an evolving area. New emerging areas include consideration of transplantation in first relapse and the impact of novel proteasome inhibitors on outcomes. New evidence is expected within a time frame of 2 to 3 years. # FUTURE RESEARCH Newer agents are being investigated in the treatment of AL amyloidosis. At this time it is not known how they may impact the need for SCT. # IMPLICATIONS FOR POLICY The number of transplants provincially for systemic AL amyloidosis remains very low, and is unlikely to change in the foreseeable future. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED PROGRAM IN EVIDENCE-BASED CARE REPORTS

In patients with early (T1) glottic cancer, what is the role of endolaryngeal surgery (with or without laser) versus radiation therapy, in terms of survival, locoregional control, laryngeal preservation rates and voice outcomes? # TARGET POPULATION The target population of this guideline is adult patients with previously untreated early (T1) glottic cancers. # INTENDED USERS This guideline is intended for use by clinicians and healthcare providers involved in the management or referral of adult patients with early (T1) glottic cancer. For patients with early (T1) glottic cancer, recommended treatment options include the equally effective endolaryngeal surgery, with or without laser, or radiation therapy. The choice between treatment modalities should be based on patient and clinician preferences and general medical condition. # QUALIFYING STATEMENT There is currently no well-designed, prospective, randomized controlled trial (RCT) that compares endolaryngeal surgery and radiation therapy. Thus, these recommendations are based primarily on other comparative study designs. Although not substantiated by the evidence, several factors are important considerations when deciding between surgery and radiotherapy for early glottic cancer. Location of disease is one factor. Anterior commissure involvement may be a factor that favours a recommendation of radiotherapy over surgery due to a common opinion that voice outcomes are particularly affected. Tumours localized to the midportion of the vocal fold, and where endoscopic accessibility is uncompromised, may be considered ideal candidates for surgery. Other important practical considerations include the ability for patients to tolerate a general anaesthetic, which is required for surgery. In contrast, radiotherapy requires patient cooperation for daily treatment for four to six weeks. Partial laryngeal surgery, including revision endoscopic surgery, is possible for local recurrence following surgery. However, re-irradiation is not an option in cases of recurrence. # KEY EVIDENCE There is a lack of high-quality evidence to explicitly inform the guideline question. Notwithstanding, the recommendation is based on the best available evidence and a consensus of expert clinical opinion of the Head and Neck Cancer Disease Site Group (DSG). One meta-analysis, fifteen cohort studies and two cross-sectional studies comparing endolaryngeal surgery (with or without laser) to radiation therapy in patients with early glottic cancer comprised the evidence base. - No statistically significant differences in overall survival or disease-free survival were detected. One retrospective cohort study (1) did report a significant (p=0.003) 15year cause-specific survival benefit in surgically treated patients (100%) over those treated with radiation therapy (91%). This result was not consistent with four other retrospective cohort studies (2,3-5) that also considered cause-specific mortality and showed no significant differences. The meta-analysis detected no statistically significant laryngectomy-free survival benefits associated with laser surgery when compared to radiation therapy (odds ratio 0.73; 95% confidence interval 0.39-1.35). - One meta-analysis (6) found no statistically significant difference in local control between radiation therapy and laser surgery (OR, 0.66; 95% CI, 0.41 to 1.05). One (7) of eight retrospective cohort studies reported a marginally significant better control rate in surgically treated patients (89%) over those treated with radiotherapy (75%) when only T1a patients were considered (p=0.05). One retrospective cohort study also reported a significant difference in recurrence rates favouring surgery. Thurnher et al (1) found a recurrence rate of 30.5% in those undergoing radiation therapy versus 9.9% in the patients treated with laser excision (p=0.001). The remaining five studies did not report any such significant differences in recurrence rates between treatment groups. - Laryngeal preservation rates were found to be better with surgery, (with or without laser) as compared to radiation in five studies (1,5,(7)(8)(9), while one study found a marginally significant better preservation rate with radiation therapy (p=0.051) (10). - Post-treatment voice and speech quality was assessed by clinician perceptual analysis in one retrospective cohort study (11), which found that the difference between radiation therapy patients and those treated surgically did not reach statistical significance. In five studies that analyzed patient self-perception, three (12)(13)(14) found no statistically significant difference between treatment groups, one (15) found radiation therapy patients scored significantly better, and one ( 16) study reported surgically treated patients scored better. One meta-analysis (6) found conflicting results. It detected significantly better maximum phonation time and fundamental frequency in the radiation therapy patients but reported that the perturbation measures of jitter and shimmer significantly favoured the patients undergoing transoral laser surgery. # FUTURE RESEARCH Carcinoma of the glottis is usually diagnosed in the early phase, and both modalities of treatment have shown high cure rates. However, controversies in the treatment of early glottic cancer remain because of the lack of high-quality prospective analyses comparing endoscopic surgery versus radiotherapy. There is no evidence in favour of one treatment modality when considering the likelihood of local control or overall survival. There is a suggestion that radiotherapy may be associated with less measureable perturbation of voice as compared to surgery but no significant differences were seen in patient perception. The likelihood of laryngeal preservation may be higher when surgery can be offered as initial treatment. Future research should focus on conducting RCTs or prospective comparative studies, with ample follow-up time, that focus on functional outcomes of patients with early glottic cancer. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

This document describes the OH (CCO)-Lung Cancer Disease Site Group endorsement of the recommendations for the treatment of patients with clinical stage III N2 non-small cell lung cancer from © NICE Lung cancer: diagnosis and management. The original publication is available at www.nice.org.uk/guidance/ng122. The recommendations were also endorsed for patients with non-operable stage III non-small cell lung cancer from Brahmer JR, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC).# Table of Contents . Recommendation 3 is reprinted with the permission of NICE. 2 The endorsement of these guidelines does not imply whether chemotherapy/radiation/surgery OR chemotherapy/radiation/immunotherapy OR a combination of all four (quad-therapy) are preferred options in patients with N2 disease. It should be noted that the NICE recommendations for surgery after chemoradiation are for patients with potentially resectable stage III N2 NSCLC, while the SITC recommendations are for inoperable patients only. A formal literature search comparing these strategies was not performed and is beyond the scope of these endorsements. # RECOMMENDATIONS Recommendation 1 Concurrent chemoradiation should be used for curative-intent treatment of patients with unresectable, lymph node-positive (N2 or N3) stage III NSCLC. - There is insufficient evidence to recommend a specific concurrent chemotherapy regimen. Reasonable treatment options include cisplatin combined with one of etoposide, vinorelbine, vinblastine, or pemetrexed and carboplatin combined with paclitaxel. Chemotherapy regimens should be similar to those given in randomized clinical trial protocols. - A standard dose fractionation of 60 to 66 Gy given in fractions of 2 Gy once per day over six weeks is recommended. Dose escalation beyond 66 Gy with conventional fractionation is not recommended. - Hyperfractionated radiotherapy regimens that do not result in acceleration of the treatment course, even though the total nominal radiotherapy dose may be modestly increased, are not recommended. - Routine use of induction chemotherapy prior to concurrent chemoradiotherapy is not recommended; however, this treatment paradigm can be considered for the management of bulky tumours to allow for radical planning after chemotherapy response. Qualifying Statements for Recommendation 1 - Parameters to determine suitability for chemoradiation or other treatment options include but are not limited to performance status, weight loss, and comorbidities. - Increased toxicity, particularly esophagitis and hematologic events, is associated with the addition of chemotherapy to radiotherapy. - Although the impact of increasing the predicted biologic equivalent dose via accelerated radiotherapy regimens is unclear, further study of accelerated hypofractionated regimens is of interest to optimize the therapeutic ratio of treatment, particularly in the context of advanced imaging, radiotherapy planning, and treatment delivery. - Depending on a patient's response to chemoradiation, surgery as salvage or completion of definitive treatment (preferably by lobectomy) may be an option in a subset of patients and should be discussed at a multidisciplinary case conference. Factors to consider include whether the cancer is potentially technically resectable, patient performance status, and patient preferences. # Recommendation 2 Durvalumab should be used in patients with stage III NSCLC who have not progressed postchemoradiation and have no contraindications to an immune checkpoint inhibitor. # Qualifying Statements for Recommendation 2 - This was based on evidence from patients with stage III NCSLC using the 7th edition staging system. Durvalumab may be considered for patients who have stage migrated to stage III NSCLC using the 8th edition staging system. - Patients should have received a volume of lung receiving 20 Gy dose (V20) of less than 35% of the total lung volume, and should have all toxicities resolved to grade 1 or less. - Patients with any pneumonitis history or interstitial lung disease history, or evidence of radiation pneumonitis of grade 2 or above, or with V20s of greater than 35% should be considered at a higher risk of toxicity and generally counseled on the uncertainty and potentially excluded. - At this time, it is inappropriate to exclude patients from therapy based solely on a biomarker such as epidermal growth factor receptor or programmed death-ligand 1 status. 1 The Creative Common License for this document can be found here: Creative Commons Attribution 4. - Durvalumab can be given at a dose of 10 mg per kilogram of body weight intravenously within one to 42 days after chemoradiotherapy and continued for a duration of 12 months. # Recommendation 3 For patients with operable, single-station, stage IIIA/B-N2 NSCLC who can have surgery and are well enough for multimodality therapy, consider chemoradiotherapy with surgery. Qualifying Statements for Recommendation 3 - Discuss the benefits and risks with the person before starting chemoradiotherapy with surgery, including that: o chemoradiotherapy with surgery improves progression-free survival o chemoradiotherapy with surgery may improve overall survival. - For patients with stage IIIA/B-N2 NSCLC who are having chemoradiotherapy and surgery, ensure that their surgery is scheduled for three to five weeks after the chemoradiotherapy. - Multidisciplinary teams that provide chemoradiotherapy with surgery should have expertise in the combined therapy and in all of the individual components. # Recommendation 4 For patients with unresectable, stage III (N2 or N3) NSCLC who cannot tolerate concurrent chemoradiation, one of the following options is recommended after a full discussion of the benefits, limitations, and toxicities of therapy: - Sequential chemotherapy followed by radical radiation o Increasing the biologic equivalent dose using accelerated hyperfractionated radiotherapy following induction chemotherapy may be considered. - Radical radiotherapy alone o A minimum dose of 60 Gy is recommended. o Options for altered fractionation schedules may include hyperfractionation (lower dose per fraction over the standard treatment duration), accelerated fractionation (conventional fraction size and same total dose, given in a shorter period of time), accelerated hyperfractionation (combination of these two), and hypofractionation (higher dose per fraction and fewer fractions # BACKGROUND FOR GUIDELINE Stage III NSCLC occurs in a heterogeneous group of patients and treatment varies considerably largely because of patient-related issues that impact application of guideline recommended treatment. Survival varies considerably. New evidence suggests that immunotherapy may be important in improving survival in these patients. The goal of this guideline was to update the 2017 OH (CCO) guideline (7-3 version 3) recommendations to include new evidence on immunotherapy. In turn, this has implications for funding of new therapies. A second goal of this project was to update and consolidate information in two OH (CCO) guidelines (7-3 version 3 and 7-4 version 2) into one document on the management of stage III NSCLC. The 7-3 version 3 guideline focused on patients with unresectable stage III NSCLC, whereas the 7-4 version 2 guideline focused on patients with potentially resectable stage III NSCLC. This current 7-3 version 4 guideline combines these two guidelines into one guideline for patients with stage III NSCLC. # GUIDELINE ENDORSEMENT DEVELOPERS This endorsement project was developed by the Treatment of Stage III NSCLC Guideline Development Group (GDG) (Appendix 1), which was convened at the request of the OH (CCO)'s Lung Cancer DSG and the Thoracic Cancers Advisory Committee. The project was led by a small Working Group of the Treatment of Stage III NSCLC GDG, which was responsible for reviewing the evidence base and recommendations in the National Institute for Health and Care Excellence (NICE) 2019 Lung cancer: diagnosis and management guideline and the Society for Immunotherapy of Cancer (SITC) 2018 consensus statement on immunotherapy for the treatment of NSCLC in detail and making an initial determination as to any necessary changes, drafting the first version of the endorsement document, and responding to comments received during the document review process. The Working Group members had expertise in radiation oncology, medical oncology, and health research methodology and included three patient representatives. Other members of the Treatment of Stage III NSCLC GDG served as the Expert Panel and were responsible for the review and approval of the draft document produced by the Working Group. Conflict of interest declarations for all GDG members are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. # PATIENT CONSULTATION PANEL Three patient representatives participated as Consultation Panel members for the Treatment of Stage III NSCLC Working Group. They reviewed copies of the project plan and provided feedback on their comprehensibility, appropriateness, and feasibility to the Working Group's Health Research Methodologist. The Health Research Methodologist relayed the feedback to the Working Group for consideration. # ENDORSEMENT METHODS The PEBC endorses guidelines using the process outlined in OH (CCO)'s Guideline Endorsement Protocol. This process includes selection of a guideline, assessment of the recommendations, drafting the endorsement document by the Working Group members, internal review by content and methodology experts, and external review by Ontario clinicians and other stakeholders. The PEBC assesses the quality of guidelines using the AGREE II tool. AGREE II is a 23item validated tool that is designed to assess the methodological rigour and transparency of guideline development and to improve the completeness and transparency of reporting in practice guidelines. Implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations may be provided along with the recommendations for information purposes. # Selection of Guidelines As a first step in developing this document, a search for recent guidelines that addressed the research questions was conducted. Research questions for tri-modality therapy and consolidation immunotherapy were developed to update the 7-3 version 3 and the 7-4 version 2 guidelines. Guidelines older than two years (published before 2017) were excluded. Evidencebased guidelines with systematic reviews that addressed the following research questions were included: 1 . The NICE 2019 guideline addressed research questions 1 and 2 and the SITC 2018 guideline addressed research question 3. # Assessment of Guidelines Guidelines were considered for endorsement if the Working Group answered yes to the following questions: - Do you agree with the recommendations and think that no new evidence would change the recommendations? 2. Do you think the recommendations would be acceptable in Ontario? Both guidelines met the criteria for endorsement. The overall quality of both guidelines was assessed using the AGREE II tool (Table 2-1). The pre-planned threshold for a high-quality guideline was a rigour of development score above 70% based on the AGREE II tool. Both guidelines met this criterion (Table 2-1). # DESCRIPTION OF ENDORSED GUIDELINES The NICE 2019 guideline covered a broad topic on the diagnosis and management of lung cancer and included recommendations on the treatment of patients with stage III NSCLC. These recommendations were based on a systematic review that included a network metaanalysis of six randomized controlled trials (RCTs) comparing chemoradiotherapy and surgery versus chemoradiotherapy alone versus chemotherapy and surgery. Therefore, their network meta-analysis addressed research questions 1 and 2 mentioned above. NICE's 2019 guideline was reviewed by stakeholders and their Guideline Executive. The SITC 2018 document also covered a broad topic on immunotherapy in NSCLC and included recommendations on the treatment of patients with stage III NSCLC. This guidance document was based on a systematic review that addressed research question 3 mentioned above and included a large phase III RCT for durvalumab. The recommendations were reviewed by the SITC membership during an open comment period. # ENDORSEMENT PROCESS The recently completed 7-3 version 3 PEBC guideline included recommendations for patients with unresectable, stage III (N2 or N3) NSCLC who can or cannot tolerate chemoradiation. The Working Group members decided to endorse these recent recommendations and the justifications for these recommendations is described further below. The Working Group developed new research questions for tri-modality therapy and consolidation immunotherapy to update the 7-3 version 3 and 7-4 version 2 PEBC guidelines. The NICE and SITC guidelines addressed these research questions. The Working Group held two meetings to review the recommendations from NICE and SITC to assess whether they agreed with the interpretation of the evidence with respect to the magnitude of the desirable and undesirable effects of treatment and took into account the certainty of the evidence, the values of key stakeholders (e.g., patients, clinicians, policy makers, etc.), and the potential impact on equity, acceptability and feasibility of implementation according to GRADE's evidence-to-decision framework. The evidence from NICE and SITC for each comparison was summarized within this GRADE framework to help the Working Group members consider the evidence used by the NICE and SITC groups and to then make a judgement as to whether they agreed with the way NICE and SITC interpreted and used the evidence. The evidence from NICE and SITC and the judgements of the Working Group can be found in Appendices 3 and 4. Taking into consideration all of these factors within the GRADE framework, the Working Group members decided to endorse the NICE recommendations, but clarified that the recommendations applied to patients with single-station N2 disease and also applied to patients with stage IIIB NSCLC. The Working Group members also endorsed NICE's recommendation to schedule surgery three to five weeks after chemoradiotherapy because this was the schedule used in the studies. The Working Group members endorsed SITC's recommendation for durvalumab in patients with stage III NSCLC who have not progressed post-chemoradiation. The Working Group decided to clarify that these patients should have no contraindications to an immune checkpoint inhibitor. Also, the Working Group members added four qualifying statements to further clarify the patient population. These clarifications were based on the inclusion and exclusion criteria of the durvalumab trial. Furthermore, the Working Group decided to replace SITC's recommendation about the duration of durvalumab, "Limited data is available concerning durvalumab duration, and this recommendation will be reassessed as more results become available" with a qualifying statement that indicates the dose, schedule, and duration of durvalumab that was used in the trial. The recommendation for concurrent chemoradiation for curative-intent treatment of patients with unresectable, lymph node-positive (N2 or N3) stage III NSCLC was endorsed from the 2017 7-3 version 3 PEBC guideline. In this prior version, the recommendation was adapted from the PEBC 2005, the American College of Chest Physicians 2013, the American Society of Radiation Oncology (ASTRO) 2015, and the American Society of Clinical Oncology (ASCO) 2015 guidelines. Concurrent chemoradiation has been recommended in all of these guidelines. Carboplatin and paclitaxel have been added to the options of chemotherapy regimens since the PEBC 2005 guideline. This is consistent with the ASTRO 2015 and ASCO 2015 guidelines. Also, cisplatin and pemetrexed have been added to options of chemotherapy regimens since the PEBC 2005 guideline. This is based on the PROCLAIM trial. Standard dosefractionation of 60 to 66 Gy was consistent across the guidelines. The dose per fraction has been altered to 2 Gy per fraction to be consistent with current standards recommended by the ASTRO 2015 and ASCO 2015 guidelines. The recommendation against the routine use of induction chemotherapy was consistent across these guidelines. The recommendations for patients with unresectable, stage III (N2 or N3) NSCLC who cannot tolerate concurrent chemoradiation were also endorsed from the 2017 7-3 version 3 PEBC guideline. In this third version, the recommendations for sequential chemotherapy followed by radical radiation or radical therapy alone were endorsed from the ASTRO 2015 guideline. Also, the recommendation for radiation for symptom palliation was endorsed from the ASTRO 2011 guideline. # ENDORSEMENT REVIEW AND APPROVAL # Internal Review For the endorsement document to be approved, 75% of the content experts who comprise the GDG Expert Panel must cast a vote indicating whether or not they approve the document, or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. In addition, the PEBC Report Approval Panel (RAP) with methodology expertise must unanimously approve the document. The Expert Panel and RAP may specify that approval is conditional, and that changes to the document are required. Results of this review are reported in Section 3. # External Review Feedback on the approved draft endorsement document is obtained from content experts through Professional Consultation. Relevant care providers and other potential users of the endorsement document are contacted and asked to provide feedback on the recommendations through a brief online survey. This consultation is intended to facilitate the dissemination of the final guidance report to Ontario practitioners. Results of this review are reported in Section 3. The endorsement document will be published on the OH (CCO) website. The Professional Consultation of the External Review is intended to facilitate the dissemination of the endorsement document to Ontario practitioners. OH (CCO)-PEBC guidelines are routinely included in several international guideline databases including the Canadian Partnership Against Cancer database, the Canadian Medical Association Infobase, NICE Evidence Search, and the Guidelines International Network Library. # UPDATING THE ENDORSEMENT The Lung Cancer DSG will review the endorsement on an annual basis to ensure that it remains relevant and appropriate for use in Ontario. The Treatment of Stage III NSCLC GDG would like to thank the following individuals for their assistance in developing this report: - Fulvia Baldassarre and Nadia Coakley for completing the AGREE II assessments - Xiaomei Yao for reviewing draft versions of this endorsement - Sara Miller for copyediting # Recommendations for the Treatment of Patients with Clinical Stage III Non-Small Cell Lung Cancer: Endorsement of the 2019 National Institute for Health and Care Excellence Guidance and the 2018 Society for Immunotherapy of Cancer Guidance Section 3: Internal and External Review # INTERNAL REVIEW The endorsement was evaluated by the GDG Expert Panel and the PEBC RAP (Appendix 1). The results of these evaluations and the Working Group's responses are described below. # Expert Panel Review and Approval Of the 24 members of the GDG Expert Panel, 22 members voted, for a total of 92% response in January 2020. Of those who voted, 22 approved the document (100%). The main comment from the Expert Panel and the Working Group's response is summarized in Table 3-1. # Table 3-1. Summary of the Working Group's response to a comment from the Expert Panel. Comments Responses 1. I suggest in Recommendation 2 that if we are going to include the current dose of durvalumab, we should also include the current schedule (since it may subsequently change, along with the dose). The schedule for durvalumab was added to the qualifying statement for Recommendation 2. # RAP Review and Approval Two RAP members reviewed this document in January and February 2020. The RAP approved the document on February 3, 2020. # EXTERNAL REVIEW Professional Consultation Feedback was obtained through a brief online survey of healthcare professionals and other stakeholders who are the intended users of the endorsement document. Ninety-two health care professionals in Ontario with an interest in lung cancer taken from the PEBC database were contacted by email to inform them of the survey. Eight (9%) responses were received. One oncologist stated that they were unavailable to review this endorsement document at the time. The results of the feedback survey from seven people are summarized in Table 3 Another year of durvalumab after chemoradiation may be difficult for patients unless they are initially primed to the idea of continued treatments. The final endorsed recommendations contained in Section 1 reflect the integration of feedback obtained through the external review processes with the document as drafted by the GDG Working Group and approved by the GDG Expert Panel. # Susanna Cheng Medical Oncologist Lung Cancer Disease Site Group - Received $500 or more in a single year to act in a consulting capacity as an advisory board member for MERCK, Astra Zeneca, and Roche exp evidence based practice/ or exp practice guideline/ or exp consensus development conference/ or guideline.pt. or practice parameter$.tw. or practice guideline$.mp. or (guideline: or recommend: or consensus or standards).ti. or (guideline: or recommend: or consensus or standards).kw. 9 exp meta analysis/ or exp "meta analysis (topic)"/ or exp meta-analysis as topic/ or exp "systematic review"/ or exp "systematic review (topic)"/ or ((exp "review"/ or exp "review literature as topic"/ or review.pt.) and ((systematic or selection criteria or data extraction or quality assessment or jaded scale or methodologic$ quality or study) adj selection).tw.) or meta-analysis.mp. or (meta-analy: or metaanaly: or meta analy:).tw. or (systematic review or systematic overview).mp. or ((cochrane or medline or embase or cancerlit or hand search$ or hand-search$ or manual search$ or reference list$ or bibliograph$ or relevant journal$ or pooled analys$ or statistical pooling or mathematical pooling or statistical summar$ or mathematical summar$ or quantitative synthes?s or quantitative overview$ or systematic) adj2 (review$ or overview$)).tw. or (medline or med-line or pubmed or pub-med or embase or cochrane or cancerlit).ab. 10 exp phase 3 clinical trial/ or exp "phase 3 clinical trial (topic)"/ or exp clinical trial, phase iii/ or exp clinical trials, phase iii as topic/ or exp phase 4 clinical trial/ or exp "phase 4 clinical trial (topic)"/ or exp clinical trial, phase iv/ or exp clinical trials, phase iv as topic/ or exp randomized controlled trial/ or exp "randomized controlled trial (topic)"/ or exp controlled clinical trial/ or exp randomized controlled trials as topic/ or exp randomization/ or exp random allocation/ or exp double-blind method/ or exp single-blind method/ or exp double blind procedure/ or exp single blind procedure/ or exp triple blind procedure/ or exp placebos/ or exp placebo/ or ((exp phase 2 clinical trial/ or exp "phase 2 clinical trial (topic)"/ or exp clinical trial, phase ii/ or exp clinical trials, phase ii as topic/ or exp clinical trial/ or exp prospective study/ or exp controlled clinical trial/) and random$.tw.) or (((phase II or phase 2 or clinic$) adj3 trial$) and random$).tw. or ((singl$ or double$ or treple$ or tripl$) adj3 (blind$ or mask$ or dummy)).tw. or placebo?.tw. or (allocat: adj2 random:).tw. or (random$ control$ trial? or rct or phase III or phase IV or phase 3 or phase 4).tw. or (random$ adj3 trial$).mp. or "clinicaltrials.gov".mp. 11 7 not ((comment or letter or note or editorial or case reports or historical article).pt. or exp case report/ or exp case study/) 12 8 and 11 13 limit 12 to yr=2012-current 14 remove duplicates from 13 15 The fixed effects network meta-analyses found that patients receiving chemoradiotherapy and surgery spent significantly longer progression free than those receiving chemotherapy and surgery or chemoradiotherapy alone, that patients receiving chemoradiotherapy alone spent significantly longer in the post-progression state than those receiving the surgical options and that there was a strong but statistically insignificant trend favouring chemoradiotherapy and surgery over the other two interventions for overall survival time and probability of survival at study endpoint. While model fit statistics did not suggest that it fit the data any better, the random effects network meta-analyses used in sensitivity analysis found no statistically significant difference for any outcome between any of the interventions. The committee noted that only one of the RCTs found a statistically significant difference in PFS but that it was also the case that the direction of effect for this outcome in each of the studies was positive for chemoradiotherapy and surgery. The committee was aware that PFS is a less reliable outcome than overall survival and discussed the potential for radiotherapy scarring to affect reliability. They did not think that there would be systematic overdiagnosis of disease progression in the non-surgical arms of the RCTs and thereby overestimation of the PFS benefit associated with surgery. Indeed, they noted that it is possible that subtle changes in disease status are missed in patients undergoing chemoradiotherapy because of radiotherapy scarring. They therefore felt that if bias towards incorrect recording of progression exists, it could work in either direction. ¨ Large ¨ Moderate ¨ Don't know þ Varies ¨ Small ¨ Trivial The adverse event profile of the different interventions is uncertain but pairwise and network meta-analyses estimates conducted for the health economic model favoured chemoradiotherapy and surgery. The committee discussed the evidence from a network meta-analysis conducted for the economic model which showed the odds ratio of death before progression was higher in the surgical interventions. They felt that this outcome was unsurprising in interventions that are more invasive in nature and noted that the other network meta-analyses had already accounted for this. Additionally, death before progression occurred in relatively few patients in any arm of any included study. They felt that discussing the risks and benefits of any surgery with patients is common practice. The undesirable effects vary in the context of the type of surgery being performed. For example, right-sided pneumonectomy may be associated with increased mortality compared with left-sided pneumonectomy or lobectomy. # Certainty of evidence 1c. What is the overall certainty of this evidence? ¨ Very low þ Low ¨ No included studies þ Moderate ¨ High The committee agreed that the six trials most relevant to current practice were The committee agreed that the outcome that matters the most is mortality. This is because the purpose of chemotherapy, radiotherapy and surgery is to reduce mortality as much as possible. Secondary outcomes were PFS, severe adverse events and quality of life. Based on the network meta-analyses, the committee agreed that it is likely that (particularly) PFS and overall survival are better for chemoradiotherapy and surgery than the other two options if patients are well enough for it. The network meta-analysis found that chemoradiotherapy and surgery was associated with a 4 month (0.32 year) improvement in PFS versus chemoradiotherapy. The adverse event profile of the different interventions is uncertain but pairwise and network meta-analyses estimates conducted for the health economic model favoured chemoradiotherapy and surgery. The committee was unsure about the clinical plausibility of this, given that chemoradiotherapy and surgery is the most intensive intervention but agreed that there was no evidence that it was more harmful than the other two interventions. The committee agreed it was likely that there would be some quality of life loss in the months following the interventions as patients recovered. This was expected to be particularly true of the interventions including surgery. They decided that a 'consider' recommendation in favour of chemoradiotherapy and surgery was justified by the evidence. This is because there were a number of key uncertainties in the clinical data. Specifically, that none of the RCTs included in the network metaanalysis found any difference in overall survival, which was the most important outcome. Also, the 3-to 5-week wait for surgery is recommended to give people time to recover from the chemoradiotherapy. The Working Group believed that the benefits would outweigh the harms, but that the values of the patients would need to be taken into consideration. A discussion about the effects of chemoradiotherapy and surgery on PFS and overall survival with the patient would need to occur. # ¨ Yes The committee thought that chemoradiotherapy and surgery is likely to be the most cost-effective intervention and that chemoradiotherapy was unlikely to be cost-effective compared to the other two interventions. The committee thought that only a small number of stage IIIA-N2 patients are currently treated with chemoradiotherapy and surgery and that these recommendations therefore represent an increase in resource use, which will depend on the extent of take-up. Chemoradiotherapy with surgery is not often offered in current practice. In addition, there are specific factors to take into account when offering all these treatments together. Therefore, multidisciplinary teams providing it should have expertise both in the combined therapy, and in all the individual components. # Appendix 1: Affiliations and Conflict of Interest Declarations In accordance with the PEBC Conflict of Interest Policy, the Members of the Treatment of Stage III NSCLC GDG Working Group, Expert Panel, Report Approval Panel, and Patient Consultation Panel were asked to disclose potential conflicts of interest.

Anthracyclines have been established to be superior to some non-anthracycline chemotherapy regimens (Table 2 in Evidence Summary). Studies included in the EBCTCG 2012 meta-analysis (1) indicate that in general, anthracycline-based regimens are superior to non-anthracycline non-taxane regimens, provided that an optimal anthracycline cumulative dosage is achieved (defined as total epirubicin dosage of >360 mg/m 2 or doxorubicin dosage of >240 mg/m 2. These studies provide evidence for use of the following regimens: CEF×6, or CAF×6, are superior to CMF×6 (with oral cyclophosphamide) AC×4 is superior to CMF×6 (with IV cyclophosphamide), but equivalent to CMF×6 (with oral cyclophosphamide) (34,35). CEF×6 resulted in improved survival rates compared with CMF×6 in a trial by Kimura et al (not included in the 2012 meta-analysis), although the difference was not statistically significant (36). The utility of FEC 100 ×6 is evidenced by the FASG 05 trial in mostly patients with locally advanced breast cancer (LABC) (37) illustrating its superiority to FEC 50 ×6. However, it is unclear if the FEC 100 regimen is comparable to CEF×6 or CAF×6. Although the total cumulative dosage of epirubicin in this regimen is >360 mg/m 2 the 2012 meta-analysis suggests that it may be equivalent to AC×4. R10. The addition of gemcitabine or capecitabine to an anthracycline-taxane regimen is not recommended for adjuvant chemotherapy. EBS 1−21. Recommendations. Page 13 The addition of gemcitabine or capecitabine to an anthracycline-taxane regimen does not improve rates of DFS or OS and is more toxic (38,39) (see Table 3 in Section 2). R11. In patients older than 65 years, capecitabine is not recommended as an adjuvant chemotherapy option in lieu of adjuvant AC or CMF (oral cyclophosphamide). In patients older than 65 years, adjuvant capecitabine was found to be inferior to CMF (oral cyclophosphamide)×6 and AC×4 (40) (see Table 1 in Section 2).) is an acceptable chemotherapy regimen for patients in whom an anthracycline and taxane is contraindicated. CMF chemotherapy has been found to be better than no chemotherapy in the adjuvant setting (41) (see Table 1 in Section 2: Evidentiary Base). CMF×6 (with oral cyclophosphamide) has been found to be no worse than AC×4 in the adjuvant setting (40).with early-stage breast cancer (also see R14 for non-anthracycline regimens): FEC×3→T×3 (superior to FEC×6) AC×4→T×4 (superior to AC×4) TAC×6 (superior to FAC×6) AC×4→P administered weekly Dose-dense, dose-intense EC→P Dose-dense AC→P (every 2 weeks) Key Evidence and Qualifying Statements Phase III clinical studies have shown improved outcomes from the adjuvant anthracycline and the anthracycline-taxane-based regimens listed in R13 (see Tables 2 and 3 in the Evidence Summary). defined by the ASCO/CAP guidelines as ER immunohistochemistry (IHC) staining ≥1%, taking into consideration overall disease risk, patient preference, and potential adverse effects. Key Evidence and Qualifying Statements Evidence is summarized in Section 2 of this guideline (see Subsection 4.3) This recommendation follows the ASCO/CAP guidelines (6-9). Discussion at the consensus meeting acknowledged that the benefit of hormone-targeted therapy was greater in patients with higher ER levels. R17. Consensus was not reached on whether to administer adjuvant endocrine therapy in patients with ER− but PR+ tumours. See Section 3 for details. R18. Tamoxifen for five years has been the standard of care, but tamoxifen for up to ten years is a reasonable option for premenopausal patients with ER+ tumours, regardless of chemotherapy use. Evidence on tamoxifen use is summarized in Section 2 of this guideline (see Subsection 4.3.1). Tamoxifen for five years improves DFS and OS rates in the adjuvant setting, in both pre and postmenopausal patients. Five years of tamoxifen monotherapy is superior to two to three years. The ATLAS trial (55) included 12,894 female patients and found that extending tamoxifen duration in ER+ patients to 10 years further reduced the risk of breast cancer recurrence (617 vs 711 cases, −2.80% difference, p=0.002), breast cancer mortality (p=0.01), and overall mortality (639 vs 722 deaths, −2.48% difference, p=0.01). For all ER groups combined (ER+, ER−, or unknown) there was an increased incidence of pulmonary embolus (41 vs 21 cases, difference of 0.31%, p=0.01) and endometrial cancer (116 vs 63 cases, difference of 0.82%, p=0.0002), although this did not result in a significant difference in mortality from these causes (10 vs 8 deaths, p=0.69 and 17 vs 11, p=0.29, respectively). There was an decrease in ischemic heart disease (127 vs 163 cases, −0.56% difference, p=0.02,) and lower rate of death due to myocardial infarction or other vascular causes (178 vs 205 deaths, difference −0.43%, p=0.10). The aTTOM trial (56) also found that extending tamoxifen to ten years compared with five years reduced recurrence (p=0.003) and breast cancer mortality rates (p=0.05), with little effect on non-breast cancer mortality rates(457 vs 467 deaths, RR=0.94). There was an increase in endometrial cancer occurrence (102 vs 45 cases, RR=2.2, p<0.0001) and death (37 vs 20 deaths, 1.1% vs 0.6%, p=0.02). Combined results with the ATLAS trial gave enhanced statistical significance for extended tamoxifen benefit for recurrence (p<0.0001), breast cancer mortality (p=0.002), and OS (p=0.005). The proportional reduction in recurrence rates was unaffected by age or nodal status. The benefit of tamoxifen in improving DFS and OS rates remained even when initiated EBS 1−21. Recommendations. Page 17 more than two years after definitive surgery or adjuvant chemotherapy (57,58); therefore, patients should be offered tamoxifen even when a delay occurred after surgery or adjuvant chemotherapy. Identifying menopause by amenorrhea or hormone levels post-chemotherapy and/or while on tamoxifen is unreliable (see Recommendation 15).or suppression is a reasonable treatment option for premenopausal patients with ER+ tumours who refuse or are not candidates for any other systemic therapy. Key Evidence and Qualifying Statements Refer to Table 12 in the Evidentiary Base (Section 2). Ovarian ablation (OA) can be achieved through surgery or radiation, and ovarian suppression can be achieved with luteinizing hormone-releasing hormone (LHRH) agonists. EBS 1−21. Recommendations. Page 21 R25. In patients with ER+ tumours who do not receive adjuvant endocrine therapy immediately after surgery or chemotherapy, delayed endocrine therapy is still clinically beneficial. Key Evidence and Qualifying Statements Evidence exists for the delayed initiation of both tamoxifen and AIs, as indicated in the Evidentiary Base (Section 2, Subsection 4.3). The relevant trials initiated endocrine therapy at a mean of two years from diagnosis. RECOMMENDATIONS 26−34. ADJUVANT TARGETED THERAPY (HER2+ CANCERS) R26. Only patients with HER2+ breast cancer (IHC 3+, ISH ratio ≥2, or 6+ HER2 gene copies per cell nucleus) should be offered adjuvant trastuzumab.# LIST OF ABBREVIATIONS CCO = Cancer Care Ontario PEBC = Program in Evidence-Based Care RAP = Report Approval Panel RCT = randomized controlled trial Disease Characteristics DCIS = ductal carcinoma in situ ER = estrogen receptor ER− = ER negative ER+ = ER positive HER2 = human epidermal growth factor receptor 2 HER2− = HER2 negative HER2+ = HER2 positive HR− = hormone receptor negative HR+ = hormone receptor positive LABC = locally advanced breast cancer LCIS = lobular carcinoma in situ LVI = lymphovascular invasion N0 = node negative (no positive lymph nodes) N+ = node positive PR = progesterone receptor PR− = PR negative PR+ = PR positive TN = triple negative (PR−, ER−, HER2−) RS = recurrence score Treatments ALND = axillary lymph node dissection BCS = breast-conserving surgery BCT = breast-conserving therapy (BCS + RT) OA = ovarian ablation OA/S = ovarian ablation and/or ovarian suppression PMRT = postmastectomy radiation therapy RT = radiation therapy SLND = sentinel lymph node dissection Outcomes BCFI = breast cancer-free interval BCFS = breast cancer-free survival rate BMD = bone mineral density cCR = clinically complete response DDFS = distant disease-free survival rate DFS = disease-free survival rate DRFI = distant recurrence-free survival rate EFS = event-free survival rate HR = hazard ratio (95% confidence intervals may be in parentheses) IDFS = invasive disease-free survival rate LVEF = left ventricular ejection fraction NNT = number needed to treat OS = overall survival rate pCR = pathologically complete response QoL = quality of life RFS = recurrence-free survival rate RR = relative risk TDR = time to distant recurrence Systemic Therapy: Chemotherapy or Hormonal Therapy A = doxorubicin (Adriamycin) AC = doxorubicin (Adriamycin) + cyclophosphamide AI = aromatase inhibitor ANA = anastrozole (Arimidex) C = cyclophosphamide CAF = cyclophosphamide (oral) + doxorubicin (Adriamycin)(IV) + 5-fluorouracil (IV) CEF = cyclophosphamide (oral) + epirubicin (IV) + 5-fluorouracil (IV) CEX = cyclophosphamide + epirubicin + capecitabine CMF = cyclophosphamide + methotrexate + 5-fluorouracil ddAC = dose-dense AC E = epirubicin EC = epirubicin + cyclophosphamide EXE = exemestane (Aromasin) F = 5−fluoruracil FAC = 5-fluorouracil + doxorubicin (Adriamycin) + cyclophosphamide (all IV) FEC = 5-fluorouracil + epirubicin + cyclophosphamide (all IV) FSH = follicle-stimulating hormone G = gemcitabine GCSF = granulocyte-colony stimulating factor GnRH = gonadotropin-releasing hormone GOS = goserelin (Zoladex) H = trastuzumab (Herceptin) LET = letrozole (Femara) LHRH = luteinizing hormone-releasing hormone M = methotrexate OA = ovarian ablation OA/S = ovarian ablation and/or ovarian suppression P = paclitaxel SERM = selective estrogen-receptor modulator T = docetaxel (Taxotere) TC = docetaxel (Taxotere) + cyclophosphamide TAC = docetaxel (Taxotere) + doxorubicin (Adriamycin) + cyclophosphamide TAM = tamoxifen TCH = docetaxel (Taxotere) + carboplatin + trastuzumab (Herceptin) TH = docetaxel (Taxotere) + trastuzumab (Herceptin) TX = docetaxel (Taxotere) + capecitabine UFT = oral uracil and tegafur X = capecitabine What is the optimal adjuvant 1 systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered? # TARGET POPULATION This guideline deals with female patients who are being considered for or are receiving systemic therapy for early-stage invasive breast cancer. The preferred definition of early breast cancer in this guideline is invasive cancers Stage I−IIA (T1N0−1, T2N0). Studies with cancer described as operable (no other description of stage) and some studies with both Stage I−IIA and operable Stage IIB−IIIA (sometimes considered locally advanced) are included. # INTENDED USERS This guideline is directed toward clinicians (medical, radiation, and surgical oncologists and general practitioners) who participate in the care of patients with early breast cancer who are suitable for or receiving systemic therapy. 1 Several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting. However, this guideline makes recommendations specifically for adjuvant therapy for the following reasons: a) there is significant variability within the patient population for whom neoadjuvant therapy may be considered (from early, operable breast cancer, to locally advanced breast cancer, which may have unique treatment needs) and b) our systematic review of the evidence focused on trials with disease-free survival (DFS) and overall survival (OS) as endpoints, and thus excluded several trials that used pathologically complete response (pCR) as a primary endpoint. Therefore, our recommendations represent only some of the data that may be relevant to neoadjuvant patients. The systemic treatment of early-stage breast cancer involves decisions based on the characteristics of the patient and the disease. There are several guidelines that address specific issues of systemic therapy either in early breast cancer or in breast cancer generally. Because of the overlapping nature of the guidelines and patient characteristics, it is difficult for the end-user to find the appropriate guideline and recommendations. The Breast Cancer Disease Site Group (DSG) determined it would be desirable to have one guideline covering all systemic treatments for early breast cancer, and to have an associated user-friendly chart, matrix, or decision tree based on disease and patient characteristics. This led to the development of a consensus panel of Ontario breast cancer oncologists. Utilizing the expertise of these clinicians from throughout the province, the available evidence was evaluated to create guidelines to ensure standardization of best practices. # SUMMARY OF METHODS (see Sections 2 and 3 for details) A systematic review was conducted based on a literature search of MEDLINE and EMBASE for the period 2008 to March 2012. Guidelines were also identified from the SAGE Directory of Cancer Guidelines. Identified systematic reviews, meta-analyses, and practice guidelines were used to identify earlier studies or as the full evidence base when there were no more recent studies. Relevant abstracts presented at large academic meetings were used to update included trials or identify ongoing trials. The Working Group summarized the evidence and drafted recommendations that were then circulated to members of the consensus group. The consensus group (including the Working Group members) consisted of medical oncologists from Ontario who either were members of the Breast Cancer DSG or were invited to ensure representation from all regional cancer centres and programs in Ontario. A consensus panel process among the participants was used as the method to review and provide feedback on the draft recommendations. In doing so, the large amount of evidence and wide scope of the document could be managed, the current use of several chemotherapy regimens that do not have direct randomized controlled trial (RCT) comparisons and that may have differential benefits in specific subpopulations of patients could be debated and judged, differences in practice patterns among different centres and regions of Ontario could be taken into account, and gaps in evidence for certain practices could be more easily identified. The consensus process was envisioned as a way to engage the larger clinical community, promote greater standardization of practice, raise awareness of some of the challenging issues surrounding treatment decisions, and reveal practices that are not according to best evidence. The draft recommendations were circulated to all consensus group members and voted on prior to the consensus meeting of November 23, 2012 using a 5−point Likert scale (strongly disagree, disagree, undecided, agree, strongly agree). Consensus was defined as at least 80% agreement (agree or strongly agree) and no strong disagreement. Recommendations without consensus from the initial questionnaire were presented, discussed, revised, and voted on at the consensus meeting. This section provides the final set of recommendations and key supporting evidence. Section 2 provides the evidence summary on which the recommendations were informed. Section 3 and Appendix B provide more detail about the consensus methods and the processes undertaken in this project, the original recommendations distributed to the consensus participants, the original feedback received from the survey, and the feedback received at the meeting. In the final recommendations, cross-referencing to tables in Section 2 or other evidence was removed from the recommendation boxes and placed with the qualifying statements and key evidence. # RECOMMENDATIONS AND KEY EVIDENCE The most recent Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview ( 1) confirms the benefit of adjuvant chemotherapy vs none in improving outcomes in early breast cancer. The EBCTCG found similar relative benefit for all subgroups, although the absolute magnitude of benefit depended on baseline risk. In all recommendations it is assumed that patient preference is considered and that final treatment is determined in consultation between the patient and the doctor. This is mentioned more explicitly in a few recommendations in which the balance between risk and benefit is less clear overall or for certain patient groups. # RECOMMENDATIONS 1−7. PATIENT/DISEASE CHARACTERISTICS AND RECURRENCE RISK Recommendations for adjuvant systemic therapy in breast cancer are mostly guided by patient and disease characteristics. In general, these factors help stratify patients into low-, intermediate-, and high-risk categories (2)(3)(4). The evidence review focused on guidelines, meta-analyses, and phase III clinical studies evaluating the impact of adjuvant systemic therapies on disease-free and/or overall survival rates; a systematic review specifically on patient and disease stratification factors was not performed. The recommendations for risk stratification were created by: - Extraction of information from clinical practice guidelines found by our systematic review. Assessment of patient and disease factors evaluated or addressed in clinical trials included in our systematic review. Initial expert consensus on additional relevant factors that may not have been specifically addressed in the reviewed guidelines and clinical trials. The Progesterone Receptor Status. The EBCTCG meta-analysis ( 5) (see Table 4 in Section 2 of this guideline) found that PR status was not an important independent factor for determining response to endocrine therapy with tamoxifen. The consensus panel members cautioned that PR status in the studies used for the EBCTCG meta-analysis may have been analyzed by older pathological methods and may not be as well-standardized as ER analysis. ER−PR+ is very rare, such that a pathological result with this profile usually requires re-testing and confirmation. The method used to ascertain ER and PR is important, and positivity should be determined according to CCO/ASCO/CAP guidelines (6)(7)(8)(9). Disease response of patients with ER−PR+ cancer to other endocrine agents besides tamoxifen was not addressed in the EBCTCG meta-analysis. Nonetheless, PR status may still have prognostic value even if it is not deemed useful in determining tamoxifen response. LVI. LVI predicted worse outcome in some studies (10,11) and may therefore be useful as a prognostic factor. According to the St. Gallen Consensus Conference (4,12) it is not sufficient to decide chemotherapy. The panel wondered whether LVI results are reproducible among various laboratories. # Other Characteristics without Consensus - Ki-67. Ki-67 is currently considered more clinically useful in other cancers, such as lymphoma. There is generally poor analytical reproducibility of Ki-67 in breast cancer between various centres because testing methods are not standardized and no clear cutoff values have been defined. Some studies show a prognostic role for Ki-67, and it is incorporated in some molecular gene signatures, such as Oncotype DX. Finally, it is not prospectively validated. It is premature to recommend its use as a standard parameter for patient risk stratification, although it may be evaluated in clinical trials. Intrinsic Subtypes. Intrinsic breast cancer subtypes (luminal A, luminal B, HER2 enriched, basal, and normal) have been established to correlate with prognosis. There exist several retrospective analyses describing the response to various systemic treatments by these subtypes. However, the utility of these subtypes beyond measurement of ER, PR, HER2, and grade is not clear. At this point, the use of these subtypes in clinical decision making outside of a clinical trial is not recommended. The following risk stratification tools may be used in determining the utility of certain systemic therapies in patients with early-stage breast cancer: # Qualifying Statements (Recommendations 6 and 7) - Cut-offs for degree of estrogen receptor expression do not formally exist. The generally accepted degree of strong estrogen receptor positivity is >90% and this was used for the consensus question. Refer to local pathology policy in regards to degree of estrogen expression. Few RCTs have addressed the role of systemic chemotherapy in female patients with good prognosis early-stage breast cancers. In addition, there is limited data available on the benefit of systemic therapy in patients with lymph node positive micrometastatic (≤2 mm) disease. The IBCSG 23−01 trial concluded that axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement (micrometastasis only), thus eliminating complications of axillary surgery with no adverse effect on survival rates (19). In this trial more than 60% of patients received adjuvant endocrine treatment alone with excellent five-year disease-free survival rate (DFS) and overall survival rate (OS). Sentinel node micrometastases has been associated with an adverse prognosis in some long-term follow-up studies. Retrospective data have shown some benefit of systemic therapy in patients with micrometastatic disease. Until the results of prospective RCTs are available, the potential role of systemic therapy should be discussed with each patient (20). Prognostic tools such as Adjuvant! Online and Oncotype DX may be used to assist healthcare providers in determining the potential benefit of chemotherapy. The potential benefit of adjuvant systemic therapy is modest for patients with small (<1 cm) node negative breast cancer that is endocrine sensitive and HER2 negative, and these patients may be considered for endocrine therapy alone. Although the majority of the consensus group agreed that patients with lymph node positive breast cancer with micrometastasis only (<2 mm) and no other high-risk features may not need adjuvant chemotherapy, 25% disagreed or were undecided and consensus was not reached. However, consensus was reached about potentially omitting chemotherapy when patients were found to have lower-risk (see R7) strongly ER/PR positive disease. There was disagreement as to whether lymph node micrometastasis alone is a high-or low-risk factor. Lymph node positivity with micrometastasis alone is therefore not included in the recommendation. # RECOMMENDATIONS 8−14. SELECTION OF OPTIMAL ADJUVANT CHEMOTHERAPY REGIMENS In patients who can tolerate it, using an anthracycline-taxane containing regimen is considered the optimal strategy for adjuvant chemotherapy, particularly in those patients deemed to be high risk. # Key Evidence - Aggregate data from several phase III clinical studies, as well as meta-analyses, have established the superiority of many anthracycline-taxane-based regimens compared with other chemotherapy (see Tables 2 and 3 in the Evidence Summary). - The 2012 EBCTCG meta-analysis ( 1) highlights that anthracycline-taxane regimens that do not alter the number of anthracycline cycles (e.g., AC×4→T×4) are superior to the anthracycline alone (e.g., AC×4). Although the EBCTCG found no significant differences in outcomes if the anthracycline treatments were truncated and a taxane was added instead (e.g., FEC×3→T×3), compared with simply increasing the number of anthracycline treatments (FEC×6), longer-term follow-up of the included studies (see Table 3) suggests benefit for taxanes exists. The PACS 01 trial of FEC×3→T×3 vs FEC×6 found improved survival rates at eight years for the anthracycline-taxane combination ( 21). Truncating the number of anthracycline cycles when adding a taxane can mitigate certain important adverse effects such as cardiotoxicity and leukemia, which occur more frequently with more cycles of anthracyclines [e.g., PACS 01 ( 22), review by Trudeau et al ( 23), and recent meta-analysis ( 24 For patients in whom a taxane is contraindicated, an optimal-dose anthracycline regimen (doxorubicin ≥240 mg/m 2 or epirubicin ≥360 mg/m 2 is recommended. - FEC followed by weekly paclitaxel was not included in the initial questionnaire. It was discussed at the meeting and participants were asked to add it to the answer sheet for the second round of voting. Four of sixteen participants did not answer this question at that round; therefore, consensus was not reached. Of those who voted, 11 agreed and 1 was undecided. - Exploratory subgroup analysis suggests that the superiority of FEC→T over FEC 100 may be restricted to subgroups such as postmenopausal patients or those aged >50 years (27). Some anthracycline-taxane regimens have been compared (AC→T, TAC, ddAC→P), showing comparable efficacy; FEC→T has not been directly compared with any other such regimen. Nonetheless, there is no clear data to show the superiority of any of these anthracycline-taxane regimens over another, and a recent analysis found no difference in patient outcomes when evaluated by these regimens, including FEC→T (42). As such, they all remain reasonable options for adjuvant treatment in the absence of any prospective, randomized studies showing otherwise. Consensus was not reached on the use of CEF (5 of 16 disagreed or were undecided). This regimen may have a role in a subgroup of patients with very high risk of recurrence and good health who can tolerate it, although there are regimens with likely similar efficacy and lower risk of adverse effects. # Anthracycline vs Anthracycline-Taxane-Based Regimens - The 2012 EBCTCG meta-analysis ( 1) highlights that anthracycline-taxane regimens that do not alter the number of anthracycline cycles (e.g., AC×4→T×4), are superior to the anthracycline alone (e.g., AC×4). Although the EBCTCG found no significant differences in outcomes if the anthracycline treatments were truncated and a taxane was added instead (e.g., FEC×3→T×3), compared to simply increasing the number of anthracycline treatments (FEC×6), longer-term follow-up of the included studies (see # Key Evidence and Qualifying Statements - Caution must be employed in defining menopause in patients who have had a previous hysterectomy with ovaries left in place. In these patients, levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measured prior to receiving chemotherapy/tamoxifen may be useful in determining menopausal status. The definition of menopause varied across studies, with most studies using a cut-off of age 50 or 60 years. Accurate identification of postmenopausal status is crucial if AI therapy is used because AIs cause a reflex increase in gonadotropin secretion in premenopausal patients (50). The incidence of chemotherapy-induced amenorrhea is dependent on the regimen used and the age of the patient (51,52). Cessation of menses does not necessarily denote the absence of ovarian function, and premenopausal estradiol levels can be found in patients with chemotherapy-induced amenorrhea (53). In addition, hormone levels and the absence of menses are unreliable indicators of menopause during treatment with tamoxifen (54). R16. Adjuvant endocrine therapy should be considered in all patients with ER+ cancer, R20. In premenopausal patients with ER+ tumours (treated with or without chemotherapy) the addition of ovarian ablation or suppression to tamoxifen is not the standard of care. Some consensus panel participants disagreed with the recommendation because it did not make allowance for subgroups and could be misinterpreted to mean that ovarian ablation and/or suppression (OA/S) plus tamoxifen should not be used. Because they did not vote "strongly disagree" the recommendation passed the consensus rules and rewording was not considered. Subsequent to completion of this guideline, additional results for the SOFT trial became available which indicate that for women who remain premenopausal after chemotherapy (as demonstrated by estradiol levels), ovarian function suppression in addition to tamoxifen reduces risk of breast cancer recurrence, which can be further reduced by the use of exemestane rather than tamoxifen (59). # Key Evidence and Qualifying Statements - In early breast cancer, OA/S plus tamoxifen is not currently the standard of care for all premenopausal patients with ER+ cancer. Some of the authors consider this combination appropriate in certain subgroups such patients who are younger or at higher risk of recurrence. Use of an AI is addressed in R21. OA/S plus tamoxifen (60) or OA/S plus endocrine therapy (3) is the standard of care for metastatic breast cancer (both pre-and postmenopausal). In the LHRH-agonists meta-analysis (61) (see Table 12 in Section 2), comparisons of recurrence rates with and without LHRH subdivided by age (≤40 and >40 years) suggested a stronger (and beneficial) effect of LHRH in younger patients. LHRH + tamoxifen compared with tamoxifen alone improved the hazard ratio for recurrence by 32% in the ≤40 years subgroup (p=0.12) compared with an improvement of 2% (p=0.91) in the >40 years subgroup. - The benefit for LHRH added to chemotherapy or any systemic therapy was statistically significant (p=0.01 and p=0.002 respectively) for the ≤40 years group (61). In younger female patients, chemotherapy is less likely to induce permanent amenorrhea, and this may explain the greater benefit of OA/S in younger patients. In addition, permanent amenorrhea after treatment using modern non-CMF-based chemotherapy is less common than with older chemotherapy regimens. It is unclear whether benefit persists when tamoxifen is also used. Results from the SOFT and TEXT trials (see R21 and Table 8 of Section 2) suggest that OA/S + exemestane is better than OA/S + tamoxifen. The SOFT and TEXT found that patients deemed by their physicians as not requiring chemotherapy had a DFS rate of 96% with exemestane + OA/S and 93% with tamoxifen + OA/S, and suggested there may be patients at low risk of recurrence who do not require chemotherapy if they receive appropriate endocrine therapy. Additional results from the SOFT trial comparing tamoxifen plus ovarian suppression to tamoxifen alone were reported subsequent to this guideline completion (59,62). There was a benefit for the addition of ovarian suppression to tamoxifen (86.6% vs 84.7% DFS, p=0.10; p=0.03 after adjustment for prognostic factors). Most recurrences and thus greater benefit was found in those who received chemotherapy; there was no difference in DFS (93.4% vs. 93.3%) or OS (99.2% vs. 99.8%) in the subgroup of patients who had no prior chemotherapy. The benefit of ovarian function suppression plus exemestane was especially seen in the patient group under 35 years old. Ovarian function suppression plus exemestane or tamoxifen, compared to tamoxifen alone, was associated with more toxicity and adverse effect on QoL and these effects need to be considered when choosing between tamoxifen, tamoxifen plus ovarian suppression, and exemestane plus ovarian suppression (59,(62)(63)(64)(65). R21. In premenopausal patients with ER+ tumours, treated with or without chemotherapy, ovarian ablation or suppression plus five years of an AI is not the standard of care. Subsequent to completion of this guideline, additional results for the SOFT trial became available which indicate that for women who remain premenopausal after chemotherapy (as demonstrated by estradiol levels), ovarian function suppression in addition to tamoxifen reduces risk of breast cancer recurrence which can be further reduced by the use of exemestane rather than tamoxifen (59). # Key Evidence and Qualifying Statements - Standard practice in Canada and the United States is to use tamoxifen in premenopausal patients, although European clinicians tend to favour an AI + ovarian suppression (66). OA/S + tamoxifen (60) or OA/S + endocrine therapy ( 3) is the standard of care for metastatic breast cancer (both pre-and postmenopausal). In postmenopausal patients, AIs have been found superior to tamoxifen (see R22, R24). It has been proposed that AIs would be better than tamoxifen in premenopausal patients, but this would require OA/S to reduce estrogen levels to postmenopausal levels. The SOFT and TEXT Trials (see Table 8 in Section 2) found that exemestane + OA/S to resulted in improved survival rates compared with tamoxifen + OA/S (DFS 91.1% vs 87.3%, HR=0.72, p=0.0002). The SOFT and TEXT also found that patients deemed by their physicians not to require chemotherapy experienced survival rates of 96% with exemestane plus OA/S and 93% with tamoxifen plus OA/S, suggesting that some patients who are at low risk of recurrence might not require chemotherapy if they receive appropriate endocrine therapy. Additional results from the SOFT trial comparing tamoxifen plus ovarian suppression to tamoxifen alone were reported subsequent to this guideline completion (59,62). There was a benefit for the addition of ovarian suppression to tamoxifen (86.6% vs 84.7% DFS, p=0.10; p=0.03 after adjustment for prognostic factors). Most recurrences and thus greater benefit was found in those who received chemotherapy; there was no difference in DFS (93.4% vs. 93.3%) or OS (99.2% vs. 99.8%) in the subgroup of patients who had no prior chemotherapy. The benefit of ovarian function suppression plus exemestane was especially seen in the patient group under 35 years old. Ovarian function suppression plus exemestane or tamoxifen, compared to tamoxifen alone, was associated with more toxicity and adverse effect on QoL and these effects need to be considered when choosing between tamoxifen, tamoxifen plus ovarian suppression, and exemestane plus ovarian suppression (59,62-65). R22. The optimal adjuvant endocrine therapy for postmenopausal patients with ER+ tumours should include an AI. # Key Evidence and Qualifying Statements - Evidence is summarized in Tables 6−9 of Section 2 (Evidence Summary). Studies consistently demonstrate that the use of an AI either alone or sequentially after tamoxifen therapy, compared with tamoxifen alone, reduces the risk of recurrence and improves DFS rate (67). The absolute gain in breast cancer endpoints is greater for patients with a poorer prognosis. EBCTCG 2010 did not report mortality rates so the survival rate data from the aggregated trials is not yet known. Some studies suggest that the relative benefit of tamoxifen or various AIs may depend on patient characteristics (e.g., nodal status, hormone receptor status), although this needs to be verified in future studies. Some consensus panel participants felt that the word "optimal" may not apply to all patients. The risk to benefit ratio of using tamoxifen vs AIs must be taken into account, recognizing the different side-effect profile of these medications. R23. Tamoxifen for up to ten years is an acceptable treatment for postmenopausal patients with ER+ tumours treated with or without chemotherapy. Switch strategy (letrozole, exemestane, or anastrozole) after two to three years of tamoxifen therapy. The IES and ARNO trials found an OS benefit as well; however, these studies had a highly selected population. BIG 1−98 provided data for switching from letrozole to tamoxifen after two to three years or from tamoxifen to letrozole; both of these were found to be have similar outcomes as five years of letrozole. Extended adjuvant therapy with three to five years of any AI after five years of tamoxifen therapy; this strategy had a small OS benefit in patients with lymph node positive cancer (MA.17). Delayed AI with the initiation of letrozole at a median of 2.8 years after completing 5 years of tamoxifen. All consensus participants either disagreed (12 of 16) or were undecided (4 of 16) with giving AIs as extended adjuvant therapy for longer than five years, after completing five years of tamoxifen. Some studies suggest that relative benefit of tamoxifen or various AIs may depend on patient characteristics (e.g., nodal status, hormone receptor status) although this needs to be verified in future studies. - Two small trials suggest trastuzumab may be beneficial when administered for shorter durations resulting in less cardiotoxicity than longer treatment. Results need to be confirmed in larger trials that are ongoing. The Short-HER and SOLD studies are looking at one year vs nine weeks trastuzumab and the Hellenic Group and PERSEPHONE trials are looking at one year vs six months trastuzumab. Based on the completed trials plus neoadjuvant trials that found trastuzumab + chemotherapy increased the pathologically complete response (pCR) rate compared with chemotherapy alone, some have suggested that shorter trastuzumab therapy (even if not optimal for preventing recurrence) may be acceptable, particularly for those patients who cannot tolerate trastuzumab for one year. The NICE guideline (97) recommends that patients receiving trastuzumab should have cardiac functional assessments every three months during trastuzumab treatment, and trastuzumab should not be offered to patients with any of the following:  A left ventricular ejection fraction LVEF of <55%  A history of documented congestive heart failure  High-risk uncontrolled arrhythmias  Angina pectoris requiring medication  Clinically significant valvular disease  Evidence of transmural infarction on electrocardiograph (ECG)  Poorly controlled hypertension. Most of the clinical trials evaluating trastuzumab excluded these patients. Patients who develop cardiotoxicity during administration of trastuzumab should be treated and monitored closely by a knowledgeable multidisciplinary team (oncologists and cardiologists). As indicated in Section 2, the systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada and issues specific to other jurisdictions (including low-or middle-income countries) were not considered. The recommendations encompassed in this guideline are most applicable to the Ontario (and likely North American) oncology practice setting. Although the approval of drugs is under the auspices of Health Canada, funding for particular systemic therapy agents is handled provincially in Canada, and this may impact on the ability to receive public reimbursement for certain therapeutic agents in each province. Some treatments as recommended by this guideline are fairly resource-intensive (e.g., taxane chemotherapy and trastuzumab). As such, these treatments may only be sustainable in higher-income nations. One must consider the local practice setting, including resource constraints, when considering the implementation of systemic therapy recommendations. Guidelines by groups such as the Breast Health Global Initiative (98-100) may help users of this guideline to better choose the most resource-appropriate systemic therapies for their unique practice setting. # RELATED PEBC/CCO GUIDELINES - Trastuzumab is the targeted therapy for HER2+ early-stage breast cancer that has been most fully evaluated in completed RCTs (69)(70)(71)(72)(73). The TEACH trial (see Table 15) compared lapatinib to placebo and found benefit in DFS but not OS rates. The effect was greater in patients with hormone receptor negative cancer, although adverse effects (diarrhea, rash, hepatobilliary effects) were also higher with lapatinib. The ALTTO trial compared lapatinib, trastuzumab, and their combinations but the lapatinib arm was discontinued for futility. The other arms detected no significant differences, although lapatinib had more adverse effects. Follow-up is ongoing. Although lapatinib and pertuzumab have been investigated in the setting of locally advanced and metastatic disease (74,75), no recommendation for these agents can be made at this time. The role of dual blockade with trastuzumab and pertuzumab is currently being evaluated in the ongoing APHINITY trial (). The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) (76,77) define a positive HER2 result as IHC staining of 3+ (uniform, intense membrane staining of >10% of invasive tumour cells); an in situ hybridization (e.g. 14 in Evidentiary Base). The majority of adjuvant trastuzumab trials included patients with lymph node positive breast cancer, or lymph node negative disease with one of the following high-risk features: ER−, grade 2 or 3, T ≥1cm, or age <35 years. Trastuzumab may still be considered in patients with HER2+ disease outside these features. Although most studies excluded patients with tumours <1 cm, the benefit of trastuzumab was equivalent in both node negative and node positive tumours in the HERA trial which included small N0 tumours (1 cm was the formal inclusion criteria, although 60 patients with tumours <1 cm were also enrolled). The BCIRG 006 trial (71,72) analysis by tumour size found benefit in tumours <1 cm, <2 cm, and ≥2 cm, but not for tumours 1−2 cm in size; however, interpretation is limited because of the small number of patients in each category. The review by Petrelli and Barni (78) concluded that patients with HER2+ tumours have a higher rate of recurrence and poorer survival rate than patients with HER2− cancer of the same size/stage, confirming that HER2 positivity itself is a risk factor. There does not appear to be a threshold according to tumour size, and size alone should not be the deciding factor in whether to administer trastuzumab to patients with tumours <1 cm. In Ontario, tumours <1 cm can be treated under the Evidence Building Program (EBP). The meta-analysis by Moja et al (Cochrane Collaboration) (79) found that the hazard ratio for trastuzumab-containing regimens vs chemotherapy alone was 0.66 for OS and 0.60 for DFS (p<0.00001 for both). The risk of congestive heart failure and left ventricular ejection decline were higher with trastuzumab (RR=5.11, p<0.00001 and RR=1.83, p<0.0008, respectively). In patients at high risk of recurrence without cardiac problems, there is clear survival rate benefit for trastuzumab. The benefit of adjuvant trastuzumab in the absence of cytotoxic chemotherapy is unknown because it has not been evaluated in clinical trials. Trastuzumab monotherapy vs trastuzumab + chemotherapy is being evaluated in elderly patients in the SAS BC07 (RESPECT) study (80). # R28. Trastuzumab therapy can be considered in small (≤1 cm) tumours as part of clinical studies or evidence-building programs (such as the one currently available in Ontario) # Key Evidence and Qualifying Statements - Evidence for trastuzumab use is included in the Evidence Summary (Section 2, Subsection 4.4). Because most major phase III trials that confirmed the benefit of adjuvant trastuzumab did not include small (≤1 cm diameter) node negative breast cancer, there is little evidence from RCTs evaluating the effect of trastuzumab in tumours ≤1cm. HERA and BCIRG 006 as discussed in R27 are exceptions. Several retrospective case series of HER2 positive pT1a/bN0M0 carcinoma seem to demonstrate that they have a higher risk of relapse compared with the HER2 negative counterpart (79). In the HERA trial (81), the subgroup of 510 patients with node negative disease and EBS 1−21. Recommendations. Page 23 tumours ranging from 1.1 to 2.0 cm in diameter had similar three-year DFS rate benefit with trastuzumab as in the overall cohort (trastuzumab vs observation HR=0.53, 95% CI 0.26−1.07; all patients HR=0.64, 95% CI 0.54−0.76). The American trials found a similar trend with benefit in pT1N0M0 tumours smaller than 2 cm. Although there has not been a confirmatory trial, there is no reason to think that high-risk pT1a/bN0M0 breast cancer cannot benefit from trastuzumab in the same way as more advanced stages of the disease. There does not appear to be a threshold according to tumour size, and size alone should not be the deciding factor in whether to administer trastuzumab to patients with tumours ≤1 cm. In Ontario, tumours ≤1 cm can be treated under the Evidence Building Program. R29. Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen. # Key Evidence and Qualifying Statements - Evidence on use of trastuzumab + chemotherapy is provided in (neoadjuvant, adjuvant, or both). There was no randomization regarding the type of chemotherapy: 68% received anthracycline, 26% anthracycline + taxane, and 6% no anthracycline. When results were censored to account for cross-over to trastuzumab after unblinding, there was persistent DFS and OS rate benefit. This trial suggests there is benefit of trastuzumab in combination with any chemotherapy, but it did not address the issue of which chemotherapy is optimal. PEBC Guideline #1−17 (86) recommended that trastuzumab be used with an anthracycline instead of CMF. Because anthracyclines are known to be cardiotoxic, and anthracyclines + trastuzumab even more cardiotoxic, non-anthracycline regimens may be more appropriate in some patients. The BCIRG 006 trial (71,72) compared both AC→docetaxel/trastuzumab (AC→TH) and docetaxel/carboplatin/trastuzumab (TCH, a non-anthracycline regimen) to the AC→T control. TCH and AC→TH were both superior to AC→T. There was no significant difference in OS or DFS rates among trastuzumab regimens, although AC→TH seemed to have a stronger effect in some subgroups. TCH had a much lower incidence of cardiotoxicity and leukemia. Whether TCH is equivalent to AC→TH was not established as the trial was not designed to test for non-inferiority between the two trastuzumabcontaining regimens. # Key Evidence and Qualifying Statements - Anthracyclines are known to be cardiotoxic and anthracycline followed by trastuzumab even more cardiotoxic. Anthracyclines administered concurrently with trastuzumab in patients with metastatic breast cancer resulted in high rates (25%) of congestive heart failure. Concurrent use of trastuzumab + anthracycline has been explored in several small trials in the neoadjuvant setting without significant cardiotoxicity. Long-term results of these trials have yet to be reported; therefore, this approach should not be considered outside the context of a clinical trial. # R31. Adjuvant trastuzumab can be initiated either concurrently or sequentially with the taxane portion of a chemotherapy regimen. # Key Evidence and Qualifying Statements - The evidence is summarized in the Evidentiary Base (Section 2, Subsection 4.4.2). There appears to be no significant differences in survival outcomes between concurrent or sequential taxane and trastuzumab; however, initiating the trastuzumab concurrently with the taxane is still generally preferred. Most adjuvant trials started trastuzumab sequentially after anthracyclines, either concurrently with or after the taxane, and administered it either weekly (2 mg/kg) or every three weeks (6 mg/kg) for one year (sometimes switching frequency at the end of the taxane cycles). All trials used a higher dosage (loading) for the first round (8 mg/kg for the 3−weekly schedule and 4 mg/kg for the weekly administration). NCCTG N9831 had both sequential and concurrent arms and there was a nonsignificant trend toward greater survival rate benefit with the concurrent arm (87). NSABP B31 and the HERA trial prescribed trastuzumab sequentially after chemotherapy whereas BCIRG 006 delivered trastuzumab concurrently with the taxane in the two relevant arms. # TCH (docetaxel/carboplatin/trastuzumab) is less cardiotoxic than AC→TH (doxorubicin/cyclophosphamide-docetaxel/trastuzumab) and is recommended for patients at higher risk for cardiotoxicity. # Key Evidence and Qualifying Statements - Evidence exists for trastuzumab in combination with docetaxel and carboplatin (TCH), and this regimen was found to be similar to AC→TH (see Table 14 in the Evidence Summary). The BCIRG 006 trial (71,72) compared both AC→TH and TCH (a non-anthracycline regimen) to the AC→T control. TCH and AC→TH were both superior to AC→T. There was no significant difference in OS or DFS rates among trastuzumab regimens, although AC→TH seemed to have a stronger effect in some subgroups. TCH had much lower incidence of cardiotoxicity and leukemia. Whether TCH is equivalent to AC→TH was not established EBS 1−21. Recommendations. Page 25 because the trial was not designed to determine non-inferiority between the two trastuzumab-containing arms. Because anthracyclines are known to be cardiotoxic, and anthracyclines + trastuzumab even more cardiotoxic, non-anthracycline regimens may be more appropriate in some patients. R33. Phase III evidence for the addition of trastuzumab to some chemotherapy regimens such as TC (docetaxel/cyclophosphamide) does not exist. However, these regimens may be in use and are reasonable options, particularly to mitigate cardiotoxicity in certain patients. # Key Evidence and Qualifying Statements - HERA (73,81,88,89) was a large phase III international RCT that randomized patients with HER2+ early breast cancer to one year vs two years vs no trastuzumab after completion of adjuvant systemic therapy (as per investigator choice). Patients experienced significant clinical benefit with the addition of trastuzumab to chemotherapy, regardless of the chemotherapy backbone. TC has not been formally evaluated with trastuzumab in the context of an RCT; however, given the results of the HERA trial (systemic therapy as per investigator choice), TC could be considered a reasonable systemic option in combination with trastuzumab, particularly in patients for whom there is a concern with regards to cardiotoxicity. Patients should be offered one year total of adjuvant trastuzumab, with regular cardiac functional assessments during this period. Results presented at ESMO 2012 (91,92) were inconclusive as to whether 6 months of trastuzumab was non-inferior to 12 months with a nonsignificant trend favouring 12 months. Further results after 3.5 years follow-up (93) also concluded that they failed to show that 6 months trastuzumab was non-inferior to 12 months trastuzumab, although there were significantly more cardiac events in the 12 month group (5.7% vs 1.9%). Updating All PEBC documents are maintained and updated through an annual assessment and subsequent review process. This is described in the PEBC Document Assessment and Review Protocol, available on the CCO website at: Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Evidence-based Series (EBS) 5-3 is ARCHIVED. The guidance for the organization of care has been updated; see 5-3ORG Version 2. The guidance for the clinical management of Head and Neck cancer patients is no longer current and should not be used to inform clinical decisions, but may still be useful for academic or other information purposes.# The HNMWG acknowledges that in some cases the available evidence listed above did not directly establish optimal strategies in the management of head and neck cancer. In such instances, the HNMWG drafted recommendations based on the collective expert opinion of the working group members. # Structure and Organization of the Head and Neck Management Recommendations # A. ORGANIZATION OF CARE RECOMMENDATIONS I. Preamble In order to ensure the provision of the highest quality of care for patients with head and neck mucosal malignancy, the working and consensus groups have developed a set of organizational standards and treatment recommendations. The organizational recommendations were developed to establish the minimum requirements to maintain a head and neck disease site program. The recommendations are intended to ensure that the proper equipment is in place, and that medical and support staff are experienced and properly trained. The recommendations establish standards for minimum new patient volumes for regional cancer centre disease site groups in an attempt to ensure that all patients have access to the highest standard of care available in Ontario. # II. Teams The teams will include a core team, primary care provider, and extended team. The care of patients with head and neck cancer should be coordinated among members of an experienced Core Team, comprised of a group of physicians and allied healthcare providers who will be responsible for the assessment, treatment, planning, management, survivorship, and rehabilitation of the patient. The Primary Care Provider will be responsible for the ongoing overall health of the patient and will offer supportive care after treatment. The Extended Team will be called upon by the core team to facilitate treatment, planning, management, survivorship, and rehabilitation of the patient. Members of the Teams must have training or experience managing patients with head and neck cancers. # The Core Team Recommendation - The Core Team is comprised of a group of physicians and allied healthcare providers who will be responsible for the assessment, treatment, planning, management, survivorship, and rehabilitation of the patient. - The care of patients with head and neck cancer should be coordinated among members of the core team, who include the following: # Primary Care Physician Recommendation The primary care physician is not involved in the day to day treatment of the head and neck cancer patient but plays an important role in post-treatment supportive care and is responsible for the ongoing overall health of the patient. (Source: HNMWG, Consensus 77%, Round 2) Reconstruction expertise is required for the surgical management of patients with head and neck tumours and necessitates a fellowship-trained microvascular surgeon with specific training in head and neck reconstruction. # The Extended Team # Histopathological Reporting Pathologists are advised to use the CAP-CCO standards for reporting head and neck malignancies (5). (Source: CAP-CCO, Consensus 86%, Round 2) # Nodal Metastatic Disease The reporting of nodal dissections should include a description of the levels and structures included in the specimen, including number of involved and uninvolved nodes, level of these nodes, and the presence and location of extracapsular spread of tumour. (Source: SIGN and HNMWG, Consensus 83%, Round 1) # Primary Site Histopathology reporting of specimens from the primary site of head and neck cancer should include: tumour site, tumour grade, maximum tumour dimension, maximum depth of invasion, margin involvement by invasive and/or severe dysplasia and margin dimensions, pattern of infiltration, and perineural involvement, The multidisciplinary team should include healthcare professionals skilled in feeding tube placement (percutaneous gastrostomy, gastrojejunostomy, nasogastric). (Source: SIGN, Consensus 82%, Round 1) Feeding tube insertion should be considered for individuals initially presenting with one or more of the following: significant weight loss (greater than 5% in one month or greater than 10% in 6 months), BMI < 18.5, dysphagia, anorexia, dehydration, pain, or any other symptoms that interfere with the ability to eat. (Source: HNMWG, Consensus 96%, Round 2) # Smoking Cessation Patients should be provided with information about, and assistance with access to, drug therapy and counselling to stop smoking prior to and during treatment. If no centre-based smoking cessation program exists, patients should be referred to their primary care physician. # Treatment of the Primary Tumour All options for definitive locoregional treatment including radiation therapy, chemotherapy, and surgery should be discussed with the patient. If an organ preservation (radiotherapy with or without chemotherapy) approach is to be utilized, follow-up and salvage surgery must be available. Following surgical resection, postoperative adjuvant radiotherapy with or without chemotherapy should be considered where indicated. (Source: HNMWG, Consensus 91%, Round 1) # Treatment of the N0 Neck Patients with a clinically N0 neck, with more than 20% risk of occult nodal metastases, should be offered prophylactic treatment of the neck, by appropriate selective or modified radical neck dissection or external beam radiotherapy. (Source: SIGN, Consensus 80%, Round 2)

Series 2-11 Version 4 REQUIRES UPDATING. It is still appropriate for this document to be available while this updating process unfolds. The PEBC has a formal and standardized process to ensure the currency of each document (PEBC Assessment & Review Protocol). EBS 2-11v4 is comprised of 4 sections.# Guideline Report History # TARGET POPULATION These recommendations apply to adult patients with resectable, operable, and potentially curable thoracic (lower two thirds of esophagus) esophageal cancer for whom surgery is considered appropriate. - Preoperative cisplatin-based chemotherapy plus radiotherapy is recommended as the preferred modality for the management of surgically resectable patients with esophageal cancer. - Preoperative cisplatin-based chemotherapy alone is an alternative choice for the management of surgically resectable patients with esophageal cancer. # QUALIFYING STATEMENTS - Based upon results from the "CROSS" trial, the Gastrointestinal Cancer Disease Site Group (GI DSG) acknowledges that recommendations indicating use of "preoperative cisplatin These guideline recommendations have been ENDORSED, which means that the recommendations are current and relevant for decision making. Please see Section 4: Document Review Summary and Review Tool for a summary of the updated evidence published between 2012 and 2016, and for details on how the Clinical Practice Guideline was ENDORSED based" chemotherapy should be revised to include the use of "preoperative platinum based" chemotherapy. The GI DSG acknowledges there is evidence indicating survival benefits with either preoperative chemotherapy or chemoradiotherapy compared with surgery alone. Based on the majority of the evidence available at this time, the GI DSG believes that preoperative chemoradiotherapy for resectable carcinoma of the esophagus is the preferred approach. - Clinicians should recognize that the survival advantage of preoperative therapy may be minimal and a discussion with patients regarding potential adverse effects is required. Decisions to administer preoperative therapy should be based on patient preferences, comorbidities, and suitability for trimodality therapy. # KEY EVIDENCE - A literature meta-analysis of 10 randomized trials comparing preoperative chemoradiotherapy followed by surgery to surgery alone showed a 13% absolute benefit in survival at two years for preoperative chemoradiotherapy (hazard ratio 0.81; 95% confidence interval 0.70-0.93; p=0.002) (1). - A published abstract of an individual patient data (IPD)-based meta-analysis of nine randomized trials (2,102 patients) comparing preoperative chemotherapy followed by surgery (CT+S) to surgery alone demonstrated a 4% (from 16 to 20%) absolute overall survival advantage for chemotherapy at five years (HR, 0.87; 95% CI, 0.79-0.95; p=0.003). Based on seven trials (1,849 patients), the HR for disease-free survival (DFS) was 0.82 (95% CI, 0.74-0.91; p=0.001) in favour of chemotherapy plus surgery, representing a fiveyear absolute DFS benefit of 4% (from 6 to 10%). No difference was seen in postoperative death (6.7%) (2). - Randomized trials demonstrated no survival benefit for radiotherapy given alone, either preoperatively or postoperatively, compared with surgery alone. - Randomized trials demonstrated no survival benefit for postoperative chemotherapy given alone compared with surgery alone. # RELATED GUIDELINES - PEBC Practice Guideline Report #2-12: Combined Modality Radiotherapy and Chemotherapy in the Non-surgical Management of Localized Carcinoma of the Esophagus. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

To update, in collaboration with Cancer Care Ontario (CCO), key recommendations of the American Society of Clinical Oncology (ASCO) guideline on the role of bone-modifying agents (BMAs) in metastatic breast cancer. This focused update addressed the new data on intervals between dosing and the role of BMAs in control of bone pain.A joint ASCO-CCO Update Committee conducted targeted systematic literature reviews to identify relevant studies.The Update Committee reviewed three phase III noninferiority trials of dosing intervals, one systematic review and meta-analysis of studies of de-escalation of BMAs, and two randomized trials of BMAs in control of pain secondary to bone metastases.Patients with breast cancer who have evidence of bone metastases should be treated with BMAs. Options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate, 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks. The analgesic effects of BMAs are modest, and they should not be used alone for bone pain. The Update Committee recommends that the current standard of care for supportive care and pain management-analgesia, adjunct therapies, radiotherapy, surgery, systemic anticancer therapy, and referral to supportive care and pain management-be applied. Evidence is insufficient to support the use of one BMA over another. Additional information is available at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki.# INTRODUCTION The American Society of Clinical Oncology (ASCO) has published a series of guidelines on the role of bone-modifying agents (BMAs) in metastatic breast cancer since 2000. ASCO updates its guidelines at intervals determined by an Update Committee of the original Expert Panel. The recent publications of phase III studies of breast cancer and dosing intervals for zoledronic acid prompted this update. This focused update of the 2011 guideline, completed in collaboration with Cancer Care Ontario (CCO), provides recommendations for the intervals between dosing and the role of zoledronic acid in the control of bone pain. The guideline also provides a discussion of cost considerations in the use of available BMAs for this population. The remaining recommendations from the 2011 ASCO guideline are unchanged because there were no new data to support substantive revisions. # FOCUSED GUIDELINE UPDATE QUESTIONS - What are the best intervals between dosing of zoledronic acid? 2. What is the role of BMAs in control of pain secondary to bone metastases? # Guideline Update Process ASCO uses a signals approach to facilitate guideline updating. 7 This approach identifies new, potentially practice-changing data-signals-that might translate into revised practice recommendations. The approach relies on targeted literature searching and the expertise of ASCO guideline panel members to identify signals. For this focused update, a set of three phase III randomized noninferiority trials addressing dosing interval of zoledronic acid provided the signal. Primarily on the basis of this signal, the ASCO Breast Cancer Advisory Group ranked updating the guideline on BMAs in metastatic breast cancer among its highest priorities. To that end, ASCO and CCO convened a joint Update Committee (Appendix Table A1, online only) to review the evidence and to formulate updated recommendations for practice. With the approval of the ASCO Breast Cancer Guideline Advisory Group, the Update Committee expanded the guideline scope to include a commentary on cost considerations in the use of BMAs in patients with metastatic breast cancer. The Update Committee conducted a search of the PubMed database to identify systematic reviews, meta-analyses, and randomized controlled trials (RCTs) that addressed the role of BMAs in the management of metastatic breast cancer. The review of the yield from this search focused on publications that reported on 4-week and 12-week intervals between the dosing of zoledronic acid and the role of BMAs in control of pain secondary to bone metastases. To inform the special commentary on cost considerations, the Update Committee conducted an additional targeted PubMed literature search to identify articles reporting on the results of cost-effectiveness analyses of BMAs. This search was limited to non-industry-supported studies. Additional information about the results of the updated literature search and search strategy strings and results, as well as a discussion of ASCO's signals approach to guideline updating, are available at www.asco. org/breast-cancer-guidelines in the Data Supplement and Methodology Supplement, respectively. The Data Supplement also includes QUORUM diagrams of the updated search and the Clinical Questions. The entire Update Committee contributed to the development of the guideline, provided critical review, and finalized the guideline recommendations. The ASCO Clinical Practice Guidelines Committee reviews and approves all ASCO guidelines. In addition, the Cancer Care Ontario Report Approval Panel reviewed this focused update manuscript. All funding for the administration of the project was provided by ASCO. # Guideline Disclaimer ASCO disclaimer. The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions. Cancer Care Ontario disclaimer. Cancer Care Ontario's Program in Evidence-Based Care, the cancer guidelines initiative of the Ontario cancer system, supports and endorses these disclaimer principles. This is the most recent information as of the publication date. For the most recent information, and to submit new evidence, please visit www. asco.org/breast-cancer-guidelines and the ASCO Guidelines Wiki (www. asco.org/guidelineswiki). # Guideline and Conflicts of Interest The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Management Procedures for Clinical Practice Guidelines ("Procedures," summarized at ). Members of the Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial effect as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Procedures, the majority of the members of the Panel did not disclose any such relationships. The PubMed search (from January 2011 to March 2017) conducted to identify publications that reported on studies of the optimal intervals between BMA dosing and studies addressing the role of BMAs in control of pain secondary to bone metastases yielded 273 records. After review of the identified abstracts, six full-text articles-three phase III noninferiority trials of dosing intervals, one systematic review and meta-analysis of studies of de-escalation of BMAs, 8 and two RCTs of the role of BMAs in control of pain secondary to bone metastases 9,10 -were selected for review by the Update Committee. The PubMed literature search (2003 to July 2016) performed to identify articles reporting on the results of cost-effectiveness analyses of BMAs yielded 32 records; however, none of the publications provided new evidence to inform the special commentary on cost considerations. A bibliography of the results of the costeffectiveness literature search is provided in Data Supplement 3. # UPDATED RECOMMENDATIONS # Clinical Question 1 What are the best intervals between dosing of zoledronic acid? Updated recommendation. As recommended in the 2011 version of the ASCO BMAs guideline, patients with breast cancer who have evidence of bone metastases should be treated with BMAs. 1 One BMA is not recommended over another. If patients are treated with zoledronic acid, 4 mg intravenously administered over no less than 15 minutes, dosing options are every 12 weeks or every 3 to 4 weeks (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong). Literature review and analysis. The dosing interval recommendation has been updated from 2011 for zoledronic acid. Table 1 presents the dose, route of administration, and dosing intervals for denosumab, pamidronate, and zoledronic acid. The literature review for this guideline update identified three RCTs (Table 2) investigating zoledronic acid dosed every 4 weeks versus every 12 weeks and a meta-analysis (Fig 1) of dose de-escalation of BMAs. 8 In each of the three RCTs, the comparisons between dosing the BMAs every 4 weeks or every 12 weeks showed a similar rate of skeletal complications as measured by proportion of skeletalrelated events (SREs) or skeletal morbidity rates (SMRs) between the 4-week and 12-week dosing study arms. SREs are defined as fracture, radiation, or surgery to bone or spinal cord compression. ZOOM 4 also included hypercalcemia as an SRE. SMR is defined as the number of SREs over time. Both ZOOM and OPTIMIZE 2 were industry-sponsored studies, while the CALGB (Alliance) study was National Institutes of Health sponsored. ZOOM and OPTIMIZE 2 both enrolled participants who had a least nine prior doses of intravenous bisphosphonate therapy for metastatic bone disease. The CALGB (Alliance) study enrolled bisphosphonate-naïve participants. Himelstein et al 5 reported on the CALGB (Alliance) protocol 70604, an open-label, noninferiority study. CALGB 70604 enrolled 1,822 patients with breast cancer (n = 855), prostate cancer (n = 689), or multiple myeloma (n = 278) who had at least one site of bone involvement from cancer and no prior intravenous bisphosphonate exposure. Participants were randomly assigned to either zoledronic acid once every 4 weeks or zoledronic acid once every 12 weeks for 2 years. The primary end point was the proportion of participants with at least one SRE at 2 years. Seven hundred ninety-five participants (43%) completed the 2 years of study. Of the 855 participants with breast cancer, 390 (45%) completed 2 years of follow-up. The most common reasons for discontinuing the study were withdrawal or refusal, disease progression, and death. With a median follow-up of 1.2 years, CALGB 70604 demonstrated noninferiority between the two study arms, with the SRE rate of 29.5% in the 4-week arm and 28.6% in the 12-week arm. The proportional difference was 0 (one-sided 95% CI, 20.04 to infinity; P.001) and 0.01 (one-sided 95% CI, 20.03 to infinity; P.001) for the intention-to-treat analysis and sensitivity analysis, respectively. In a planned disease-site analysis, in patients with breast cancer, the between-group difference was 20.02 (99.9% CI, 20.13 to 0.09; P =.50). The probability of at least one SRE occurring within 2 years of randomization was consistent across breast cancer, prostate cancer, and multiple myeloma groups and was not statistically different between the 4-week and 12-week arms. There was no statistically significant difference between the treatment arms in Eastern Cooperative Oncology Group performance status or in any measures of the mean pain scores. The SMR (0.4) was equal in both arms. There were numerically more cases of osteonecrosis of the jaw (ONJ) in the 4-week dosing arm (18 participants; 2.0%) than in the 12-week dosing arm (9 participants; 1.0%); however, the difference was not statically significant (two-sided Cochran-Mantel-Haenszel P =.10). Grade 3 or grade 4 kidney dysfunction occurred in 10 participants (1.2%) in the 4-week arm and in four participants (0.5%) in the 12-week arm. This difference was not statistically significant. A post hoc analysis evaluated the risk of significant increases in creatinine level, defined as an increase of $ 0.5 mg/dL when the baseline creatinine level was # 1.4 mg/dL or an increase of $ 1 mg/dL when the baseline creatinine was. 1.4 mg/dL. In this post hoc analysis, 19.9% of participants in the 4-week dosing arm and 15.5% of participants in the 12-week dosing arm experienced elevations in serum creatinine (Cochran-Mantel-Haenszel P =.02). Grade 4 hypocalcemia (, 6 mg/dL) occurred in eight patients (0.9%) in the 4-week dosing arm and in five patients (0.6%) in the 12-week dosing arm (two-sided x 2 P =.61). There was no statistical difference in hypocalcemia between the two arms. The percentage of patients experiencing grade 4 hypocalcemia is particularly notable given that the CALGB 70604 protocol advised participants on daily intake of calcium and vitamin D. The biochemical marker of bone resorption, C-terminal telopeptide, was serially measured in 553 study participants. In both treatment arms, the C-terminal telopeptide values were lowered from baseline and suppressed during the course of the study. Note that this ASCO guideline update does not alter the prior recommendation (No. 7) that the use of the biochemical markers to monitor BMA use is not recommended for routine care. The randomized clinical trials ZOOM 4 and OPTIMIZE-2 6 each enrolled slightly over 400 women with metastatic breast cancer involving the bone. The trials are different, but they are relatively similar in that eligible patients had prior exposure to pamidronate or zoledronic acid for approximately 1 year or more, and study participants were randomly assigned to either 4 mg zoledronic acid intravenously every 4 weeks or 4 mg zoledronic acid every 12 weeks. ZOOM was open label, while OPTIMIZE-2 was double-blind and placebo-controlled. Initially, OPTIMIZE-2 included a placebo arm, but this was subsequently discontinued. Both ZOOM and OPTIMIZE-2 followed patients for about 1 year. In ZOOM, 68% of participants completed the study. SMR was the primary end point and was 0.22 (95% CI, 0.14 to 0.29) in the 4-week group and 0.26 (95% CI, 0.15 to 0.37) in the 12-week group. The between-group difference of 0.04 and the upper limit of the one-tailed 97.5% CI was 0.17, indicating noninferiority of the 12-week schedule. The negative binomial model for the SMR ratio of the 4-week versus 12-week schedule was 97% (95% CI, 0.60 to 1.57; P =.896). In both arms, 15% of participants experienced onstudy SREs (P =.898). The Anderson-Gill multiple event analysis did not demonstrate a statistically significant difference between the 4-week and 12-week dosing arms. The median time to first SRE on study was not calculated due to a low event rate. Pain scores and analgesic use did not differ between the two arms. Renal adverse events and ONJ were deemed adverse events related to zoledronic acid. Renal adverse events occurred in 1% of participants in the 4-week dosing arm and in 1% in the 12-week dosing arm. Post hoc analysis of deterioration of renal function did not demonstrate clinically meaningful difference between treatment groups. ONJ occurred in 1% of participants in the 4-week dosing arm (n = 3) and in 2% of the 12-week dosing arm (n = 4). The median change from baseline in the biochemical marker of bone resorption, N-telopeptide, was statistically significantly lower in the 4-week dosing arm than in the 12-week dosing arm at 6, 9, and 12 months. In OPTIMIZE-2, the primary end point was the SRE rate. Between 53% and 63% of OPTIMIZE-2 participants completed the study. Twenty-two percent of the OPTIMIZE-2 participants in the 4-week group and 23.2% of participants in the 12-week group experienced one or more SREs. The proportional difference of 1.2% had a one-sided 97.3% CI bound that was less than the noninferiority threshold (P =.02), and the 12-week dosing arm was noninferior to the 4-week dosing arm. The time to first SRE, time to multiple SRE events, SMR, and SRE-free survival were not significantly different between the 4-week and 12-week arms. Likewise, the patient-reported pain scores and analgesic consumption were not statistically different between the two arms. The most common treatment-emergent adverse event was a rise in serum creatinine leading to discontinuation of the study drug occurring in six patients in the 4-week arm and one in the 12-week arm. Renal adverse events occurred at similar rates between the two arms. ONJ occurred in two participants in the 4-week dosing arm; no cases of ONJ occurred in the 12-week dosing arm. Atypical femur fractures were not observed. A statistically significant difference in the mean change from baseline of the biochemical bone resorption marker N-telopeptide was seen at 36 weeks only (P =.01), and there was no statistically significant mean change in the biochemical marker of bone formation bone-specific alkaline phosphatase. The systematic review and meta-analysis by Ibrahim et al 8 identified five studies comparing 4-weekly versus 12-weekly dosing of denosumab, pamidronate, or zoledronic acid. Analysis of on-study SRE demonstrated that these bisphosphonates and denosumab 8 for on-study skeletal-related events. Reprinted with permission. Oxford University Press. Abbreviation: IV, intravenous. jco.org produced a summary risk ratio of 0.90 (95% CI, 0.63 to 1.29) for standard 4-week dosing interval versus the 12-week dosing interval. The authors did not perform a meta-analysis on pain outcome data due to the variability in study measures and pain-reporting outcomes. However, on-study bone pain as an adverse event was not statistically different between the 4-week dosing interval and the 12-week dosing interval (95% CI, 0.46 to 1.62). ONJ summary risk ratio comparing the 4-week dosing interval to the 12-week dose interval was 0.83 (95% CI, 0.16 to 4.42). There was no statistically significant difference in onstudy hypocalcemia as an adverse event, although more cases occurred in the 4-week dosing interval group. The biochemical markers of bone resorption, C-telopeptide and N-telopeptide were not statistically different between the 4-week and 12-week dosing schedules. The literature review for this guideline update did not identify publications addressing BMA dosing intervals specific to hypercalcemia of malignancy. The Food and Drug Administration-approved packet inserts for denosumab, pamidronate, and zoledronic acid address the management of hypercalcemia of malignancy. # Clinical Question 2 What is the role of BMAs in control of pain secondary to bone metastases? Updated recommendation. The analgesic effects of bonemodifying agents (denosumab, pamidronate, or zoledronic acid) are modest, and BMAs should not be used alone for bone pain. The Update Committee recommends that the current standard of care for supportive care and pain management be applied. This can include analgesia, adjunct therapies, radiotherapy, surgery, systemic anticancer therapy, and referral to supportive care and pain management. Evidence of a clinically meaningful benefit is insufficient to support the use of one BMA over another. Further research is needed on this clinical question (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: weak). Literature review and analysis. This recommendation remains unchanged from 2011. BMAs are an adjunctive therapy for pain control and are not recommended as primary therapy for analgesia. Clinicians should provide comprehensive pain management care for patients with metastatic breast cancer-related pain and can refer to the ASCO clinical practice guidelines on management of chronic pain in survivors of adult cancers 11 and integration of palliative care into standard oncology care. 12 When used concurrently with analgesics, BMAs may be of benefit for women with metastatic breast cancer with pain caused by bone metastases. BMAs have been associated with a modest pain control benefit in controlled trials (Table 3). The evidence is not sufficient to favor one BMA over another with regard to analgesic effect. Randomized studies of denosumab versus zoledronic acid evaluating effects on pain suggest a modest advantage of denosumab by Brief Pain Inventory-Short Form, FACT-G quality of life scores, and skeletalrelated events. 9,10 In the Martin et al trial, 10 approximately 10% more patients had a clinically meaningful improvement in health-related quality of life with denosumab compared with zoledronic acid, regardless of their pain levels at baseline. Cleeland et al 9 observed that fewer patients who received denosumab progressed from no or mild pain to moderate/severe pain, compared with patients who received zoledronic acid (relative difference, 15%; absolute difference, 5%); there was almost a 4-month delay in the median time to pain worsening to moderate or severe with denosumab versus zoledronic acid (9.7 months v 5.8 months; P =.002). However, the studies are limited, and absolute differences between the two agents were small. # COST CONSIDERATIONS IN THE USE OF BMAs IN PATIENTS WITH METASTATIC BREAST CANCER Increasingly, individuals with cancer are required to pay a larger proportion of their treatment costs through deductibles and coinsurance. Higher patient out-of-pocket costs have been shown to be a barrier to initiating and adhering to recommended cancer treatments. 13,14 Table 4 shows estimated prices for BMAs. Of note, medication prices of BMAs vary markedly, depending on negotiated discounts and rebates. Discussion of cost can be an important part of shared decision making. 15 Clinicians should exercise judgment and, whenever it is practical and feasible, discuss with patients the use of less expensive alternatives when considering two or more treatment options that are comparable in terms of benefits and harms. 15 Depending on a patient's particular insurance coverage, reimbursement for the BMA may originate in their medical or pharmacy benefit, which may have different cost-sharing arrangements. Patients should be aware that different products may be preferred or covered by their particular insurance plan. Even with the same insurance plan, the price may vary between different pharmacies. Patients should be asked about their financial concerns by their caregivers and be offered financial counseling to address this complex and heterogeneous landscape. 15 As mentioned previously, the search for published costeffectiveness analyses that might inform the clinical question of the relative value of available BMAs provided no definitive evidence to inform cost considerations. The Update Committee excluded articles from consideration identified from a first-level review of the literature search (Data Supplement) because the analyses in question lacked contemporary cost data for the agents studied, included agents that are not currently available in either the United States or Canada, and/or were industry sponsored. # DISCUSSION AND DIRECTIONS FOR FUTURE RESEARCH The recent publications on the dosing interval of zoledronic acid are expected to change clinical practice. It is anticipated that there will soon be data on dosing intervals of denosumab in patients with metastatic bone disease from breast cancer. Until there are data to suggest otherwise, the Panel recommends that denosumab be prescribed as per packet insert labeling and clinical judgment. The ongoing, open-label phase III study SAKK 96/12 (ClinicalTrials.gov identifier: NCT02051218; REDUSE) randomly assigns participants with metastatic breast cancer or prostate cancer to denosumab dosed every 4 weeks or every 12 weeks. The primary outcome is the time to first on-study symptomatic skeletal event. Secondary end points include additional measures of bone morbidity, as well as assessment of toxicity, quality of life, health economics, biochemical markers of bone turnover, and overall survival. The REaCT-BTA Study (ClinicalTrials.gov identifier: NCT-02721433) will also add to our understanding of dosing intervals for denosumab. REaCT-BTA is an open-label, phase III, Pain worsening among patients who had no or mild pain at baseline to moderate or severe pain on study: Fewer patients who received denosumab progressed from no or mild pain to moderate or severe pain compared with zoledronic acid (relative difference, 15%; absolute difference, 5%), with an almost 4-month delay in the median time to pain worsening to moderate or severe with denosumab compared with zoledronic acid (P =.002). Palliation of pain severity : Similar between treatment groups: 26% at 1 month to 16% at 18 months for denosumab (n = 975) and from 26% at 1 month to 18% at 18 months for zoledronic acid (n = 951). Median time to meaningful improvement in worst pain score : denosumab (n = 747), 2.7 months; zoledronic acid (n = 745), 2.8 months ; HR, 1.02; 95% CI, 0.91 to 1.15; P =.72; in the subgroup of patients who had moderate or severe pain at baseline: denosumab (n = 433), 1.9 months; zoledronic acid (n = 452), 1.9 months; HR, 0.97; 95% CI, 0.84 to 1.12; P =.68. Pain interference with daily functioning : Time to an increase in aggregate pain interference of $ 2 points from baseline: denosumab, 16.0 months; zoledronic acid, 14.9 months; HR, 0.89; 95% CI, 0.78 to 1.02; P =.09. Time to decreased pain interference (P =.92) was similar between the groups, denosumab: median, 2.9 months; zoledronic acid: 3. No known RCTs are currently investigating the optimal duration of therapy with a BMA. Since 2000, the ASCO guidelines have recommended the use of BMAs indefinitely. There are no new data to alter the 2000 duration of therapy recommendation. The data reviewed for this update demonstrate that an extended interval of dosing did not significantly affect the outcomes analyzed over the relatively short duration of the studies published. However, these studies did not address duration of bone-modifying therapy. Although initially designed with a placebo arm, OPTIMIZE-2 did not provide data on discontinuation of zoledronic acid after 1 year of therapy. There is a need to weigh the potential benefits and harms of therapy when considering long-term use of a BMA. In addition, the different mechanism of action between a bisphosphonate and denosumab should be also considered. There are no data outlining the riskbenefit ratio of stopping and potentially restarting BMA therapy during long-term care. Data on the long-term dosing and long-term effects of BMAs are needed. Bone metastases and the risk of SREs continue throughout the trajectory of metastatic breast cancer. This has been shown in the early studies in which BMAs were compared with placebo, 16 in the studies comparing the now US Food and Drug Administrationapproved BMAs against one another, 17,18 and in the dosing interval studies described in this ASCO guideline update. CALGB 70604, ZOOM, and OPTIMIZE-2 demonstrate that the risk of SREs is approximately 15% to 29% into the second year of dosing. The duration of bone-modifying therapy in these studies is of note given that the life expectancy of metastatic breast cancer involving the bone may approach or exceed the median length of follow-up of these studies. 19,20 It is also of note that a minority (15% to 29%) of participants in these studies continued to have SREs on BMAs. Research is needed to identify those individuals who may not benefit from BMAs due to either being at low risk for developing an SRE or due to a high likelihood of having an SRE despite bonemodifying therapy. For those identified as at greatest risk of experiencing an SRE, a clinical trial should be offered to develop interventions to decrease that risk. # AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. # AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors # AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. The Update Committee thanks Charles Shapiro, MD, and Alexander Solky, MD, the Clinical Practice Guidelines Committee, and Melissa Brouwers, PhD, and Craig Earle, MD, from the Cancer Care Ontario Report Approval Panel for their thoughtful reviews and insightful comments on this guideline. The Update Committee also thanks Glenn Fletcher of Cancer Care Ontario's Program in Evidence-Based Care for his assistance in facilitating the ASCO-CCO guideline collaboration.

# GUIDELINE OBJECTIVES To evaluate the appropriateness of, and make recommendations on, routine testing for human papillomavirus (HPV) status in adult patients with primary, or neck nodal metastatic, squamous cell carcinoma (SCC) of the head and neck. # TARGET POPULATION Adult patients with squamous cell carcinomas arising in oropharynx, larynx, hypopharynx, nasopharynx, sinonasal tract, or oral cavity subsites or an unknown primary head and neck site. # INTENDED USERS This guideline is targeted for: 1. Clinicians involved in the delivery of care of adult patients with head and neck squamous cell carcinoma (HNSCC). 2. Pathologists involved in the evaluation of HNSCCs. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # RECOMMENDATION 1 The tumours of all adult patients presenting with oropharyngeal squamous cell carcinomas should be routinely tested for HPV status. # Summary of Key Evidence for Recommendation 1 - A meta-analysis showed a definite survival benefit for HPV-positive patients compared to those whose tumour was HPV negative in terms of overall survival (OS) (HR: 0.43 (95%CI: 0.32-0.58), progression-free survival (PFS) (HR: 0.40, 95%CI: 0.28-0.56), and disease-specific survival (DSS) (HR: 0.45 (95%CI: 0.27-0.76). - A published data meta-analysis by Ragin and Taioli (1) demonstrated that patients with HPV-positive oropharyngeal tumours had a 28% reduced risk of death compared to patients with HPV-negative oropharyngeal tumours (HR: 0.72, 95%CI: 0.5-1.0). Similar results were calculated for disease-specific survival (DSS) (HR: 0.51, 95%CI: 0.4-0.7). However, no benefit in overall survival (OS) or DSS was seen in HPV-positive versus negative patients with non-oropharyngeal tumours. # Justification for Recommendation 1 There is evidence from a meta-analysis of randomized trials that HPV-positivity is a strong predictor of prognosis in patients with oropharyngeal squamous cell carcinoma. In addition, it is likely that HPV status will influence management decisions in the near future and is now regarded as a mandatory stratification factor for clinical trials. Therefore, even though at this time no recommendation can be made to base clinical management decisions on HPV status, the valuable prognostic benefits of HPV testing are sufficient to warrant routine testing. # Qualifying Statements for Recommendation 1 - The above recommendation only applies to patients with squamous cell carcinoma of the oropharynx, which includes tonsil, base of tongue, soft palate and associated pharyngeal walls. The data and recommendation do not apply to patients with nonoropharyngeal cancers. - Altering management decisions based on results from HPV testing is not recommended beyond the context of a clinical trial at this time. # RECOMMENDATION 2 It is recommended that the neck nodal tissue of patients with metastatic squamous cell carcinoma to neck nodes from an unknown head and neck primary be routinely tested for HPV status. # Summary of Key Evidence for Recommendation 2 - Twelve studies (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) found the prevalence of HPV-positive lymph node metastases ranged from 0%-19% in patients with non-oropharyngeal primary sites compared to 66%-87% in those whose primary tumour originated in the oropharynx. # Justification for Recommendation 2 The evidence indicates that there is relationship between HPV positivity and whether the initial cancer arises in the oropharynx or not. As detection of the primary tumour offers a reduction in morbidity due to the benefits of localized treatment, the additional diagnostic information provided by HPV status is sufficient to warrant routine testing of these tissues. # Qualifying Statements for Recommendation 2 Currently, there are no standardized protocols or extensive published experience regarding the performance of p16 immunohistochemical (IHC) or HPV in situ hybridization (ISH) in fineneedle aspiration (FNA) or cytology material from metastatic squamous cell carcinoma to cervical lymph nodes. # RECOMMENDATION 3 It is recommended that HPV status in oropharyngeal SCC be initially determined using immunohistochemical (IHC) staining for p16. IHC staining for p16 can be considered positive when the following three criteria are met: - cytoplasmic and nuclear staining - staining is moderate to strong and diffuse - staining is present in at least 70% of tumour cells (See Section 4 for explanation) A validated polymerase chain reaction (PCR) or in situ hybridization (ISH) technique for highrisk HPV subtypes may be necessary to confirm p16 results in selected cases according to the following algorithm: # Technical Considerations for Recommendation 3 While it is not possible to make evidence-based recommendations regarding the minimum set of criteria requiring adherence in a pathology laboratory with respect to HPV testing at this time, the following guidance is offered based on expert opinion and a consensus process by members of the Head and Neck DSG: - Analysis should be performed on sections from paraffin blocks or unstained slides cut at 4 microns - In cases of metastatic disease, where a core biopsy may not be a possibility, all efforts should be made to obtain enough tissue with FNA to prepare cell blocks. # Justification for Recommendation 3 The current evidence suggests that PCR, DNA ISH, and IHC staining are all comparable. With no unequivocal evidence exclusively supporting any particular scheme, the Head & Neck Disease Site Group believes this scheme is practical and simple, and it minimizes the impact of testing on available pathology resources and is appropriate until such time as further evidence becomes available. The Head & Neck DSG acknowledges that the algorithm may be considered controversial by some, but it is believed to address the proficiencies that are most readily available in laboratories across the province. # Qualifying Statements for Recommendation 3 - The Head & Neck DSG considers quality assurance and quality control in HPV-status testing to be paramount. As such, all testing should be carried out in licensed and accredited laboratories, and test results should be interpreted by experienced pathologists/scientists. Laboratories need to follow proper quality control and participate in external proficiency testing to ensure test accuracy. Further discussion of specific quality and proficiency parameters necessary for individual laboratories performing HPV-status testing is beyond the scope of this guideline. - Qualitative HPV PCR assay detection alone should be avoided - The above recommendations do not apply to samples from dental procedures. # FUTURE RESEARCH Insufficient data currently exist to assess the prognostic benefit of HPV positivity in SCC of the larynx, hypopharynx, nasopharynx, sinonasal tract and oral cavity. There is evidence in the literature to suggest that the prevalence of HPV in these subsites may be higher than originally believed. Meta-analyses (1,27,28) report a pooled prevalence in the oral cavity and the larynx as high as 40% and 24%, respectively. Lip and oral cavity, pharynx, larynx, nasopharynx and lymph nodes combined have a reported pooled HPV prevalence of 32%. Such values warrant further prospective local data collection via the creation of a provincial patient registry to establish the prevalence of HPV-associated SCC and to clarify the prognosis associated with HPV positivity in these patients. This will ensure the acquisition and availability of evidence upon which future clinical decisions can be based. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

# GUIDELINE OBJECTIVE This guideline was written to provide guidance on the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease-free after receiving primary treatment. This guideline is an update of a previous version, which was published in 2009. The update was initiated when the members of the Program in Evidence-Based Care (PEBC) Gynecologic Cancer Disease Site Group become aware of new publications related to follow-up for the target population. The Disease Site Group members wanted to determine whether this new evidence would result in modifications to the existing recommendations. # TARGET POPULATION This practice guideline applies to women who are clinically disease free and asymptomatic after receiving potentially curative primary treatment for cervical cancer. This guideline does not apply to the follow-up of women who have been treated for cervical precancer. # INTENDED USERS This practice guideline is for clinicians involved in the care and follow-up of women who have received treatment for cervical cancer. Note: the content of these recommendations has not changed since the 2009 version of this guideline, however the evidence-base has been updated and now includes studies published up to 2014. - Follow-up care after primary treatment should be conducted and coordinated by a physician experienced in the surveillance of patients with cancer. Continuity of care and dialogue between the healthcare professional and patient about symptoms of recurrence may enhance and facilitate early cancer recurrence detection because the majority of women who develop a recurrence have symptoms and signs that occur outside scheduled follow-up visits. # Follow-up to Five Years - A reasonable follow-up strategy involves visits at the following intervals: o every three to four months within the first two years, o every six to 12 months from years 3 to 5. - At a minimum, follow-up visits should include a patient history and a complete physical examination. o Symptoms elicited during the patient history should include general performance status, lower back pain (especially if it radiates down one leg), vaginal bleeding, or unexplained weight loss. Focused imaging or testing appropriate to findings is warranted. o A physical examination should attempt to identify abnormal findings related to general health and/or those that suggest vaginal, pelvic sidewall, or distant recurrence. Because central pelvic recurrences are potentially curable, the physical examination should include a speculum examination with bimanual and pelvic/rectal examination. Focused imaging or testing appropriate to findings is warranted. o If vaginal vault cytology examination is used to detect new precancerous conditions of the vagina it should be performed no more frequently than once a year. An abnormal cytology result that suggests the possibility of neoplasia warrants colposcopic evaluation and directed biopsy for histological confirmation. - Because their role has not been evaluated in a definitive manner, the following investigations are not advocated: o Positron emission tomography (PET) with computed tomography (PET-CT), o Other imaging or biomarker tests in asymptomatic patients. - Although there is evidence showing that HPV DNA testing has promise as a method of detection of recurrence after radiotherapy, data are preliminary and need verification in higher quality studies with larger sample sizes, and HPV DNA testing is currently unfunded at this time in the province of Ontario. # Follow-up Beyond Five Years - After five years of recurrence-free follow-up: o Patients may return to annual assessment with a history, general physical, including pelvic examination with cervical/vaginal cytology performed by the primary care physician that is consistent with standards for well-woman care; however, some patients with treatment complications such as those related to radiotherapy may require more prolonged follow-up at the cancer centre. o Routine lower genital tract screening to identify new pre-invasive disease according to population-based guidelines is recommended for patients who have undergone surgical treatment. Cytological follow-up is not recommended for patients who have been treated with radiotherapy.

# GUIDELINE OBJECTIVES To make recommendations with respect to: 1. a) The use of multiparametric magnetic resonance imaging (MPMRI) in patients with an elevated risk of clinically significant prostate cancer (CSPCa) who are biopsy naïve, b) The use of MPMRI-targeted biopsy plus transrectal ultrasound systematic biopsy (TRUS-SB) or MPMRI-TB alone for biopsy-naïve patients who have undergone MPMRI; - a) The use of MPMRI in patients with an elevated risk of CSPCa who have had a prior negative TRUS-SB for any prostate cancer, b) The use of MPMRI-TB plus TRUS-SB or MPMRI-TB alone for patients who have had a prior negative TRUS-SB defined as no prostate cancer on biopsy of any grade group; - The minimum acceptable standards in the acquisition, interpretation and reporting of MPMRI and the minimal acceptable standards for performance of MPMRI-TB. # TARGET POPULATION Patients with an elevated risk of CSPCa (defined as International Society of Urologic Pathology Grade Group ≥2), as estimated by available clinical information and tools such as risk calculators and nomograms, of who are A) biopsy naïve or B) have had a prior negative TRUS-SB defined as no prostate cancer on biopsy of any grade group. # INTENDED USERS Radiologists, oncologists, urologists, and other clinicians who provide care for patients defined by the target population. # RECOMMENDATIONS Recommendation 1 (Recommendation to use the diagnostic tool) For biopsy-naïve patients at elevated risk of CSPCa: - MPMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer. - If the MPMRI is positive, MPMRI-TB and TRUS-SB should be performed together to maximize detection of CSPCa. - If the MPMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision making and ongoing followup. Qualifying Statements for Recommendation 1 - Between 8% and 24% of patients with CSPCa may be missed by a negative MPMRI. For this reason, patients should be made aware of the risks and benefits of biopsy avoidance when MPMRI is negative. - MPMRI should only be performed if there is availability of high-quality MPMRI interpretation and operators with experience performing targeted biopsies (see Recommendation 3). - Due to the limited availability, MPMRI is recommended only for patients where there is intent of curative management should the biopsy be positive for CSPCa. # Recommendation 2 (Recommendation to use the diagnostic tool) In patients who had a prior negative TRUS-SB and demonstrate a high risk of having CSPCa in whom curative management is being considered: - MPMRI should be performed, - If the MPMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patients risk profile and time since prior TRUS-SB biopsy, - If the MPMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision making and ongoing follow-up. Qualifying Statements for Recommendation 2 - Prior negative TRUS-SB is defined as no cancer of any grade group on prior biopsy. - MPMRI should only be performed if there is availability of high-quality MPMRI interpretation and operators with experience performing targeted biopsies (see Recommendation 3). - Due to the limited availability, MPMRI is recommended only for patients where there is intent of curative treatment in the case of a positive biopsy.

# TARGET POPULATION Adult and paediatric patients who have received an allogeneic transplant and are experiencing graft-versus-host disease. # RECOMMENDATIONS AND JUSTIFICATION # Extra-corporeal Photopheresis (ECP) in the Management of Graft-Versus-Host Disease (GVHD) - ECP is an acceptable therapy for the treatment of steroid-dependent / refractory acute GVHD in adult and paediatric patients Justification: Three non-comparative studies in adult patients and six studies in paediatric patients reported response rates in favour of the ECP ranging from 32% to 100%. Only one of the paediatric studies reported comparable response rates between patients who received ECP and patients who remained on conventional treatment (6). In the opinion of the Expert Panel, although the quality of the data for steroid refractory aGVHD is limited, patients with primarily refractory skin GVHD should be considered for ECP treatment. - ECP is an effective therapy for the treatment of steroid-dependent / refractory chronic GVHD in adult and paediatric patients This recommendation is supported by the evidence obtained from two studies because in both studies, significant increase in response rates favour the ECP over conventional corticosteroid treatment. Five additional comparative studies (3,4,(11)(12)(13)) and six non-comparative studies (2,5,7,8,14,15) reported response rates ranging from 50% to 80%. # QUALIFYING STATEMENTS - ECP is currently a covered therapy in Ontario for patients with steroid refractory GVHD who meet certain eligibility criteria The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

# Guideline Report History # Target Population These recommendations apply to women with newly diagnosed stage I ovarian cancer. - The stage of ovarian cancer is an important prognostic factor that influences survival and the choice of therapy. The quality of the surgical staging is a key determinant of treatment recommendations (Draft Evidence Summary "#4-15 Management of an Ovarian Mass" will further describe optimal surgical staging). - Women who have undergone optimal surgical staging, including pelvic and para-aortic lymph node sampling, and have stage I disease may or may not benefit from adjuvant platinum-based chemotherapy (see Qualifying Statements section below). - Women who have not undergone optimal surgical staging can be offered two options. The first option is that they undergo re-operation to optimally define the tumour stage and then be offered adjuvant therapy based on the findings. The other option is that they be offered platinum-based chemotherapy to decrease the risk of recurrence and improve survival. - There is insufficient evidence to make a recommendation on the role of adjuvant pelvic radiation, whole abdominal-pelvic radiotherapy, or intraperitoneal radioactive chromic phosphate. # Qualifying Statements - Accurate staging and tumour histology information is essential for developing recommendations on the management of ovarian cancer. A tumour pathology causing doubt should be reviewed by an expert. − A subgroup analysis of the ACTION Trial showed no benefit from adjuvant chemotherapy in women who underwent optimal surgical staging, but that analysis was underpowered. − The entry criteria for the ICON Trial were vague and did not reflect the standard of surgical care offered in Canadian centres. − The meta-analysis included in this practice guideline demonstrates that stage I patients have an improved outcome with adjuvant chemotherapy. However, an estimated 90% of women undergoing surgical resection for ovarian cancer do not undergo optimal surgical staging. If the restaging of a sub-optimally staged patient reveals a more advanced disease, chemotherapy is the preferred treatment option. If reoperation confirms stage I disease, there is insufficient evidence for or against adjuvant chemotherapy. The treatment decision must be based on a discussion with the patient about potential benefits and risks. Entries to MEDLINE (1965through May 2003, CANCERLIT (1975through October 2002, and Cochrane Library (2003, Issue 1) databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997Oncology ( to 2003 were systematically searched for evidence relevant to this practice guideline report. Evidence was selected and reviewed by three members of the Practice Guidelines Initiative's Gynecology Cancer Disease Site Group and methodologists. This practice guideline report has been reviewed and approved by the Gynecology Cancer Disease Site Group, which is comprised of medical oncologists, radiation oncologists, a pathologist, an oncology nurse, and patient representatives. External review by Ontario practitioners is obtained for all practice guidelines through a mailed survey. Final approval of the guideline report is obtained from the Practice Guidelines Coordinating Committee. The Practice Guidelines Initiative has a formal standardized process to ensure the currency of each guideline report. This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Key Evidence - Twenty-five randomized controlled trials were identified that compare treatments for stage I ovarian cancer. Eight of the studies reported results for stage I patients only. - The randomized trials compared a variety of adjuvant therapies (chemotherapy, radiotherapy, and surgery), making it difficult to form recommendations on the optimal adjuvant therapy. - Eleven randomized controlled trials reported at least minimal surgical staging. - The majority of patients in the five randomized controlled trials comparing adjuvant chemotherapy to no chemotherapy did not receive lymphadenectomy as part of their surgical staging. The pooled results for stage I patients indicated a survival benefit with the addition of chemotherapy (relative risk, 0.71; 95% confidence interval, 0.56 to 0.90; p=0.005), and there was a benefit in terms of reduced recurrence favouring adjuvant chemotherapy (relative risk, 0.62; 95% confidence interval, 0.47 to 0.80; p=0.0003). - A subgroup analysis of one randomized controlled trial demonstrated that if lymph node sampling is not conducted as part of the staging surgery then adjuvant chemotherapy is favoured in terms of overall survival (relative risk, 0.71; 95% confidence interval, 0.54 to 0.92). - The largest trial to date randomized 925 women with stage I ovarian cancer to receive either adjuvant chemotherapy or no adjuvant chemotherapy. Platinum-based adjuvant chemotherapy was reported to improve overall five-year survival (absolute survival difference,8%; 95% confidence interval, 2% to 12%; hazard ratio, 0.67; 95% confidence interval 0.50 to 0.90; p=0.008). - The most frequently reported adverse effects associated with chemotherapy were grade 3 or 4 vomiting/nausea and grade 3 or 4 leukopenia. # Future Research Future research needs to evaluate the implementation of surgical staging as a means of avoiding the use of chemotherapy in women who may not require toxic therapy. The role of adjuvant therapy in women with poor prognostic factors who are optimally staged needs to be assessed. The optimal chemotherapy regimen in terms of agents, dose, and duration has yet to be defined. For further information about this practice guideline, please contact: Dr. Michael Fung Kee Fung,Chair,Gynecology Cancer Disease Site Group;Ottawa General Hospital,501 Smyth Road,Ottawa,Ontario;. # Related Guidelines

# GUIDELINE OBJECTIVES The guideline objective was to make evidence-based recommendations about APN roles (i.e., CNS, NP) for optimizing patient, provider, and health system outcomes across the cancer journey. Based on this objective, this guidance document address two specific questions: (1) For which patient populations and in which situations (types of needs, practice settings, phase of the cancer journey) have APN roles demonstrated equivalence or improved outcomes or reduced harms in appropriate controlled comparative studies of cancer care? (2) What specific patient, provider, or health system outcome indicators are associated with CNS or NP roles? # TARGET POPULATION The target population includes patients across the cancer journey (i.e., prevention, screening/diagnosis, treatment, survivorship/recovery, palliative care, end-of-life care). # OUTCOMES OF INTEREST Potential outcomes of interest include: quality of life; physical, functional, psychosocial and mental health; morbidity; mortality; symptom management; patient and provider satisfaction; health care utilization; costs; and quality of care. # INTENDED USERS The intended users of this guideline include: As with any planning strategy, the complete range of clinicians with the knowledge, skills, and competence to provide various care options should be considered in the context of patient need, quality goals, access, demand, and availability of resources. This guideline provides evidence-based recommendations related to appropriate clinical roles for advanced practice nurses. Canada recognizes two types of APN roles, the CNS and the NP. According to the Canadian Nurses Association, CNSs and NPs provide "an advanced level of clinical nursing practice that maximizes the use of graduate educational preparation, in-depth nursing knowledge and expertise in meeting the health needs of individuals, families, groups, communities and populations. It involves analyzing and synthesizing knowledge; understanding, interpreting and applying nursing theory and research; and developing and advancing nursing knowledge and the profession as a whole" (1). CNSs and NPs have overlapping and complementary skill sets. Both roles are involved in the delivery of direct and indirect clinical care, providing organizational leadership, leading or participating in research and evidence-based practice activities, and educating patients, nurses, and other health providers. The two roles differ with respect to their scope and focus of practice. CNSs have the same regulated scope of practice as an RN. While CNSs provide clinical care they tend to have greater expertise and responsibilities for leading organizational change, education, evidence-based practice, and research (2,3). NPs have an expanded regulated scope of practice (i.e., RN-EC) that gives them the authority to diagnose, prescribe, treat and refer patients to other providers, and to admit and discharge patients from hospital (4,5). With this expertise, NPs tend to have greater role responsibilities related to clinical care but also engaged in leadership, education, evidence-based practice, and research. # ALTERNATE APN ROLES Alternate APN roles are introduced as a replacement or substitute for another provider, most often a physician. The aim is to provide services that reduce cost or address workload or workforce shortages while maintaining or improving the quality of care (6). Studies of alternate roles are usually designed to assess for equivalent outcomes. # COMPLEMENTARY APN ROLES Complementary APN roles are introduced to augment the services of existing healthcare provider roles with the goal of improving quality of care (7). Studies of complementary roles compare APN plus standard care with standard care alone and are designed to assess for improved outcomes. Note, this guideline focuses solely on direct evidence specific to CNS and NP roles and does not include evidence or recommendations related to additional roles that could be provided by RNs or other types of clinicians (e.g., radiation therapists). Clinical activities listed below may also be appropriate to be offered by alternative, appropriately trained care providers. In the section that follows, recommendations related to Questions 1 and 2 are provided beginning with recommendations for Question 1. These recommendations are presented by phase of the cancer journey. (11). In 2013 in Ontario, there were 497 RNs (includes CNSs), 55 NPs, and 138 registered practical nurses working in oncology (8). Given the rising incidence/prevalence of cancer and gaps in access and quality of care, there are opportunities to optimize generalist, specialized, and advanced nursing roles in cancer control. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # Quality of Evidence - Multiple systematic reviews demonstrate the safety and effectiveness of CNS and NP roles in a variety of contexts (12)(13)(14). The findings of this systematic review are consistent with other reviews. - The overall quality of the evidence reported in this systematic review is poor (moderate to high risk of bias in all but one study) and the results of individual studies must be interpreted with caution. However, the consistent pattern of results demonstrating equivalent or improved quality of care and patient health outcomes for different types of APN roles across varied patient populations, geographic jurisdictions, and phases of cancer is compelling. # Future Directions - Further research about the effective development and use of CNS and NP roles in Canada is required. - Innovative approaches that optimize the scope of practice and expertise of all members of the healthcare team are required to deliver timely, coordinated, accessible, and efficient models of patient-centred cancer care (15). # PREVENTION RECOMMENDATION 1 No recommendations can be made about the utilization of APN roles for cancer prevention owing to a lack of data at this time. Future research should: i) examine the broader international literature about the effectiveness of primary prevention strategies delivered by advanced practice nurses in the non-cancer literature that may be relevant to cancer; and ii) assess the need to optimize APN role involvement in primary and secondary cancer prevention services. # Summary of Key Evidence for Recommendation 1 - No comparative studies about the effective use of advanced practice nurses related to the primary or secondary prevention of cancer were identified. # Justification for Recommendation 1 There is no evidence currently available on which to make a recommendation regarding the use of advanced practice nurses in cancer prevention. # Qualifying Statements for Recommendation 1 The lack of research studies related to cancer prevention was a surprising finding given that health promotion and illness prevention are important aspects of APN and, in particular, NP roles in primary care (16-18). - Relevant studies on the primary prevention of chronic diseases including cancer (e.g., health promotion/healthy lifestyle interventions related to diet, exercise, smoking cessation, alcohol use) may have been missed in this review because of the cancerspecific focus of the literature search strategies. The absence of research about APN roles in primary prevention has been noted in a non-cancer-specific systematic review of CNSs and NPs (14). Research on these roles has focused on the management of episodic conditions, secondary prevention, and chronic disease management (14). - People with a history of cancer may be at risk for developing a second cancer and other chronic conditions including cardiovascular disease, pulmonary disease, diabetes, and hypertension (19)(20)(21). Efforts to improve the long-term health of cancer survivors through secondary prevention strategies are required. # SCREENING RECOMMENDATION 2 In primary care and community-based settings, NPs working in alternate provider roles can be utilized to improve access to breast and cervical cancer screening. # Summary of Key Evidence for Recommendation 2 - NPs providing same-day services in primary care clinics for underscreened patients had improved breast and cervical screening rates compared with physician chart reminders (22). - Two studies demonstrated that the quality of Papanicolaou (Pap) smears conducted by NPs was not detectably different and, in some cases, was superior to physicians (23,24). # Justification for Recommendation 2 The evidence demonstrated consistent results with similar or improved patient outcomes, and no reported harms, with respect to breast and cervical cancer screening for NPs working in alternate provider roles. # Qualifying Statements for Recommendation 2 - No studies compared RNs and NPs in performing Pap smears. - Quality of Pap smear is defined as the proportion of satisfactory smears and the proportion of smears with endocervical cells. # Additional Implementation Considerations - In Canada, RNs (who have acquired competency through additional training) and NPs are authorized to perform Pap smears. # RECOMMENDATION 3 As alternate providers to physicians, NPs can provide safe and effective care in performing esophagoscopy, flexible sigmoidoscopy, and colonoscopy for cancer screening. # Summary of Key Evidence for Recommendation 3 - The sensitivity and specificity of NP-conducted sigmoidoscopy and esophagoscopy was found to be no different to that of physicians (25,26). - Compared with physicians, NP-led colonoscopy was found to provide equivalent quality of care with respect to procedural pain, duration of the procedure and depth of insertion, and improved care related to patient satisfaction and detection of adenomas (27). # Justification for Recommendation 3 The evidence demonstrated consistent similar (i.e., no difference) or improved patient outcomes, with no reported harms, with respect to esophagoscopy, flexible sigmoidoscopy, and colonoscopy for cancer screening for NPs working in alternate provider roles. # Qualifying Statements for Recommendation 3 - The studies included patients at average risk for colorectal cancer and at above-average risk for colorectal cancer and esophageal cancer. # Additional Implementation Considerations - In Ontario, RN-performed flexible sigmoidoscopy is standard care in 14 sites and has been found to be a safe and effective model of care (28). No studies were identified that compared RNs with NPs in performing flexible sigmoidoscopies. # DIAGNOSIS RECOMMENDATION 4 For women with cervical dysplasia, NPs are an appropriate alternate provider to physicians in performing colposcopy-guided biopsies to diagnose cervical cancer. # Summary of Key Evidence for Recommendation 4 - Two studies found the sensitivity and specificity of colposcopy-guided cervical biopsies conducted by NPs to be no different than those conducted by physicians (29,30). NPs were more likely to take two or more biopsies and this was associated with improved sensitivity (29). These results are based on randomized controlled trial and chart review data. - One study found that compared with physicians, there was greater consistency between Pap smear and biopsy, less variability and greater consistency with standards of care, higher rates of patient follow-up, and better documentation by NPs. # Justification for Recommendation 4 The evidence demonstrated consistent similar (i.e., no difference) or improved patient outcomes, with no reported harms, with respect to colposcopy-guided biopsies to diagnose cervical cancer performed by NPs working in alternate provider roles. # Additional Implementation Considerations: - NPs may be particularly effective at improving access to care for women with cervical dysplasia in underserved communities. - No studies of NPs related to the treatment phase of the cancer journey were identified. # Justification for Recommendation 5 Several studies demonstrated consistent reduced harms, or similar (i.e., no difference) or improved patient outcomes, with very few reporting negative outcomes with respect to patients undergoing surgery or radiation therapy for CNSs working in alternate provider roles. The benefits of CNS care exceeded the harms. # Qualifying Statements for Recommendation 5 - It is not possible to make recommendations about the specificity of interventions to be included in the package of services offered in alternate models of CNS-led care for patients receiving cancer treatment. Overall, the studies are small and heterogenous. # Additional Implementation Considerations - In general, CNS care most commonly involved a package of interventions or services that included comprehensive and holistic patient assessments, provision of information, development of patient self-care management skills, symptom management, psychosocial support, and care coordination with patient referral to other healthcare providers and services, including physicians as required (31)(32)(33)(34)(35). Patients also had ondemand access to the CNS as needed via telephone and ad hoc clinic appointments (31,(33)(34)(35). - Developing CNS care interventions requires careful assessment of unmet patient population health needs and integration of clinical practice guidelines for the assessment and management of specific disease-and treatment-related symptoms and side effects. - In some instances, CNSs provided medical care outside of their regulated scope of practice such as communicating a diagnosis (33), discussing treatment options (31,33), and ordering diagnostics tests (33,34) or symptom management medications (34,35). In these cases, CNSs used predetermined and physician agreed-upon protocols or medical directives (33)(34)(35), and had completed additional training (31,35). # RECOMMENDATION 6 The addition of complementary CNS care to usual care may improve psychological and mental well-being and survival for patients with a new diagnosis of cancer who are post cancer surgery or receiving chemotherapy or radiation treatment. # Summary of Key Evidence for Recommendation 6 - Complementary CNS care was evaluated in six studies for patients receiving chemotherapy and/or radiation therapy (36,37), undergoing radiation therapy alone (38,39), or who were post cancer surgery (40-42). - The studies included patients with breast, gynecological, head and neck, gastrointestinal, lung, or urological cancers. - The addition of CNS care to usual care did not improve HRQL for patients receiving radiation or chemotherapy (36)(37)(38), except for unmarried women with breast cancer who had improved HRQL and mood (37). - There were no differences in symptom distress (42) or radiation treatment side effects for patients who did or did not receive CNS care (38,39). - There were variable results related to psychosocial and mental health outcomes. - One study evaluated the impact of CNS care on survival (42). There were no survival benefits for elderly patients post cancer surgery who had early stage solid tumour cancers. Patients with advanced stage cancer in the CNS group had improved survival at two years (67% versus 40%, 95% confidence interval 1.33 to 3.12; p=0.001) due to fewer deaths from postoperative complications. - The addition of CNS care to usual care did not lead to reduced health service use, but importantly, was also not associated with increased healthcare costs. # Justification for Recommendation 6 Several studies demonstrated consistent similar (i.e., no difference) or improved patient outcomes with respect to newly diagnosed cancer patients who were post cancer surgery or receiving chemotherapy or radiation therapy for CNSs working in complementary provider roles. The benefits of CNS care exceeded the harms. # Qualifying Statements for Recommendation 6 - No studies evaluated complementary NP roles. - Patients who may benefit the most from CNS care are unmarried women with breast cancer, and those who have more intensive and complex healthcare needs related to psychological distress, older age, and advanced cancer. - CNS care focused on the prevention, early detection, and management of health problems following patient discharge from hospital may have contributed to improved survival for patients with advanced stage cancer. # SURVIVORSHIP/POST-TREATMENT FOLLOW-UP CARE RECOMMENDATION 7 For patients with breast and colorectal cancer, CNS-or NP-delivered telephone follow-up may provide a safe and acceptable alternate model to outpatient clinic follow-up care provided mostly by physicians. # Summary of Key Evidence for Recommendation 7 - CNS-or NP-led telephone follow-up for patients with breast and colorectal cancer, respectively, was associated with improved patient satisfaction and achieved similar (i.e., no difference) outcomes including anxiety, psychological well-being, quality of life, selfcare, recurrence, and time to detect recurrence (43)(44)(45). - There were no differences in hospitalization, numbers of tests, or contacts between scheduled appointments for CNS or NP telephone follow-up care for patients with breast or colorectal cancer (43,46). - In one study, the combination of longer consultation times and a 20% increase in consultations, resulted in higher overall per patient costs for CNS care (mean difference £55, 95% CI, £26 to £77) (46). It is unclear whether these costs would generalize to the Ontario context. - Patients receiving CNS telephone follow-up had lower travel and lost productivity costs (46). # Justification for Recommendation 7 The evidence demonstrated consistent similar (i.e., no difference) or improved patient outcomes with respect to follow-up care of low to moderate risk for cancer recurrence in breast or colorectal cancer patients for NPs and CNSs working in alternate provider roles. There were very few negative outcomes and the benefits of APN-delivered care exceeded the harms. # Qualifying Statements for Recommendation 7 - CNS or NP telephone follow-up is suitable for patients at low to moderate risk for cancer recurrence and those wishing to avoid clinic visits due to long travel distance and/or mobility issues (44,45). - Standard post-treatment follow-up care for breast cancer was delivered in outpatient clinics and was most often provided by junior doctors (residents), but also by oncologists, CNSs, or a colorectal NP (43,44). # RECOMMENDATION 8 The addition of a complementary and comprehensive assessment and intervention program provided by a NP may be effective for reducing menopausal symptoms in women following treatment for breast cancer. # Summary of Key Evidence for Recommendation 8 - Women receiving the NP-led intervention had significant improvements in menopausal symptoms and sexual functioning compared with those in the attention control/usual care group (47). There were no significant differences in vitality. # Justification for Recommendation 8 The evidence consisted of one randomized controlled trial (RCT) that demonstrated decreased harms or similar (i.e., no difference) or improved patient outcomes, with no reported harms, with respect to menopausal symptoms in women following breast cancer treatment for NPs working in complementary provider roles. # Qualifying Statements for Recommendation 8 - Study participants were female, and between eight months and five years following a diagnosis of stage I or II breast cancer. They had completed chemotherapy or radiation therapy at least four months prior to study participation, but could be taking tamoxifen (47). - Study participants had at least one menopausal symptom (hot flashes, vaginal dryness, or stress urinary incontinence) of moderate to severe intensity (47). One study evaluated CNS-performed flexible cystoscopy for the follow-up care of patients with bladder cancer (48). Based on the results of this one study, there is insufficient evidence to make recommendations about the use of CNS or NPs as alternate providers to physicians in performing follow-up flexible cystoscopy for patients with bladder cancer. # PALLIATIVE CARE # RECOMMENDATION 9 The complementary addition of CNS care to cancer services may improve HRQL and mental and social well-being for patients with advanced cancer or cancer-related pain while providing similar or improved outcomes related to healthcare utilization. # Summary of Key Evidence for Recommendation 9 - Three studies evaluated very different models of complementary CNS care in providing proactive palliative care services for patients with advanced cancer in oncology settings (49,50) and coaching for cancer pain management (51). - No studies evaluating NPs were identified. - The early introduction of CNS palliative care services did not lead to improved HRQL, symptoms, or mood but was associated with increased survival and fewer hospital admissions (49). - In contrast, Bakitas et al. (50) found higher HRQL and less depression but no differences in symptom severity, survival, hospital days, and intensive care unit days for patients receiving a CNS-delivered self-care program. - Similarly, a CNS coaching intervention using motivational interview techniques also led to better HRQL, mood, and psychosocial well-being (reduced pain interference) but no improvement in pain attitudes or symptoms (pain relief, pain intensity) (51). Health service utilization outcomes were not evaluated in this study. # Justification for Recommendation 9 The addition of CNS care was similar to usual care for most patient and health system outcomes. No harms were reported for CNS care. In select studies, CNS care led to improved patient outcomes for survival, HRQL, mental well-being, and pain interference and improved health system outcomes related to reduced hospitalization. # END-OF-LIFE CARE RECOMMENDATION 10 No evidence-based recommendations can be made about the utilization of APN roles for end-of-life care owing to a lack of data at this time. # Summary of Key Evidence for Recommendation 10 - No comparative studies about the effective use of advanced practice nurses related to end-of-life care were identified. # Justification for Recommendation 10 There is insufficient evidence currently available on which to make a recommendation regarding the use of advanced practice nurses in cancer end-of-life care. 9A). Of these, HRQL, symptoms, and mental health were the most frequently reported outcomes. - Health systems outcomes evaluated in studies of CNS and NP roles related to indicators of care quality, healthcare costs, and health service utilization including hospital length of stay, hospital readmission, emergency department visits, number of advanced practice nurse consultations, and number of physician visits (Table 9B). Quality of care indicators were the most frequently reported outcome. # RECOMMENDATION 12 No recommendations can be made about the effectiveness of CNS or NP roles for improving healthcare provider outcomes owing to a lack of data at this time. # Summary of Key Evidence for Recommendation 12 - No comparative studies about the effective use of advanced practice nurses for improving healthcare provider outcomes, such as job satisfaction, workload, or team functioning, were identified. # Justification for Recommendation 12 There is no evidence currently available on which to make a recommendation regarding the use of advanced practice nurses for improving healthcare provider outcomes. # RECOMMENDATION 13 No recommendations can be made about the cost-effectiveness of CNS or NP roles in cancer control. # Summary of Key Evidence for Recommendation 13 - No studies identified for this review conducted an economic analysis. In the few studies measuring costs, only a direct cost comparison is provided, rather than a comprehensive assessment of the incremental costs and benefits of APN care (37,46,48). - One study reported on health utilization outcomes for NPs (43). There were no differences in the number of tests ordered but NPs had longer consultation times. - Longer consultation times were also reported for CNSs (35,46). - Overall, CNS outcomes related to healthcare utilization including hospital length of stay, hospital readmission, emergency department visits, consultations, physician visits, and tests and investigations were equivalent to standard care and costs were either similar or reduced (Section 2, Table 11 and 9B). - Increased costs may be associated with the time required for CNSs to develop cystoscopy skills and experience (48) with the increased number and length of CNS consultations (46). # Justification for Recommendation 13 There is insufficient evidence on which to make a recommendation regarding costeffectiveness of advanced practice nurses in alternate or complementary provider roles in cancer control. # FUTURE RESEARCH Several recommendations regarding future research were developed by the Working Group as follows: - Further research about the cost-effectiveness of CNS and NP roles in cancer control is required, particularly within the context of the Ontario and Canadian healthcare systems. - Further research to evaluate innovative models of CNS and NP care is required across all phases of the cancer journey, but particularly for prevention, palliative care, and end-oflife care. - Beyond screening and diagnosis, future research should evaluate alternate and complementary models of NP care in other phases of the cancer journey. - In addition to patient outcomes, future research should examine the impact of CNS and NP roles in cancer control on families and family caregivers, healthcare teams and providers, productivity and efficiency, quality of care and evidence-based practice, and access to care. - Future research should provide decision-makers with guidance about the appropriate use of RNs, CNSs, and NPs in alternate and complementary models of care for specific patient populations and phases of the cancer journey. - To build capacity to conduct timely and meaningful evaluations of innovative models of CNS and NP care in Ontario that permit comparison across regional cancer programs, practice settings, and patient populations, Cancer Care Ontario should provide leadership and support to: o develop an evaluation framework with associated tools to examine the structures, processes and outcomes associated with CNS and NP care; o establish an agreed-upon template of priority patient, provider and health system outcome indicators and measures; and o strengthen the use of technology and data management support to collect and analyze administrative data relevant to CNS and NP roles. - To improve the quality of research and generalizability of the results, researchers should address the following methodological issues: o use of mixed-method study designs and relevant evaluation theories and concepts to evaluate and understand how CNS and NP roles impact on outcomes; o provide more detailed reporting of key study methods (i.e., randomization, randomization concealment, power calculations, and outcome assessment); o explicitly report the type of APN role being evaluated (i.e., CNS or NP) and details about APN education and training and the package of APN interventions provided; and o measure and evaluate the impact of the APN intervention dose (timing, frequency, intensity, duration of advanced practice nurse-patient interactions) for different at-risk or vulnerable populations. # Important Considerations for the Uptake of Practice Guideline Recommendations This practice guideline identifies the potential for introducing new models of cancer care delivery that expand the use of CNSs and NPs and maximize their expertise to improve access, quality of care, and health outcomes for patients and families in Ontario. The introduction of new care delivery models, especially those requiring the optimization or expansion of existing nursing roles or the introduction of new roles, is a complex process necessitating thoughtful planning and strategic implementation to ensure successful achievement of expected outcomes. Research-based approaches and strategies to promote the successful integration of CNS and NP roles in Canada provide important guidance for the application of practice guideline recommendations (52,53). Key considerations for planning, implementing, and evaluating the introduction of CNS and NP roles in cancer control include, but are not limited to, the following: - Decisions to expand the role of CNSs and NPs for Ontario cancer services should be based on established patient, healthcare team, organization, and healthcare system needs, and assessment of existing health human resources and expertise (15). - Substantive planning and use of change management strategies to identify and address potential barriers to optimal role implementation. Frequently reported or common issues include: - allocation and/or reallocation of healthcare funding dollars for new CNS and NP roles, especially with those roles that are aligned with strategic provincial priorities for improving cancer care; o current physician funding models and reimbursement policies do not make it attractive for institutions to substitute advance practice nurses for physicians o regulatory and legislative barriers and the need for new organizational structures, policies, and other strategies to support enhanced or expanded scopes of practice (e.g., medical directives, referral policies, documentation systems); o engagement of the healthcare team and other key stakeholders in the role design and planning process and targeted education and marketing to ensure role clarity and to foster stakeholder understanding and support for the role; o physician concerns about liability, especially for alternate CNS and NP roles; o need for CNS or NP education, training, and mentorship; o need to increase the pool of CNSs and NPs; and o mechanisms and resources for appropriate role supervision and support. - Given the paucity of information about the use of CNS and NP roles in Canada, the introduction of these roles in new models of care should be evaluated to determine their impact on patient and family, healthcare team and provider and health system outcomes. - Use of the PEPPA Framework, a Participatory, Evidenced-Informed, and Patient-Centred Process for APN Role Development, Implementation and Evaluation. This framework is a best practice approach outlining systematic steps and strategies to guide activities and inform decision making about the introduction and effective use of CNS and NP roles in cancer control (54,55). In Canada and internationally, the framework has been used to successfully introduce and evaluate CNS, NP, and other advanced healthcare provider roles. Designing Innovative Cancer Services and APN Roles -Toolkit (56) is a researchbased resource that was developed and tested in Ontario regional cancer centres. It provides guidance, tools, and resources for PEPPA framework application and is freely available at: ew.pdf The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

Questions What is the optimal surgical management of ductal carcinoma in situ (DCIS) of the breast? Should breast irradiation be offered to women with DCIS, following breast-conserving surgery (defined as excision of the tumour with microscopically clear resection margins)? Are there patients who could be spared breast irradiation post-breast-conserving surgery for DCIS? What is the role of tamoxifen in the management of DCIS? # Target Population These recommendations apply to women with DCIS. They do not apply to women with DCIS with microinvasion. # Recommendations and Key Evidence # Surgical Management Women with DCIS of the breast who are candidates for breast-conserving surgery should be offered the choice of breast-conserving surgery or total mastectomy. Mastectomy with the option for reconstruction remains an acceptable choice for women preferring to maximize local control. No randomized trials designed to compare total mastectomy with breast-conserving surgery for DCIS were found. The National Surgical Adjuvant Breast Project (NSABP) B-06 trial (1) involved women with invasive malignancy. However, a small number of women entered were found, on pathology review, to have only DCIS. An analysis based on this subgroup of DCIS patients (2) found a trend towards a much higher local recurrence rate in patients who received breast-conserving surgery alone (9/21; 43%), compared with those who received either breast-conserving surgery plus radiotherapy (2/27; 7%) or mastectomy (0/28; 0%). Two meta-analyses (3,4), consisting mainly of non-randomized trials, also demonstrated higher local recurrence in patients treated by breast-conserving surgery alone versus those treated by mastectomy. One reported no significant differences in local recurrence rates between patients treated by breast-conserving surgery followed by radiotherapy and mastectomy, whereas the second showed improved local recurrence rates with mastectomy. To date, no survival benefit for either type of surgery has been reported. The expert opinion of the Breast Cancer DSG is that this non-randomized data supports the recommendation that breast-conserving surgery followed by radiation or mastectomy are both acceptable treatment options. Qualifying Statements When breast-conserving surgery is performed, all mammographically suspicious calcifications should be removed and margins should be microscopically clear of DCIS. Mastectomy, with the option of reconstruction, is recommended for those women who have an area of DCIS large enough that breast-conserving surgery would leave them with an unacceptable cosmetic result. Added to the 2017 Endorsement: A 2016 joint guideline from the Society of Surgical Oncology (SSO), American Society of Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO) recommends margins of at least 2 mm to reduce the risk of local recurrence (See Section 4 for details). The ASTRO/ASCO recommendation (above) does not change the pathologic definition of a "positive" margin. It remains entirely appropriate in pathology practice to report only DCIS at inked margin as "positive," and to provide distance to closest margin(s) when margins are negative. For patients with DCIS treated with breast-conserving surgery and whole-breast irradiation, a positive margin (ink on DCIS) is associated with a significant risk of ipsilateral breast tumour recurrence (IBTR). A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins. In patients with negative margins less than 2 mm, the need for re-excision should take into account other factors known to impact IBTR and routine mastectomy is discouraged. # Women with DCIS who have undergone breast-conserving surgery should be offered adjuvant breast irradiation. Randomized trials of post-lumpectomy radiation versus observation in patients at relatively low risk of recurrence following surgery alone are ongoing. Until the results of those studies are available, these patients should be referred to a radiation oncologist for a thorough discussion of what is currently known about the potential benefits and toxicities of post-lumpectomy radiation in their particular situation. Three randomized trials (5-12) investigated the role of radiotherapy after breast-conserving surgery in patients with DCIS. In each, the risk of invasive and non-invasive ipsilateral recurrence was reduced with adjuvant radiotherapy. There were no significant differences in distant metastasis or overall survival. # Qualifying Statements Added to the 2017 Endorsement: RCT evidence showed that radiotherapy after breast-conserving surgery reduced local failure compared with observation (RTOG 9804) (See Section 4 for details). Emerging evidence exists on the use of hypofractionation and radiation boost (See Section 4 for details). While there is some evidence to suggest that tamoxifen is effective in the reduction of ipsilateral recurrence and contralateral incidence in women with DCIS, the absolute benefit is small and the evidence is conflicting. Women should be informed of the option of five years of tamoxifen therapy and of the potential toxicities and benefits associated with tamoxifen. Two trials (12,13) investigated the role of tamoxifen versus no tamoxifen in addition to breast-conserving surgery and radiotherapy in the treatment of DCIS. The first demonstrated a significantly lower cumulative incidence of ipsilateral or contralateral breast malignancy for patients in the tamoxifen group versus those in the placebo group. In the second, tamoxifen treatment did not significantly reduce the incidence of either ipsilateral or contralateral breast malignancy. Qualifying Statement In a subset analysis of one of the randomized studies ( 14), the beneficial effect of tamoxifen was most apparent in the estrogen receptor-positive patients. Therefore, if it is felt that a patient might benefit from tamoxifen for one of the above reasons, hormone receptor assessment could be considered in order to aid in the decision regarding tamoxifen treatment. Randomized studies suggest that women who are most likely to have a positive benefit/risk ratio with tamoxifen are those who are less than 50 years of age or who have positive resection margins and refuse further surgery. Women who have a contraindication to radiation or who refuse this treatment but still want to avoid mastectomy should also be considered for tamoxifen therapy. # Added to the 2017 Endorsement # Related Guidelines Evidence Based Series #1-21: Optimal systematic therapy for early female breast cancer. clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way. # Contact Information For further information about this series, please contact Dr. Wendy Shelley; Kingston Regional Cancer Centre, 25 King St W, Kingston ON, K7L 5P9; Telephone: 613-544-2631 x4502; Fax: 613-546-8209; Email: wendy.shelley@krcc.on.ca. For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca

# INTENDED PURPOSE This recommendation report is primarily intended to guide the Ontario PET Steering Committee in their decision making concerning indications for the use of PET imaging. This recommendation report may also be useful in informing clinical decision making regarding the appropriate role of PET imaging and in guiding priorities for future PET imaging research. # RECOMMENDATIONS AND KEY EVIDENCE These recommendations are based on an evidentiary foundation consisting of one recent high-quality U.K. Health Technology Assessment (HTA) systematic review (1) that included systematic review and primary study literature for the period from 2000 to August 2005 and update searches based on those in that systematic review undertaken to retrieve the same level of evidence for the period from August 2005 to May 2010. The routine use of PET is not recommended for the diagnosis or staging of clinical Stage I-III colorectal cancers. PET is recommended for determining management and prognosis if conventional imaging is equivocal for the presence of metastatic disease. Diagnosis PET: One systematic review of two primary studies and one additional primary study in the 2007 Health Technology Assessment (HTA) review (1) summarized the fact that PET has good sensitivity to detect primary tumours > 2 cm, but not smaller tumours, with variable specificity. No additional studies were identified in the update searches. PET/CT: No studies of PET/CT for diagnosis were identified. PET: Two primary studies in the HTA review (1), and four studies from the update searches (Furukawa et al Llamas-Elvira et al Nahas et al and Kosugi et al were identified. These studies had different patient case mixes and proportions of patients with stage IV disease. While some studies showed changes in patient management because of changes in M-staging, such findings were in studies with a relatively large proportion of stage IV disease. Furukawa et al (2) and Nahas et al (4) did not show any significant changes in Mstaging. Kosugi et al (5) included 53 patients with lymph node metastases on CT. PET detected 24 para-aortic and 29 epicolic/paracolic/or intermediate lymph nodes. The results of Kosugi et al (5) showed that PET has lower sensitivity, higher specificity, higher accuracy and higher positive value (PPV) than CT for N1 and N2-3 lymph nodes. For N4 lymph node, PET has high sensitivity and high specificity, while CT has only high sensitivity but low specificity and low PPV. Thus, it is reasonable to consider using PET when N4 nodes are suspected. The HTA review did not identify any studies that involved the use of PET/CT exclusively for staging prior to any therapy. The 2005-2008 update search identified five studies (Veit-Haibach et al Park et al Kinner et al Tsunoda et al and Orlacchio et al. Park et al (8) included only patients with equivocal CT findings or elevated carcinoembryonic enzyme (CEA), which resulted in 49% stage IV patients. PET/CT changed the management in 24% of those patients. Tsunoda et al (10) evaluated the detection rate of PET/CT with respect to nodal metastasis (proximal and distal). PET/CT had better performance than CT overall. Given the small proportion of patients with distant nodal metastasis plus the fact that the study did not separately compare PET/CT and CT with respect to distant nodal metastasis only, it is difficult to know whether distant nodal Mstaging is changed significantly with the use of PET/CT. Veit-Haibach et al (7) and Kinner et al (9) did not show a significant change in M-staging. In Orlacchio et al (10), which included 467 patients, there was concordance among PET, CT, and PET/CT in 91.2% of the cases. Seventytwo percent (72%) of the cases were true positive for liver metastases, suggesting the patients in the study had a higher index of suspicion for liver metastases than might be expected in the routine clinical setting. The study provided formal statistical Z test comparison which showed that PET/CT is better than PET alone or CT alone with p-values < 0.05. The sensitivity and specificity were all greater than 90% in CT, PET, and PET/CT. # Qualifying Statements Some studies evaluated the diagnostic performance of PET or PET/CT with respect to each metastatic site/organ/lesion, while some evaluated it with respect to the M-staging of each patient. It would appear that studies that analyzed results based on each site/organ/lesion showed a better performance of PET or PET/CT, while studies that analyzed results based on the overall M-staging of patients did not show an obvious improvement in performance of PET or PET/CT. As solitary or oligo-metastasis is not a very common presentation in the initial diagnosis of colorectal cancer, it would be unlikely that PET or PET/CT would detect such a situation when CT missed it, if the objective was to change the M-staging and management of these patients. However, in patients who already have suspicious or confirmed metastasis based on CT, it is quite possible that PET or PET/CT could detect further metastases in other sites/organs that were not conclusively detected by CT alone. This would inflate the diagnostic performance of PET or PET/CT, if an analysis was based on sites/organs/lesions instead of the overall M-staging of each patient. This factor might be important when making recommendations for early-stage disease versus metastatic disease. On the other hand, for patients who already have what appears to be solitary or oligometastases on CT only, and who are potential candidates for resection, and given that the possibility of further metastasis in other sites/organs is not low, PET or PET/CT might assist in the decision making of resection with curative intent by helping to assess the extent of metastasis. Studies that analyzed the diagnostic performance of PET or PET/CT, with respect to sites/organs/lesions, provided evidence to support this approach. Therefore, there may be a role for the use of PET or PET/CT when conventional imaging raises suspicion of the presence of potentially resectable metastatic disease, and patients are potential candidates to undergo such surgery. The incremental benefit of PET or PET/CT over magnetic resonance imaging (MRI) of the liver is unclear in such populations as none of the studies included the routine use of MRI as part of conventional imaging. Most studies that showed that PET or PET/CT changed the management of a significant proportion of patients included a relatively large number with stage IV disease (up to 46% of patients). Studies that included a relatively small proportion of stage IV patients did not appear to show a significant benefit or change in the patient management plan with PET or PET/CT. Some of those changes in management involved the detection of a larger than expected volume of disease in the liver or extrahepatic metastasis by PET or PET/CT in patients originally diagnosed with low-volume resectable liver metastasis by conventional imaging. Most studies that compared PET or PET/CT with conventional imaging were done in the time period when multidetector CT (MDCT) was not yet widely available. The only study (Furukawa et al that clearly stated that MDCT was used did not show clinically relevant superiority of PET in addition to MDCT. As MDCT is being used routinely in most of the cancer centres and hospitals in Ontario, the incremental benefit of PET or PET/CT for the routine staging of colorectal cancers remains to be established. While some studies reported the numerical comparisons of diagnostic performance between PET, or PET/CT, and conventional imaging, few studies tested whether the numerical differences observed were statistically significant or not. It is unclear whether PET or PET/CT leads to an improvement in survival or simply results in stage migration. Nonetheless, many practitioners may accept that more accurate staging will lead to a better choice of treatment plan, thereby avoiding overtreatment and sparing patients the unnecessary risks or side effects of therapy or avoiding undertreatment when patients might otherwise benefit from aggressive curative-intent therapy. There are very few studies that evaluated rectal cancer and colon cancer separately. The current limited evidence did not obviously suggest or refute that PET or PET/CT significantly changed management in patients with non-metastatic rectal cancer. However, some studies seemed to suggest that PET or PET/CT has better N-stage accuracy than CT. It is unclear how PET or PET/CT compares with MRI or trans-rectal ultrasound (TRUS) with respect to N-staging. There may be a role for PET/CT with respect to Nstaging in the decision making for patients with non-metastatic rectal cancer who might be candidates for preoperative chemoradiotherapy. When conventional imaging with CT suggests equivocal para-aortic lymph node involvement as the only potential site of concern and that the patient is otherwise a potential candidate for curative intent surgery of the primary colorectal cancer, PET can be considered in order to rule in or out para-aortic region metastatic disease. # Assessment of Treatment Response The routine use of PET is not recommended for the measurement of treatment response in locally advanced rectal cancer before and after preoperative chemotherapy. PET: The update searches identified a randomized control trial (RCT), Bystrom et al (11), that evaluated PET before and after 2 cycles of chemotherapy and also evaluated CT before and after 4 cycles of chemotherapy. The results showed that PET correlated with CT and had a relatively low sensitivity and specificity. PET also failed to predict the time to progression or overall survival in patients with metastatic colorectal cancer. The study suggested that PET should not be used as a substitute for CT for short-term response and should not be used as a surrogate for long-term clinical endpoints. The HTA review identified six non-randomized studies showing that changes in standardized uptake values (SUV) between pretherapy and posttherapy scans may predict response. The update searches identified four additional primary studies evaluating treatment response. Cascini et al, 2006 (12) included patients receiving PET before and 12 days after the initiation of preoperative therapy and supported the finding of the HTA review that changes in SUV may predict response. However, one-time PET after preoperative therapy poorly predicted complete pathologic response after preoperative therapy in Capirci et al (13) and Kalff et al (14) and poorly predicted posttherapy staging in Capirci et al (12). Glazer et al (15) conducted a prospective cohort study of 138 patients, each with presumptive diagnosis of liver metastasis, who had at least one PET scan after chemotherapy and before liver resection. The study showed that ultrasonography also guides surgical decision during intraoperative assessment and suggested PET after chemotherapy should not be used in decision making for liver resection. PET/CT: The HTA review did not have any studies of PET/CT in predicting treatment response. The update searches identified 2 studies (Capirci et al, 2007 Kristiansen et al, 2008. Capirci et al (16) suggested that a change in SUV before and after preoperative chemoradiotherapy predicted a tumour regression grade (TRG) in rectal cancer, while Kristiansen et al ( 17) suggested a single PET/CT after preoperative therapy poorly predicted complete pathologic response. # Qualifying Statements Recurrence/Restaging PET is not recommended for routine surveillance in patients with colorectal cancer treated with curative surgery at high risk for recurrence. PET is recommended to determine the site of recurrence in the setting of rising carcinoembryonic antigen (CEA) when a conventional workup fails to unequivocally identify metastatic disease. HTA review (1) : One systematic review with 13 primary studies and two additional primary studies showed that PET had a sensitivity for detecting recurrence of ≥ 85% and specificities varying from 43% to 90%. Accuracy and sensitivity were superior to CT and similar to MRI. Two studies noted that PET's ability to detect lesions < 1 cm was poor. The update searches identified one RCT (Sobhani et al, 2008, which evaluated the role of PET in surveillance of colorectal cancer in patients who underwent curative surgery and were at high risk for recurrence. Overall, there was no difference in recurrence rate with the addition of PET to conventional workup, but there was a significant improvement in the time to detection of recurrence and in the numbers of patients treated with potentially curative surgery. The small sample size (n=130) precludes definitive conclusions on the role of PET as part of surveillance in colorectal cancer. # Qualifying Statements # Liver Metastasis PET is recommended in the preoperative assessment of colorectal cancer liver metastasis prior to surgical resection. HTA review (1): One systematic review with nine primary studies and five additional studies in primary and recurrent populations showed PET to be more accurate than comparators for the detection of liver metastases. Furthermore, in 15 studies of mixed populations, including patients with suspected recurrence, PET sensitivity was about 90% compared with 73% sensitivity for CT. PET specificity was ≥ 85%. The change in management attributed to PET (compared with conventional imaging) varied from 9% to 39% in reported trials. Two studies noted that 6% and 15%, respectively, had the staging incorrectly changed. The update searches identified one prospective randomized study (Ruers et al, 2009 that considered 150 patients with colorectal cancer liver metastasis eligible for potentially curative surgery suggested a significant decrease in futile laparotomy (45% versus 28%) when 18-fluoro-deoxyglucose (FDG) PET was added to the preoperative imaging strategy and seven studies (Rappeport et al, 2007 Huguet et al, 2007 Lubezky et al, 2007 Adie et al Liu et al Kitajima et al and Potter et al that supported the recommendation. Rappeport et al (20) showed that CT and MRI were more sensitive but less specific than PET/CT in the detection of liver metastases. However, PET/CT was more sensitive and specific for the detection of extrahepatic metastasis than CT alone. In Huguet et al (21), PET had a higher sensitivity than did CT for hepatic, pulmonary, and extrahepatic/extrapulmonary sites. Clinical management was changed in nine of 31 patients (29%), and the change was attributed to the results of PET. Adie et al (23) suggested preoperative assessment with PET/CT is not useful for hepatic colorectal metastases, particularly when preoperative chemotherapy is used, with a trend towards the underestimation of lesions. Liu et al (24) supported the superiority of PET/CT over contrastenhanced CT for the detection of metastatic lesions of colorectal cancer. Kitajima et al (25) showed that integrated PET/contrasted-enhanced CT is an accurate modality for assessing colorectal cancer recurrence, with results that led to changes in the subsequent therapy. Potter et al (26) recommended serial imaging review, with a careful correlation of suspicious findings with previous studies in any suspected recurrence. Therefore, PET/CT was suggested as useful tool when findings remain equivocal after a serial imaging review for colorectal cancer. # Qualifying Statements Despite the change in management reported in these nonrandomized studies, the possibility cannot be ruled out that factors other than PET results were involved in that change (Facey et al. In the evaluation of patients potentially eligible for the curative resection of colorectal cancer liver metastasis, a diagnostic CT is necessary in addition to PET/CT to provide information on hepatic vasculature and anatomy (Facey et al. The sensitivity of PET for detecting metastases decreases following neoadjuvant chemotherapy in patients with colorectal cancer liver metastasis (Lubezky et al. PET is less sensitive than CT for detecting metastases following neoadjuvant chemotherapy. If PET is to be used for staging purposes, it should be performed before and after neoadjuvant chemotherapy. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

GUIDELINE OBJECTIVES 1. To determine whether sentinel lymph node biopsy (SLNB) can safely and effectively identify women with node-negative, early-stage vulvar cancer and can be used as an alternative to inguinofemoral lymph node dissection (IFLD). 2. To provide guidance with respect to the appropriate techniques and procedures in SLNB for women with early-stage vulvar cancer. These include: # TARGET POPULATION Women in Ontario with early-stage (T1 or T2, <4 cm) squamous cell cancer of the vulva are the target population. # INTENDED USERS This guideline is intended for use by gynecologic oncologists and other clinicians involved in the surgical management of early-stage vulvar cancer. The use of SLNB in the case of previous excision of the primary tumour, or in recurrent disease was not covered in this guideline. The Working Group feels there is currently insufficient high quality evidence to warrant a review of this literature at this time. (added January 2018) # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # RECOMMENDATIONS FOR PATIENT SELECTION - SLNB is recommended for women with unifocal tumours <4 cm in size and clinically nonsuspicious nodes in the groin. - There is insufficient evidence to make a recommendation for or against SLNB for women with tumours ≥4 cm or women with multifocal disease. - SLNB is not recommended when there are clinically suspicious groin nodes. # Summary of Key Evidence for Recommendations for Patient Selection The studies in the literature were judged to be of lower quality because of the observational and mainly noncomparative study designs used and an absence of randomized controlled trials. There were similar detection rates for the combined technique of blue dye and radiocolloid (87%, 95% CI 81%-92%) and the radiocolloid alone group (84%, 95% CI 74%-93%). The pooled detection rate per groin was higher with the combination of blue dye and radiocolloid (87%, 95% CI 81%-92%) or radiocolloid (technetium-99 alone (84%, 95% CI 74%-93%) compared to blue dye alone (63%, 95% CI 49%-77%). The false-negative rates were similar for the three techniques (blue dye 9%, 95% CI 0%-27%; radiocolloid 10%, 95% CI 1%-23%; combined 7%, 95% CI 4%-9%). The pooled rate of groin recurrence after a negative SLNB result was 3% (95% CI 2%-5%) and after a negative complete IFLD result was 1% (95% CI 0%-3%). As well, the rate of complications was higher with complete IFLD for wound infection (28%, 95% CI 17%-40%), wound breakdown (23%, 95% CI 18%-28%), lymphocysts (18%, 95% CI 11%-25%), and lymphedema of greater than six months' duration (25%, 95% CI 18%-33%) compared with SLNB (wound infection 4%, 95% CI 1%-9%; wound breakdown 6%, 95% CI 2%-12%; lymphocysts 4%, 95% CI 0%-10%; lymphedema 2%, 95% CI 0%-7%). One paper by van der Zee et al. 2008 included in the Reade et al. review found that women with multifocal disease had higher recurrence rates after SLNB (11.8%, 2/17) compared with women with unifocal disease (2.3%, 6/259) (1,2). Also, most studies that assessed patient outcomes after SLNB selected women with tumours that were <4 cm (2). Therefore, very little information is available to assess the safety of SLNB in women with larger tumours. # Justification for Recommendations for Patient Selection The Working Group considered the benefits of SLNB (lower rates of wound infection, wound breakdown, formation of lymphocysts, and long-term lymphedema) outweighed the potential increased risk of death in 90% of patients with missed metastatic spread to the lymph nodes (2). There is emerging data that SLNB with ultrastaging, a technique that examines more sections than routine pathology, is more sensitive at detecting lymph node metastases than conventional lymphadenectomy for other cancers (3,4). If this is the case for vulvar cancer, then SLNB will potentially have fewer missed metastases. The Working Group also concluded that the evidence suggested that the rate of recurrence of vulvar cancer was similar for SLNB and IFLD. The Working Group chose to recommend SLNB for patients with unifocal disease based on the large GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) by van der Zee et al. in 2008 (1). Also, since most studies included patients with tumours that were <4 cm, the Working Group recommended SLNB for this subgroup of patients. SLNB was not recommended for patients with clinically suspicious groin nodes because of the potential elevated false-negative rate and because this subgroup of patients were not included in many of the studies. # RECOMMENDATIONS FOR APPROPRIATE TECHNIQUES AND PROCEDURES Vulvar cancer is a rare condition and the recommended procedure is technically challenging. Appropriate surgical training (i.e., supervised experiences with SLNB procedures followed by complete IFLD without any false negatives and ongoing annual experience with cases to maintain competence) is recommended to optimize patient outcomes and safety. - This procedure should be performed by gynecologic oncologists in Gynecologic Oncology Centres. For more information on organization of gynecologic oncology services in Ontario, including a recommendation for centralization of services for vulvar cancer, please refer to EBS #4-11: Organization of Gynecologic Oncology Services in Ontario ( 5). Although volume has not been explicitly studied, the Working Group agrees that successful experience with SLNB followed by IFLD in at least 10 patients per centre is recommended. - Radiocolloid tracers should be used alone or with blue dye. In patients where lymphoscintigraphy did not identify a sentinel node in the groin(s) of interest, the addition of blue dye should be used. - Blue dye alone should be discouraged because of its low detection rate. - There is insufficient evidence to make a recommendation for or against the use of nearinfrared tracers. - There is insufficient evidence to make recommendations regarding lymphoscintigraphy, although it may facilitate the surgical procedure by identifying the presence, location (unilateral vs. bilateral), and the number of sentinel nodes. - Four quadrant intradermal injections into normal tissue at the margins of the tumour are recommended. - Radiocolloids can be injected 30 minutes to 24 hours before the surgical procedure. The timing depends on the size of the radiocolloid. The directions in the manufacturer package insert should be followed. - Blue dye should be injected in the same location as the radiocolloid after induction of anesthesia. - A node with five times more than the background radioactivity should be used to identify a sentinel lymph node. - To help identify blue nodes, surgeons should look for and follow blue lymphatic channels. - There is insufficient evidence to make a recommendation for or against the use of frozensection analysis. - Ultrastaging should be used to assess for metastatic tumour(s) in the sentinel lymph nodes. # Qualifying Statements for Recommendations for Appropriate Techniques and Procedures For squamous cell carcinoma only, after trimming the fat, the sentinel lymph node should be subjected to ultrastaging by serially sectioning the lymph nodes into 3-mm blocks. At least two sections from each block, located 40 µm apart, should be examined to determine whether they contain tumour cells. If routine hematoxylin and eosin staining tests negative for metastatic disease on the first slide, immunohistochemical cytokeratin staining should be performed on the second slide. # Summary of Key Evidence for Recommendations for Appropriate Techniques and Procedures Only one study by Levenback from the Reade et al. review (2) examined the impact of the learning curve on detection rates of SLNB (6). They found a 36% failure rate to detect a sentinel node in groin dissections in the first two years, and a 15% failure rate afterward. The pooled detection rate per groin was substantially higher with the combination of blue dye and radiocolloid (87%, 95% CI 81%-92%) compared with blue dye alone (63%, 95% CI 49%-77%). The radiocolloid (Tc99) alone group had higher pooled detection rates (84%, 95% CI 74%-93%) than the blue dye alone group (63%, 95% CI 49%-77%). There were similar detection rates for the combined technique (87%, 95% CI 81%-92%) and the radiocolloid alone group (84%, 95% CI 74%-93%). All three techniques (blue dye 9%, 95% CI 0%-27%; radiocolloid 10%, 95% CI 1%-23%; combined 7%, 95% CI 4%-9%) had similar false-negative rates. No evidence was found for infrared tracers. The Reade et al. review included three studies that reported on the diagnostic accuracy of frozen-section analysis (2). A large study found low sensitivity (48%) but high specificity (100%) for frozen-section analysis ( 7), whereas two older and smaller studies found sensitivities and specificities of >90% (8,9). Eight of 12 studies included in the Reade et al. review found that ultrastaging increased the detection of metastases in sentinel lymph nodes previously found to be negative and four studies found no difference with additional ultrastaging (2). Two studies suggested that immunohistochemistry increased the detection rate beyond routine pathology (7,10) and one study did not (11). Furthermore, although one study did not find a correlation between occult lymph node metastases and survival rate (p>0.05) (12), a recent, large study found that the five-year disease-specific survival rate was significantly higher for women with positive sentinel lymph nodes detected by ultrastaging (92.1%) versus the survival rate for women identified by routine pathology (64.9%, p<0.0001) (7). # Justification for Recommendations for Appropriate Techniques and Procedures The Working Group agreed upon a minimum of at least 10 correlated procedures per centre with full-node dissection based on the van der Zee study (1). This large study had a low recurrence rate after a negative SLNB result (2%) and centres needed to have completed at least 10 successful procedures to participate. From the evidence, using radiocolloid tracer with or without blue dye had the highest detection rates. Therefore, the Working Group recommended radiocolloid tracers should be used either alone or with blue dye routinely; for patients in which lymphoscintigraphy does not identify a sentinel node in the groin(s) of interest, the addition of blue dye should be used. The recommended techniques in administering the tracers were based on the standard practice of the Working Group. The qualifying statements for the minimum number of sections were based on the standard practice of the Working Group and were used by the Gynecologic Oncology Group study by Levenback et al. 2012 (10). The Working Group believed there was insufficient evidence to make a recommendation for or against the use of frozen-section analysis. The advantage of analyzing frozen sections is that it avoids a potential second procedure. The disadvantage is that processing the specimen for frozen section may reduce the amount of available tissue for permanent section analysis. There was also insufficient evidence to make a recommendation for lymphoscintigraphy. Ultrastaging examines more sections than usual in addition to immunohistochemical staining and was recommended because the evidence suggested it may increase the detection of metastases in sentinel lymph nodes previously found to be negative and may have a positive effect on survival rate. The Working Group believed the benefit of increased detection of metastases using ultrastaging outweighed the harms, including potential overtreatment of patients with micrometastases and the unclear clinical significance for patients with isolated tumour cells. The Working Group also believed the benefit of increased detection of metastases using ultrastaging outweighed its disadvantages of being timeconsuming and costly. # Other Considerations The Working Group believes that it is reasonable to omit a lymph node dissection in the contralateral side of a positive node when the sentinel node has tested negative in that contralateral side, although there are no data to make a recommendation for or against this statement. The Working Group expects the incidence of metastases on the contralateral side would be low because of the relatively low false-negative rate (~7% with combined technique, ~10% with radiocolloid only) and the two sides are biologically independent of each other. Also, performing a complete lymphadenectomy would increase morbidity. # FUTURE RESEARCH GROINSS-V II is accruing patients until the end of 2015. This is a large observational study in which patients with positive sentinel lymph nodes will receive radiotherapy without undergoing a complete bilateral lymphadenectomy. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

# Evidence-Based Series #2-4 Version 3: Preoperative Therapy Preoperative chemoradiotherapy (CRT) is preferred, compared to preoperative RT (standard fractionation: longer course: 45-50.4Gy in 25-28 fractions) alone, to decrease local recurrence. Preoperative CRT is preferred, compared with a postoperative approach, to decrease local recurrence and adverse effects. For patients with relative contraindications to CT in the preoperative period, acceptable alternatives are preoperative standard fractionation (longer course; 45-50.4Gy in 25-28 fractions) or hypofractionation (short course; 25Gy in 5 fractions) RT alone followed by surgery guided by the risk of adverse effects. Patients eligible for preoperative RT+/-CT should also be considered for adjuvant CT. Postoperative Therapy Patients with resected stage II or III rectal cancer who have not received preoperative RT should be offered postoperative therapy with concurrent CRT in addition to fluoropyrimidine-based CT. The evidence reviewed demonstrates that this treatment improves survival and reduces local recurrence rates compared to observation alone or RT alone after surgery. Informed discussions regarding the potential advantages of adjuvant therapy also need to address the significant acute and long-term toxicity that can potentially occur with combined treatment with RT and CT. It is the expert opinion of the Gastrointestinal Cancer Disease Site Group (GI DSG) that patients who have received preoperative CRT or RT should receive postoperative CT. # QUALIFYING STATEMENTS - Recommendations for preoperative therapy presuppose adequate preoperative staging investigations, including transrectal ultrasound and/or magnetic resonance imaging (MRI) with surface or endorectal coil to assess the T category, MRI with surface or endorectal coil to assess the N category, a good digital rectal exam, computerized axial tomography (CAT) scan or MRI to assess the mesorectal margin, CAT scan or MRI of the abdomen to assess for potential metastatic or stage IV disease, and chest x-ray for pulmonary imaging. Potential inaccuracies of preoperative testing on tumour staging should be discussed with patients to allow them to make informed decisions (1). The eventual rectal surgery is expected to include total mesorectal excision (TME) principles. The quality of surgery greatly influences the potential benefits of preoperative treatments. A substantial number of trials included in the evidentiary base did not use currently recommended standards of surgery, including TME. The rationale for the opinion that patients who have received standard fractionation (45-50.4Gy in 25-28 fractions) preoperative RT+/-CT should be offered postoperative CT in the absence of direct evidence for this is described in more detail in the Discussion section of the systematic review for preoperative therapy (Section 2. Part 1). Enteritis, diarrhea, bowel obstruction or perforation, and fibrosis within the pelvis are associated with RT. Delayed adverse effects from RT include radiation enteritis (4%), small bowel obstruction (5%), rectal stricture (5%), pelvic fracture, and worsening sexual and bowel function. A greater number of hematological and non-hematological adverse effects are associated with CT plus RT than with CT alone or RT alone. Combined CT plus RT is associated with acute gastrointestinal and hematologic adverse effects that may be severe or life threatening. # QUALIFYING STATEMENTS -Added to the 2019 Endorsement: (See Section 4 for details about the modifications) - Capecitabine or infusional 5FU are the preferred regimens for use in CRT (2). Choice of regimen should be based on an informed discussion or risks, benefits, and convenience of these regimens with the patient. In most instances, there should be a delay of more than 7 weeks but less than 11 weeks from the completion of RT to surgery, to allow for maximum downstaging of the tumour and facilitate TME surgery with a negative CRM. The GRECCAR trial suggested that a delay of 11 weeks was associated with poorer quality of the mesorectal excision, however the results of this trial remain controversial. (3,4). With respect to pathological response, the trial grouped patients in an unconventional manner (complete vs almost complete + incomplete). If patients had been categorized in the more common grouping (complete + almost complete vs incomplete), the results might not have been significantly different. Furthermore, the trial did not report the proportion of patients with <1 mm tumour circumferential margin. The exception to delay of surgery is the use of short-course RT Postoperative Therapy Twenty-nine RCTs, six meta-analyses on adjuvant RT and/or CT in stage II and III resected rectal cancer, and a review of the adverse effects of adjuvant RT and CT were reviewed. Some multi-arm trials contributed to more than one comparison. Data on overall survival and local failure were pooled for the following comparisons: RT versus observation alone, CT versus observation alone (systemic and oral), combined CRT versus observation, CT versus RT, CRT versus RT alone, and CRT versus CT alone (See Table 1). Preoperative versus Postoperative Therapy One trial (11) comparing preoperative versus postoperative CRT (with 4 cycles of postoperative 5FU CT) for patients with clinical stage II and III rectal cancer showed superior local recurrence rate (relative risk 0.46; 95% CI, 0.26-0.82; from 6% to 13%) and lower acute and late toxicities in favour of preoperative CRT. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# GUIDELINE OBJECTIVES The objectives of the guideline are to make recommendations regarding the addition of neoadjuvant/concurrent/adjuvant chemotherapy to chemoradiotherapy in the management of locally advanced squamous cell or undifferentiated nasopharyngeal cancer (NPC) and to identify the optimal chemotherapeutic regimen that improves overall survival. Our recommendations are based on the 2021 Guideline on Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. # TARGET POPULATION Newly diagnosed patients, eligible for chemotherapy, with locally advanced squamous cell or undifferentiated NPC (stage III or IV). # INTENDED USERS Healthcare providers involved in the management of NPC patients. The Chemotherapy and Radiotherapy for Nasopharyngeal Cancer Development Group (GDG) of Ontario Health (Cancer Care Ontario) endorses the Chinese Society of Clinical Oncology (CSCO)/American Society of Clinical Oncology (ASCO) recommendations of Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline modified by the endorsement process described in this document. They were reprinted with the permission of Wolters Kluwer Health, Inc. and Copyright Clearance Center. Sixteen of the 21 CSCO/ASCO recommendations were endorsed without changes. Four (R 1.1, R 3.3, R 4.1, R 5.1) recommendations were endorsed with modifications and/or clarifications and one recommendation (R 3.4) was not endorsed (see Table 1-1). In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC. # Endorsed (with clarification) R 4.2. For patients with NPC receiving induction chemotherapy, the regimens should be administered every three weeks for a total of three cycles, or at the minimum two cycles. # Endorsed R 4.3. For patients with NPC receiving induction chemotherapy, chemoradiotherapy should be commenced within 21-28 days from the first day of the last cycle of induction chemotherapy. Adjuvant chemotherapy R 5.1. For all patients with NPC receiving adjuvant chemotherapy, PF (cisplatin 80 mg/m 2 d1 or 20 mg/m 2 per day, d1-5; 5-fluorouracil 1000 mg/m 2 per day, continuous intravenous infusion d1-4, or 800 mg/m 2 per day, continuous intravenous infusion d1-5) administered every four weeks for a total of three cycles should be offered. Use of GP for a total of three cycles as adjuvant therapy is a reasonable alternative to PF. # Endorsed (with modification) R 5.2. For all patients with NPC receiving adjuvant chemotherapy and with a contraindication to cisplatin, carboplatin (AUC 5) may be combined with 5fluorouracil. # BACKGROUND FOR GUIDELINE During the annual document assessment and review, this guideline was identified as needing an update because the recommendations no longer reflect current practice. Current practice standards include using radiotherapy with concurrent cisplatin-based chemoradiation to treat locally advanced squamous cell or undifferentiated NPC. The question now is whether the use of neoadjuvant chemotherapy and/or adjuvant chemotherapy after chemoradiotherapy is worthwhile. # GUIDELINE ENDORSEMENT DEVELOPERS This endorsement project was developed by the Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG, which was convened at the request of the Head and Neck Cancer Advisory Committee (CAC). The project was led by a small Working Group of the GDG, which was responsible for reviewing the evidence base and recommendations in "Chemotherapy in Combination with Radiotherapy for Definitive-Intent Treatment of Stage II-IVA" in detail and making an initial determination as to any necessary changes, drafting the first version of the endorsement document, and responding to comments received during the document review process. The Working Group members had expertise in medical oncology, radiation oncology, and pathology. Other members of the Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG served as the Expert Panel and were responsible for the review and approval of the draft document produced by the Working Group. Conflict of interest declarations for all GDG members are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. # ENDORSEMENT METHODS The Program in Evidence-based care endorses guidelines using the process outlined in Ontario Health (Cancer Care Ontario)'s Guideline Endorsement Protocol. This process includes selection of a guideline, assessment of the recommendations (if applicable), drafting of the endorsement document by the Working Group, internal review by content and methodology experts, and external review by Ontario clinicians and other stakeholders. The Program in Evidence-based care assesses the quality of guidelines using the AGREE II tool. AGREE II is a 23-item validated tool that is designed to assess the methodological rigour and transparency of guideline development and to improve the completeness and transparency of reporting in practice guidelines. Implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations may be provided along with the recommendations for information purposes. # Selection of Guidelines The following sources were initially searched for existing guidelines in September 2020 with the search term(s) nasopharyngeal cancer, chemotherapy # Assessment of Guideline(s) The Working Group selected the CSCO/ASCO guideline because the rigour of development domain, which assesses the methodological quality of the guideline, had the highest score. Details of the AGREE II assessment can be found in Appendix 2. The overall quality of the guideline was rated as "6" by one appraiser and "7" by the other (on a scale of 1 to 7). Both appraisers stated that they would recommend this guideline for use. The AGREE II quality ratings for the individual domains were varied; they were assessed at 97% for scope and purpose, 86% for stakeholder involvement, 89% for rigour of development, 89% for clarity of presentation, 92% for applicability, and 92% for editorial independence. # DESCRIPTION OF ENDORSED GUIDELINE(S) The CSCO/ASCO guideline (published on-line January 2021) assessed treatment options with chemotherapy in combination with radiotherapy for patients with stage I-IVA NPC. As pointed out by the authors "the nonkeratinizing pathological subtype accounts for more than 95% of NPC cases in endemic areas, which is highly associated with Epstein-Barr virus (EBV) infection, whereas the keratinizing subtype constitutes, <20% of cases worldwide. Despite the relatively lower radiotherapy sensitivity of the keratinizing compared with nonkeratinizing subtypes, NPC almost exclusively relies on (chemo-)radiotherapy to achieve disease control in most presentations, particularly in the definitive treatment of stage II to IVA disease". The guideline recommendations were based five clinical questions and assessed on the basis of a systematic literature review and expert consensus. Forty-two systematic reviews and 66 randomized controlled trials published between 1990 and August 2020 were included, focusing on radiotherapy techniques and fractionation regimens, chemotherapy sequence in addition to radiotherapy, chemotherapy options for patients receiving concurrent chemoradiotherapy, options for patients receiving induction chemotherapy, and options for patients receiving adjuvant chemotherapy. A complete list of recommendations from the CSCO and ASCO guideline are presented in Table 1-1. # ENDORSEMENT PROCESS The Working Group assessed the 2021 CSCO/ASCO Guideline in detail and reviewed each recommendation of the guideline to determine whether it could be endorsed, endorsed with modifications, or rejected. There are 21 recommendations based on five research questions. The Working Group considered the following issues for each of the recommendations: 1) Does the Working Group agree with the interpretation of the evidence and the justification of the original recommendation? 2) Are modifications required to align with the Ontario context? 3) Is it likely there is new, unidentified evidence that would call into question the recommendation? 4) Are statements of qualification/clarification to the recommendation required? # ENDORSEMENT REVIEW AND APPROVAL # Internal Review For the endorsement document to be approved, 75% of the content experts who comprise the GDG Expert Panel must cast a vote indicating whether or not they approve the document, or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. The Expert Panel may specify that approval is conditional, and that changes to the document are required. # External Review Feedback on the approved draft endorsement document is obtained from content experts through Professional Consultation. Relevant care providers and other potential users of the endorsement document are contacted and asked to provide feedback on the recommendations through a brief online survey. This consultation is intended to facilitate the dissemination of the final guidance report to Ontario practitioners. # DISSEMINATION AND IMPLEMENTATION The endorsement document will be published on the Ontario Health (Cancer Care Ontario) website. Ontario Health (Cancer Care Ontario) -Program in Evidence-based Care guidelines are routinely included in several international guideline databases including the CPAC Cancer Guidelines Database, the CMA/Joule CPG Infobase database, NICE Evidence Search (UK), and the Guidelines International Network (GIN) Library. # UPDATING THE ENDORSEMENT Ontario Health (Cancer Care Ontario)/Program in Evidence-based Care will review the endorsement on an annual basis to ensure that it remains relevant and appropriate for use in Ontario. # ENDORSEMENT and MODIFICATIONS Sixteen of the 21 CSCO/ASCO recommendations were endorsed without changes. Four (R 1.1, R 3.3, R 4.1, R 5.1) recommendations were endorsed with modifications and/or clarifications and one recommendation (R 3.4) was not endorsed (Table 2-1). See Section 1, Table 1-1 for a list of all 21 recommendations. VMAT is a reasonable alternative to IMRT and may be preferred in this setting. # Endorsed (with modification) R 3.3. For patients with NPC with a contraindication to cisplatin, nedaplatin (100 mg/m 2 triweekly) may be offered for concurrent chemoradiotherapy. Other options that may be offered are carboplatin (area under curve 5-6 triweekly) or oxaliplatin (70 mg/m 2 weekly). # Clarification and Modification: The recommendation is endorsed for carboplatin only. Carboplatin plus infusional fluorouracil is considered an acceptable alternative based on its activity in NPC generalized from the meta-analysis of chemotherapy in head and neck cancer (MACH-NC). In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC. # Endorsed (with clarification) R 5.1. For all patients with NPC receiving adjuvant chemotherapy, PF (cisplatin 80 mg/m 2 d1 or 20 mg/m 2 per day, d1-5; 5-fluorouracil 1000 mg/m 2 per day, continuous intravenous infusion d1-4, or 800 mg/m 2 per day, continuous intravenous infusion d1-5) administered every four weeks for a total of three cycles should be offered. Modification: Use of GP for a total of three cycles as adjuvant therapy is a reasonable alternative to PF. # Endorsed (with modification) Abbreviations: AJCC = American Joint Committee on Cancer; ASCO = American Society of Clinical Oncology; AUC = area under curve; CSCO = Chinese Society of Clinical Oncology; EBV = Epstein Barr virus; IMRT = intensity-modulated radiotherapy; MRI = magnetic resonance imaging; NPC = nasopharyngeal carcinoma; VMAT = volumetric modulated therapy # INTERNAL REVIEW The endorsement was evaluated by the GDG Expert Panel (Appendix 1). The results of these evaluations and the Working Group's responses are described below. # EXPERT PANEL REVIEW AND APPROVAL Following the formulation of the first draft, the recommendation endorsement was reviewed by the Director and Assistant Director of the Program in Evidence-based and the Working Group was responsible for ensuring the necessary changes were made. An Expert Panel of clinical content experts (members of the head and neck community) reviewed the draft endorsement document, provided feedback, and approved the final version (See Appendix 1 for a list of Expert Panel members and conflict of interest declarations). All nine members of the GDG Expert Panel voted, for a total of 100% response in September 2021. All nine GDG members approved the document (100%). The main comments from the Expert Panel and the Working Group's responses are summarized in Table 3-1. - DPYD testing prior to fluoropyrimidine-based chemotherapy should be addressed for all patients receiving these drugs with guideline recommendations; however, it is out of scope for this specific guideline. - Agreed. Statement modified to "In the absence of head-to-head comparisons, based on familiarity to clinicians, toxicity profile, and technical ease of administration, GP is the preferred regimen for EBV-related NPC." - I approve these guidelines with one general comment. - R 4.1 indicates many different allowable "induction" chemotherapy regimens but the clarification states that only gemcitabine (G) and cisplatin (C) is endorsed and the others are not. There seems to be a disconnect with those two statements. Either you should say GC is preferred and others are allowable or do not indicate the others as allowable at all. The clarification says other regimens are not endorsed indicating that they are not allowable. Please try to reconcile this gap. Agreed. See modification above. # EXTERNAL REVIEW Professional Consultation Feedback was obtained through a brief online survey of healthcare professionals and other stakeholders who are the intended users of the endorsement document. All head and neck oncologists in the Program in Evidence-based database were contacted by email to inform them of the survey (n=67). Five of the 67 approached (7.5%) indicated that they were interested in participating. Four of the non-responders stated that they did not have interest in this area or were unavailable to review this endorsement document at the time; the remaining nonresponders did not give a reason. The results of the feedback survey from five clinicians are summarized in Table 3-2. The main comments from the consultation and the Working Group's responses are summarized in Table 3- We agree and have endorsed the recommendation as originally written in the EAU guideline ("For patients with NPC receiving induction chemotherapy, chemoradiotherapy should be commenced within 21-28 days from the first day of the last cycle of induction chemotherapy") (see Table 3.1 above for previous changes made during internal review). The final endorsed recommendations contained in Section 1 reflect the integration of feedback obtained through the external review processes with the document as drafted by the GDG Working Group and approved by the GDG Expert Panel. - The overall objective(s) of the guideline is (are) specifically described. 7 - The health question(s) covered by the guideline is (are) specifically described. 7 - The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described. The Chemotherapy and Radiotherapy for Nasopharyngeal Cancer GDG would like to thank the following individuals for their assistance in developing this report: - Jonathan Sussman and Sheila McNair for providing feedback on draft versions. - Sara Miller for copy editing.

# Section 1: Recommendations Summary …………………………………………… 1 Section 2: Guideline …………………………………………………………………………… 3 Section 3: Section 4: Section 5: Guideline Methods Overview …………………………………………… 9 Evidence Review.………………………………………………………………. 12 Internal and External Review ………………………………………... 56 For information about this document, please contact Dr. Roanne Segal, the lead author, through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Lung cancers are the leading cause of cancerrelated deaths for men and women throughout the world. In the United States, approximately 224,000 new lung cancers are expected in 2016, and more than 158,000 individuals are expected to die as a result of the disease. 1 Five-year survival rates range from 67% for T1N0 disease to 23% for patients with T1-3N2 disease. 2 Adenocarcinomas and squamous cell lung cancers, which are the focus of this guideline, comprise approximately 85% of all lung cancers. 2 This update of the 2007 joint Cancer Care Ontario (CCO)/American Society of Clinical THE BOTTOM LINE Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non-Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update Guideline Question What is the role of adjuvant systemic therapy and adjuvant radiation therapy in patients with completely resected stage I to IIIA non-small-cell lung cancers (NSCLCs)? Oncology (ASCO) clinical practice guideline 2 addresses two principal questions in the treatment of patients with completely resected non-small-cell lung cancers (NSCLCs): the overall survival benefit and role of adjuvant systemic therapy, including chemotherapy and newer targeted therapy and immunotherapy options, and adjuvant radiation therapy. The 2007 joint CCO/ASCO guideline recommended chemotherapy for stage II and IIIA disease but not stage IA. Adjuvant chemotherapy was not routinely recommended in stage IB. Adjuvant radiation therapy was not recommended for patients with stage I or II and also not routinely recommended for those with stage IIIA. 2 This guideline update incorporates the latest published research on adjuvant therapy in patients with completely resected stage I to IIIA lung cancers. CCO recently updated its systematic review on adjuvant systemic therapy, 3 including longer-term results from key clinical trials, recent trials of targeted therapy and immunotherapy, and subgroup analyses of chemotherapy in patients with stage IB disease with larger tumors. These studies and the latest evidence on adjuvant radiation therapy from the National Cancer Database (NCDB) and the 2015 ASCO endorsement of the American Society for Radiation Oncology (ASTRO) evidencebased recommendations for adjuvant radiation therapy for NSCLC are included in this guideline update. A panel of clinical experts (Appendix Table A1, online only) used this evidence base to reaffirm or modify the recommendations contained in the 2007 CCO/ASCO joint guideline on adjuvant therapy in completely resected NSCLC to verify the relevance of the guideline recommendations. A summary of the key recommendations can be found in the Bottom Line Box. # GUIDELINE QUESTIONS This clinical practice guideline addresses two overarching clinical questions: - What is the benefit of adjuvant systemic therapy in patients with completely resected stage I to IIIA NSCLCs? 2. What is the benefit of adjuvant radiation therapy in patients with completely resected stage I to IIIA NSCLCs? # Guideline Update Development Process Panel formation. The Expert Panel met via teleconference and Webinar and corresponded through e-mail. Based upon the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. Members of the multidisciplinary Expert Panel, with expertise in medical, radiation, and surgical oncology, were responsible for reviewing and approving the penultimate version of guideline, which was then circulated for external review and submitted to Journal of Clinical Oncology for editorial review and consideration for publication. A patient representative and a representative from the Practice Guidelines Implementation Network were also included on the panel. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Clinical Practice Guideline Committee before publication. After the ASCO process was completed, CCO provided approval through its Program in Evidence-based Care approval process. Systematic literature review. In 2007, ASCO and CCO published a joint guideline on adjuvant chemotherapy and adjuvant radiation therapy for stage I to IIIA resectable NSCLC. 2 CCO recently updated the systematic review on adjuvant chemotherapy, bringing it current to January 2016, and expanded the search strategy to include recent trials of targeted therapy and immunotherapy. 3 That CCO systematic review and accompanying guideline recommendations serve as the basis for the adjuvant systemic therapy portion of this updated CCO/ASCO joint guideline. To improve the currency of the evidence base, a final literature search for any additional adjuvant systemic therapy trials published between January and June 2016 was conducted. In 2015, ASCO endorsed ASTRO's evidence-based guideline on adjuvant radiation therapy in locally advanced NSCLC, 4,5 with a systematic review that was current to March 2013. The ASTRO systematic review and accompanying guideline recommendations serve as the basis for the adjuvant radiation therapy portion of this guideline. To update the evidence base, a search for any additional adjuvant radiation therapy trials that were published between March 2013 and June 2016 was conducted. Literature search strategy. MEDLINE was searched using PubMed on June 21, 2016, using keywords and MeSH terms related to NSCLC and chemotherapy, radiation therapy, targeted therapy, and immunotherapy. The complete literature search strategy used in the PubMed database is available in Data Supplement 1. Reference lists of included articles were scanned for additional eligible citations. Study selection criteria. Publications with the following study designs were eligible for inclusion in the evidence base: - Systematic reviews of randomized controlled trials (RCTs) with or without meta-analyses, - Phase III RCTs, - Observational comparative studies based on the: - NCDB, a large, prospectively acquired database that is gathered and maintained by the American College of Surgeons, the Commission on Cancer, and the American Cancer Society; 6 - SEER Program database, which collects registry data on cancer cases from various locations and sources throughout the United States (seer.cancer.gov/about). Studies were considered for inclusion if they reported the following outcomes by TNM stage for comparisons of surgery alone versus surgery plus adjuvant systemic therapy or surgery plus radiation therapy with or without systemic therapy in the target population of patients with completely resected lung cancers (ie, no macroscopic disease and uninvolved resection margins after surgery): - Overall survival (OS), - Disease-free survival (DFS), - Adverse events. Articles were not considered if they were: - Published only as an abstract; - Trials of neoadjuvant (ie, preoperative) chemotherapy; - Trials of tegafur and uracil; - Included patients with incomplete resections (ie, had positive margins or macroscopic residual disease); - Noncomparative study designs, including editorials, commentaries, letters, news articles, case reports, and narrative reviews; - Non-English language publications. # Data Extraction The guideline recommendations are crafted, in part, using the Guidelines Into Decision Support (GLIDES) methodology and accompanying BRIDGE-Wiz software. 7 In addition, a guideline implementability review is conducted. Based on the implementability review, revisions were made to the draft to clarify recommended actions for clinical practice. Ratings for the type and strength of recommendation, evidence, and potential bias are provided with each recommendation (Methodology Supplement). Detailed information about the methods used to develop this guideline update is available in the Methodology Supplement at www.asco.org/lungcancer-guidelines, including an overview (eg, panel composition, development process, and revision dates), literature search and data extraction, the recommendation development process (GLIDES and BRIDGE-Wiz), and quality assessment. The ASCO Expert Panel and guidelines staff will work with co-chairs to keep abreast of any substantive updates to the guideline. Based on formal review of the emerging literature, ASCO will determine the need to update. The Methodology Supplement (available at www.asco.org/lung-cancerguidelines) provides additional information about the "Signals" 8 approach to updating. This is the most recent information as of the publication date. Visit the ASCO Guidelines Wiki at www.asco.org/guidelineswiki to submit new evidence. # Guideline Disclaimers ASCO disclaimer. The Clinical Practice Guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (ASCO) to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions. Cancer Care Ontario disclaimer. Care has been taken in the preparation of the information contained herein. Nevertheless, any person seeking to consult the report or apply its recommendations is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician. CCO makes no representations or guarantees of any kind whatsoever regarding the report content or its use or application and disclaims any responsibility for its use or application in any way. # Guideline and Conflicts of Interest The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Policy Implementation for Clinical Practice Guidelines ("Policy," found at ). All members of the Expert Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy. # ADJUVANT SYSTEMIC THERAPY The CCO systematic review was current to January 2016 and included phase III RCTs comparing adjuvant systemic therapy with observation, other adjuvant systemic therapy, or adjuvant systemic therapy plus targeted agents in adult patients with completely resected NSCLC. 3 It includes the most recent update of the individual patient data (IPD) NSCLC Collaborative Group (NSCLCCG) meta-analyses, longer-term results, and exploratory analyses from trials that were included in the 2007 CCO/ASCO guideline and two new phase III RCTs. Also included are phase III trials of newer systemic therapy options: epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and immunotherapy. The PubMed search conducted by ASCO from January 2016 to June 21, 2016, for additional trials of adjuvant systemic therapy found no new articles that met the inclusion criteria; however, one study that had been included in the CCO review as an abstract was fully published in April 2016. A flow diagram of the search results can be found in Data Supplement 2. # QUALITY ASSESSMENT Quality assessments conducted by CCO were adopted for this guideline and have been published elsewhere. 3 Briefly, the NSCLCCG meta-analysis scored well on the AMSTAR tool because it included an a priori design and comprehensive literature search, provided characteristics of included studies, and reported on heterogeneity. However, the NSCLCCG authors did not assess the likelihood of publication bias or the quality of the included studies or state any conflicts of interest. In a quality assessment of individual phase III trials of chemotherapy included in the NSCLCCG meta-analysis and CCO review, studies were judged using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology 9 to be at a moderate to high risk of bias due to lack of reporting of allocation concealment during randomization and lack of blinding. Two newer trials that were not included in the meta-analyses were also at risk for bias due to lack of blinding. 10,11 The quality of evidence for trials of immunotherapy and EGFR-TKIs was judged to be moderate due to inconsistency of comparators between trials. Evidence from NCDB or SEER is considered low quality because of the retrospective, nonrandomized nature of the data, which increases the risk of bias in the estimated effect. # KEY EVIDENCE # Adjuvant Chemotherapy New randomized trial data. The first NSCLCCG meta-analyses of studies of adjuvant chemotherapy were published in 1995, 12 and the previous version of this guideline included the 2007 version, 13 which included 8,147 patients and 30 RCTs. The 2016 CCO systematic review 3 included the most recent 2010 edition, 14 with the Cancer and Leukemia Group B (CALGB) 15 trial of chemotherapy in patients with stage IB disease and three additional RCTs, bringing the total number of included studies to 34 and patients to 8,447. 14 The NSCLCCG meta-analyses 14 cover two key comparisons: - Surgery plus adjuvant chemotherapy versus surgery alone; 2. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy. For the comparison of OS at 5 years with surgery alone compared with surgery plus adjuvant chemotherapy, the NSCLCCG meta-analysis included 26 trials and found a significant advantage for the primary outcome of OS with adjuvant chemotherapy (hazard ratio 0.86; 95% CI, 0.81 to 0.92; P.001; I 2 = 4%). 14 Likewise, the meta-analysis of 12 trials that compared curative surgery and radiotherapy with or without adjuvant chemotherapy found an HR for OS of 0.88 (95% CI, 0.81 to 0.97; P =.009; I 2 = 0%). In the latter analysis, patients with incomplete resections or unclear treatment schedules and those who had undergone neoadjuvant chemotherapy were included. There were no significant differences by patient characteristics, including stage. 14 Two additional phase III trials were published after the most recent version of the NSCLCCG meta-analysis (Table 1). 10,11 One study compared surgery plus adjuvant carboplatin and paclitaxel versus surgery alone in early-stage NSCLCs. 10 No significant differences were found between groups for DFS (HR, 0.87; 95% CI, 0.54 to 1.38; P =.54), which was the primary end point, or OS (HR, 0.99; 95% CI, 0.75 to 1.3; P =.93). This study had a lack of power to detect differences between study groups. Sixty-six percent of patients who underwent resection received the planned adjuvant treatment. A smaller trial that was terminated early compared adjuvant chemotherapy with resection alone in stage IIIA-N2 NSCLCs and found significantly poorer outcomes with resection alone for the primary end point of DFS (HR, 1.560; 95% CI, 1.064 to 2.287; P =.02), as well as for OS (HR, 1.466; 95% CI, 1.017 to 2.114; P =.037). 11 An additional comparison with preoperative chemotherapy was outside the scope of this guideline. Pooled analyses from randomized trials. In the previous version of this guideline, the Lung Adjuvant Cisplatin Evaluation (LACE) IPD meta-analysis of the five largest trials of cisplatin-based chemotherapy in NSCLCs demonstrated an overall HR for death of 0.89 (95% CI, 0.82 to 0.96; P =.005) after a median follow-up of 5.2 years. 16 A recent unplanned subgroup analysis found that there was significant interaction of cisplatin plus vinorelbine chemotherapy and stage (test for trend P =.02 for OS and P =.008 for DFS). 17 Patients with stage IIIA disease benefited the most from cisplatin plus vinorelbine, followed closely by those with stage II. In stage IB disease, which comprised approximately 34% of the total group, there was no significant effect compared with observation. 17 Longer-term follow-up of phase III RCTs. Longer-term followup was available for JBR.10, 18 CALGB, 15,19 and the International Adjuvant Lung Cancer Trial (IALT), 20 which were included in the NSCLCCG analysis 14 and the previous version of this guideline 2 (Table 2). Detailed characteristics of these trials have been published elsewhere. 2, 14 The LACE meta-analysis included earlier results for these trials, demonstrating a significant difference in favor of cisplatin-based chemotherapy after a median follow-up of 5.2 years. 16 In all three trials, OS was no longer significantly different between resected patients treated with or without chemotherapy after median follow-up intervals of 9.3, 18 7.5, 20 and 9 years, 15,19 respectively. Median DFS was significantly better in the chemotherapy group after longer-term follow-up in the IALT study 20 (Table 2), and in a Cox regression model with disease stage, chemotherapy, and their interaction term, patients with stage II NSCLCs in the JBR.10 study had a significant benefit in survival with chemotherapy (HR, 0.68; 95% CI, 0.50 to 0.92; P =.01). 18 Administrative databases. Morgensztern et al 22 evaluated the role of adjuvant chemotherapy in an NCDB data set of 25,267 Other Systemic Therapy Options. Three additional fully published phase III RCTs met the inclusion criteria for the CCO review, including trials of EGFR-TKIs gefitinib 23 and erlotinib 24 and a trial of immunotherapy. 25 One abstract that was included in the CCO review was fully published after the final data search and is included in our results 26 (Table 3). EGFR-TKIs. The RADIANT (Randomized Double-Blind Trial in Adjuvant NSCLC With Tarceva) trial 24 compared erlotinib versus placebo in a population of patients with completely resected stage IB to IIIA NSCLC whose tumors were not selected by the presence of sensitizing EGFR mutations, the robust biomarker that underlies sensitivity of tumors to EGFR-TKIs. 27 Instead, patients were entered if their tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization, factors not proven to be predictive of benefit from EGFR-TKIs. No significant differences in DFS or OS were detected in the overall unselected study population. DFS favored erlotinib in patients with an EGFR sensitizing mutation (HR, 0.61; 95% CI, 0.384 to 0.981; P =.039); however, due to the hierarchic structure of the analysis, this result is not considered significant. There was no overall survival benefit from erlotinib in this subgroup (HR, 1.09; 95% CI, 0.55 to 2.16). The BR19 trial compared gefitinib versus placebo in a population of patients with completely resected stage IB to IIIA NSCLC whose tumors were not selected by the presence of sensitizing EGFR mutations or copy number or EGFR protein expression. Approximately half (500 patients) of the planned sample was accrued. After discontinuation of medication, patients were observed for at least 4 years before the final analysis was performed. The HR for OS, the primary end point, was 1.24 (95% CI, 0.94 to 1.64; P =.14), and the HR for DFS was 1.22 (95% CI, 0.93 to 1.61; P =.15). There was no benefit for either of the subgroups with EGFR wild-type tumors or the 15 tumors (4% of the total sample) with EGFR sensitizing mutations. Immunotherapy. In a single-institution study of 51 patients, Kimura et al 25 investigated adjuvant immunotherapy, which consisted of the adoptive transfer of autologous activated killer T cells and dendritic cells obtained from the patients' own regional lymph nodes. Patients were observed for 5 years. This study showed a significant OS benefit (HR, 0.229; 95% CI, 0.093 to 0.564; P =.0013) for the combined immunotherapy plus chemotherapy group. In the MAGRIT (MAGE-A3 As Adjuvant Non-Small-Cell Lung Cancer Immunotherapy) trial, Vansteenkiste et al 26 found no significant difference in the primary outcome DFS for patients treated with MAGE-A3 immunotherapeutic in a combined population that did or did not receive chemotherapy (HR, 1.02; 95% CI, 0.89 to 1.19; P =.74). They also found no difference in DFS in the subset of patients who did not receive chemotherapy (HR, 0.97; 95% CI, 0.80 to 1.18; P =.76). Because there was no difference between groups, the study was unable to identify a biomarker that would enable selection of patients for this treatment. # Adverse Events In the LACE meta-analysis of cisplatin-based chemotherapy, the rate of overall grade 3 to 4 toxicity was 66% among 1,190 patients in four trials for which this information was available. 16 With data from five trials, the rate of grade 4 toxicity was 32%. The most frequent toxicity was neutropenia (grade 3, 9%; grade 4, 28%); however, the rate was highly variable across trials, likely due to differing methods of surveillance and data collection. There were 19 chemotherapy-related deaths (0.9%) reported. Butts et al 18 reported that no unexpected late toxicity or increase in second malignancies from adjuvant chemotherapy were observed. A meta-analysis of randomized and nonrandomized studies found that the overall rate of grade 3 or greater adverse events with EGFR-TKI adjuvant therapy was 42.3% (95% CI, 39.1 to 45.6). 28 # CLINICAL QUESTION 1 What is the OS benefit of adjuvant systemic therapy in patients with completely resected stage I to IIIA NSCLCs? # Factors Other Than Tumor Stage to Consider in Recommending Adjuvant Chemotherapy Beyond stage, many tumor-specific variables have been studied to determine their utility in delineating prognosis for patients with resected lung cancers, and the results of a selective review of the literature pertaining to prognostic characteristics are provided in this section. Many of these studies are in patients with stage I tumors. The ability of these features to estimate prognosis, assist in the recommendation of adjuvant therapy, or predict the benefit of adjuvant chemotherapy remains unknown. Although post hoc analyses of completed adjuvant chemotherapy studies have identified some putative genetic predictors of response, none have been validated prospectively. Resected tumor size between 3 and 7 cm. In patients with resected lung cancers and no nodal spread, the 5-year survival rate declines with increasing tumor size: 3 to 4 cm, 74%; 4 to 5 cm, 65%; and 5 to 7 cm, 57%. 29 Survival data in a cohort of 25,267 patients with resected T2N0M0 tumors in the NCDB demonstrated that adjuvant chemotherapy was associated with improved median survival and 5-year OS for all tumor size groups with the T2 stage. 22 Earlier subgroup analyses of completed randomized adjuvant chemotherapy trials demonstrated survival improvement with chemotherapy for patients with tumors $ 4 cm. 15,18 Histopathologic features. The presence of selected histopathologic features has been associated with higher recurrence risk and poorer prognosis, including perineural invasion, 30 tumor necrosis, 30 vascular invasion, 31 and/or lymphatic invasion. 31,32 The presence of visceral pleural invasion, regardless of T stage, upstages tumors 3 cm to pT2a. 33,34 A study of resected stage I lung adenocarcinomas found mitotic index (zero to 10 v. 10 mitoses per 10 highpowered fields) to be an independent prognostic marker. 35 In addition, the following risk levels are associated with International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society adenocarcinoma subtypes 36-42 : - Micropapillary or solid: high risk; - Acinar, papillary, or invasive mucinous: intermediate risk; - Minimally invasive or lepidic: low risk. Presence of oncogenic drivers. Mutations in KRAS are not predictive for benefit from adjuvant chemotherapy. 18,43,44 The results with adjuvant EGFR-TKIs in patients with EGFR-mutant cancers have been discussed under Key Evidence. Presence of determinants of DNA repair capacity. Multiple genes, particularly those related to DNA repair, have been studied for their impact on prognosis and chemosensitivity, such as ERCC1, 45,46 RRM1, 46 and BRCA1. Biomarker-selected adjuvant trials, including the completed SWOG feasibility study 47 and the Spanish BRCA1-directed trial (reported to be negative) and the trials of ERCC1 and RRM1 to select patients with advanced disease for benefit, 48 have all been unsuccessful. Gene signatures. Genomic assays (microarrays and polymerase chain reaction based) have been used to identify high-and low-risk disease subsets. These separately developed signatures have little overlap in genes analyzed, and all require prospective validation before they can be recommended for use. One of these has been further combined with the subtype of adenocarcinoma to create a combined score for recurrence. 53 A predictive gene signature derived from JBR.10 specimens demonstrated a benefit from chemotherapy in the signature defined high-risk cohort and not in the low-risk subset. 54 # Adjuvant Radiation Therapy The evidence base until March 2013 for postoperative radiotherapy (PORT) in patients with completely resected stage IIIA to N2 NSCLCs is described in the 2015 ASCO endorsement of the ASTRO guideline "Adjuvant Radiation Therapy in Locally Advanced Non-small Cell Lung Cancer." 4 Since that endorsement, there has been no new evidence that would alter the recommendation against PORT in patients with stage I or II disease. New or updated research has been published in the population of patients with stage IIIA disease; the search for additional studies published between March 2013 and June 21, 2016, found an update to the IPD meta-analysis by the Medical Research Council PORT Meta-analysis Trialist Group, using newer statistical methodology 55 ; three studies based on data from the NCDB 6,56,57 and one systematic review that compared outcomes in stage IIIA-N2 NSCLC for patients who did or did not receive PORT) 58,59 were also included. The quality and results of these studies are discussed subsequently. # Quality Assessment The evidence base for adjuvant radiation therapy in resected stage IIIA-N2 disease was determined to be of moderate quality according to the ASTRO systematic review, which used the American College of Physicians methodology for assessment of study quality. 4 # Key Evidence A 2013 update with 11 trials (2,343 patients) showed a detrimental effect of PORT for OS (HR, 1.18; 95% CI, 1.07 to 1.31; P =.001), and for local (HR, 1.12; 95% CI, 1.02 to 1.24; P =.02), distant (HR, 1.13; 95% CI, 1.02 to 1.25; P =.02), and overall (HR, 1.09; 95% CI, 1.0.99 to 1.21; P =.08) recurrence-free survival. 55 An analysis by stage of eight trials, using the sixth edition of the TNM staging system and updated methodology found that while PORT still seemed to be detrimental in patients with stage I or II disease, the result by stage was no longer significant (P =.12). 55 These authors recommended that PORT not be routinely used until supporting evidence from trials using modern PORT techniques was available. Billiet et al 58,59 conducted a non-IPD meta-analysis using a heterogeneous mix of studies of PORT in patients with stage I to III NSCLCs that were published between 1980 and 2002. For all types of therapy beams combined (ie, cobalt or linear accelerators or a combination of both), there was a nonsignificant difference in OS (relative risk 1.07; 95% CI, 0.89 to 1.29; P =.45); however, local tumor failure was significantly reduced in the group that received surgery plus PORT versus PORTalone (RR, 0.42; 95% CI, 0.27 to 0.67; P =.001; I 2 = 74.8%). A subgroup analysis of OS for surgery plus PORT with linear accelerators versus surgery alone, which included four studies with 439 patients, did not find an OS difference (RR, 0.85; 95% CI, 0.59 to 1.22; P =.38) but did find a significant difference in local tumor failure favoring surgery plus PORT versus surgery alone (RR, 0.31; 95% CI, 0.12 to 0.79; I 2 = 49.2%). Three NCDB studies met the inclusion criteria 6,56,57 (Table 4). These comparative, observational studies assessed more contemporary delivery of PORT for N2 disease, relative to the studies included in the Medical Research Council PORT meta-analysis. 60 In Mikell et al, 6 where 82% of patients received adjuvant chemotherapy, there was a significant difference in OS in favor of the adjuvant radiation therapy group on multivariable analysis (HR, 0.89; 95% CI, 0.79 to 1.00; P =.046). Robinson et al 57 assessed socalled modern PORT in patients with resected NSCLCs with N2 extent who received adjuvant chemotherapy. The HR for OS significantly favored the PORT group on multivariable analysis (HR, 0.888; 95% CI, 0.798 to 0.988; P =.029). In an older cohort of patients with stage II to IIIA NSCLCs in which 34% received chemotherapy, there was no significant difference in OS between PORT versus no PORT on multivariable analysis (HR, 0.96; 95% CI, 0.88 to 1.05; P =.337); however, there was a significant benefit of PORT compared with no PORT when the analysis was restricted to patients who had received a dose of 45 to 54 Gy (5-year OS: HR, 0.85; 95% CI, 0.76 to 0.94; P.001), and no improvement in OS was seen with PORT in patients receiving more than 54 Gy. 56 # Adverse Events The three NCDB studies lacked outcome data for toxicity, treatment compliance, and quality of life. 6,56,57 The most commonly encountered adverse events with radiation therapy have previously been reported in a meta-analysis to be mild esophagitis, dysphagia, and odynophagia. 61 In that study, cough and pneumonitis requiring steroid therapy were the most common pulmonary toxicities, radiation myelitis was reported in one patient, and no severe late complications were noted. Late complications were few, although analysis of this outcome was likely limited by the follow-up duration. 61 The adverse effect of PORT on cardiac events has not been adequately studied. # CLINICAL QUESTION 2 What is the OS benefit of adjuvant radiation therapy in patients with completely resected stage I to IIIA NSCLCs? # Strategies to Improve Communication With Patients Considering Adjuvant Chemotherapy This section is intended to help health care practitioners discuss the benefits and risks of adjuvant therapy and address the unique concerns of persons with lung cancers to reach a shared decision. Few studies have addressed physician-patient communication specifically in patients with lung cancers, and even fewer have involved patients with curable lung cancers. These recommendations represent consensus with low evidence quality. A discussion of adjuvant chemotherapy in persons with resected lung cancers must cover the complex medical, psychological, and social issues faced by these individuals. Many patients have pain, impaired breathing, or fatigue related to surgery. Most patients with lung cancers have underlying debility due to smoking-related illnesses and psychological distress as a result of their lung cancer diagnosis. Smoking cessation, a necessary component of the care of persons with lung cancers, can result in at least a short-term increase in stress in patients as they withdraw from nicotine. 65 Furthermore, a majority of persons with lung cancers in the United States are age older than 70 years, increasing the likelihood of significant comorbidities and the attendant greater susceptibility to the adverse effects of chemotherapy and radiation therapy. From an actuarial standpoint, many elderly patients may be more likely to die as a result of causes other than lung cancer than younger patients with similar stage disease, and a discussion of competing health risks is essential. Practitioners must consider these complex issues when discussing the benefits and risks of adjuvant therapy, recognizing some patients may be unprepared, overzealous, or unmotivated to proceed with additional therapy after major surgery. There is no one way to discuss this topic, and each session must be individualized. Studies have found that patients are most satisfied if they perceive an effort by their physician to share decision making and are afforded sufficient time to make their decision. One way to accomplish the latter is to offer a session dedicated solely to the discussion of adjuvant treatment. Patients with lung cancers who lack a precise understanding of their prognosis tend to overestimate their probability of cure. 69 One way to determine the patient's level of understanding is to ask an open-ended question early in the dialogue, such as, "Tell me what you know about your lung cancer?" The discussion of adjuvant therapy is especially difficult because it involves informing patients about their risk of recurrence and death while they are clinically free of cancer. Many patients conclude they are cured because of postoperative discussions with their surgeon where they were told all visible disease was removed and the completeness of the surgery was confirmed by the pathology report describing clear margins. On the other hand, the discussion may be especially rewarding in that the goal of adjuvant therapy is cure. 70 The challenge is balancing a clear assessment of the patient's prognosis while maintaining hope. It is important to ask the patient how he or she would like to hear information regarding his or her risk of recurrence and the potential benefit of additional therapy. Some patients prefer general terms, others numbers, charts or graphs. A factual discussion between the oncologist, the patient, and the care team is critical. If a graphical representation like that in Figure 1 is used, the medical oncologist should guide the patient through it. Thoracic surgeons can facilitate this discussion by referring patients to a medical oncologist with expertise in lung cancers. After evaluating the patient with N2 disease extent and leading a discussion on the risks and benefits of adjuvant chemotherapy, the medical oncologist can facilitate a discussion of postoperative radiation therapy by arranging a referral to a radiation oncologist with expertise in lung cancers. For patients who prefer numbers, the physician can quote both the relative reduction in the risk of death (ie, the HR), as well as absolute survival benefit of the therapy. Studies have found that quoting absolute survival benefit is easier for patients to understand compared with RR reduction. 71 Patients quoted RR reduction are significantly more likely to agree with the recommendation for chemotherapy but less likely to demonstrate a true understanding of the benefit. 71 Figure 1 is a graphical representation of estimated absolute risk and benefit for 100 patients with lung cancers treated with surgery and adjuvant chemotherapy, based on reported, stagespecific 5-year survival rates in the control arms of each clinical trial. This series of graphs is intended to help physicians and patients understand the absolute mortality risk and benefit of adjuvant chemotherapy for the various stages of lung cancers based on all available data and is best presented to patients with direct physician guidance. These graphs separate the patient sample into four groups: those who die within 5 years, whether they receive jco.org chemotherapy or not (blue); those who live without receiving chemotherapy (gold); those who live because of chemotherapy (gray); and those who die because of chemotherapy (red). Using the LACE data to estimate absolute benefit, adjuvant chemotherapy raises 5-year survival from 64% up to 67% for stage IB, from 39% up to 49% for stage II, and from 26% up to 39% for stage IIIA disease extent. With the physician providing guidance and interpretation, graphs such as these may help patients gain a better understanding of absolute risk and benefit. Software applications are available on the Internet that may further aid clinicians and patients in this process. 72,73 There are no studies to test whether these decision-aid tools have an impact on compliance, understanding, or outcome in patients with lung cancers. The guideline panel concludes that therapeutic nihilism toward adjuvant chemotherapy for stage IB to IIIA lung cancers should be abandoned. The recommendations contained in this guideline provide clinicians with the evidence that justifies presenting the option of adjuvant chemotherapy to all patients. We are confident that increasing understanding of the benefits and risks, employment of adjuvant strategies in all patients where evidence justifies their use, and better compliance with guidelines can cure more individuals with stage IB to IIIA lung cancers. Little new evidence has been published regarding adjuvant chemotherapy in early-stage lung cancers since the previous version of this guideline. 74 Cisplatin-based adjuvant chemotherapy was recommended for routine use in patients with stage II or IIIA disease extent and for consideration in patients with stage IB NSCLCs. A pooled exploratory analysis based on two RCTs found a nonsignificant trend for increased chemotherapy effect on OS with larger tumor size in patients with no nodal spread. 43 Additionally, an exploratory subgroup analysis of the NSCLCCG meta-analysis found no significant difference in the effect of adjuvant chemotherapy on survival by stage and concluded that in the absence of comorbidities and contraindications to chemotherapy, adjuvant platinum-based chemotherapy should be considered when there is a high risk of recurrence (ie, in stage IB, II, and III disease). 75 This update recommends that physicians discuss the benefits and risks of adjuvant chemotherapy with patients with node-negative NSCLCs. This is a moderate-strength recommendation. This review found no unexpected late toxicities. 18 No completed trials have been designed to specifically compare survival outcomes with and without adjuvant EGFR-TKIs in patients whose tumors harbor sensitizing EGFR mutations. Two phase III trials on their effectiveness were included in this review. A trial of gefitinib that included 15 patients with sensitizing EGFR mutations failed to show a survival benefit. 23 A second trial of erlotinib that included 161 patients with tumors with sensitizing EGFR mutations demonstrated a large effect on DFS (median, 46 v 29 months; P =.039); however, this finding was not considered significant, because of a hierarchic statistical design. A meta-analysis 28 included these two trials as well as a phase II RCT and two retrospective comparative studies. This meta-analysis did not meet our inclusion criteria, because of the inclusion of retrospective data, and should be interpreted with caution. However, it showed that the treatment effect of EGFR-TKIs varied by EGFR mutation rate, and in the population of patients with EGFR mutations, the HR for DFS significantly favored the treatment group (HR, 0.48; 95% CI, 0.36 to 0.65). There was no significant difference in OS. These data were considered insufficient to justify the routine use of EGFR-TKIs in patients with tumors with sensitizing EGFR mutations. Several trials are currently under way that assess EGFR-TKIs in patients who have EGFR mutation-positive tumors, for example, trials of gefitinib versus placebo (clinicaltrials.gov identifier NCT01405079) and erlotinib versus cisplatin plus vinorelbine (clinicaltrials.gov identifier NCT01410214) 76 and ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial), which includes a platform to test adjuvant crizotinib, erlotinib, and nivolumab (clinicaltrials.gov identifiers NCT02201992 and NCT02193282). 77 We await the publication of a phase III RCT enrolling 1,501 patients (Intergroup trial E1505), which found that the addition of angiogenesis inhibitor bevacizumab to chemotherapy failed to improve DFS or OS for individuals with surgically resected earlystage NSCLCs compared with chemotherapy alone. 78 A phase III immunotherapy trial using T cells and dendritic cells included in this review demonstrated an OS benefit for combined immunotherapy and chemotherapy 25 ; however, the panel felt the results of this 51-patient single-institution trial were insufficient to recommend this approach. Immune checkpoint inhibitors inhibiting programmed death-1 or programmed deathligand 1 have demonstrated significant activity in advanced NSCLCs and are now being evaluated in the adjuvant setting. 3 Studies of large databases have explored the use of PORT in stage IIIA-N2 disease, 79 where there has been suggestion of better local control. However, due to the retrospective nature of these studies, these data are considered insufficient to justify routine use of PORT. In concert with ASTRO, ASCO recommends that adjuvant chemotherapy followed by adjuvant radiation therapy may be used to improve local control in patients with resected NSCLCs with mediastinal lymph node spread (N2). 5 A postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiotherapy in patients with N2 disease. In conclusion, this guideline updates the strength of the recommendations for adjuvant chemotherapy and adjuvant radiation therapy in patients with stage IB and IIIA disease, respectively. It also includes studies of targeted treatments. It is critical that a multidisciplinary team address the recommendation of adjuvant therapies in each patient with resected stage I to IIIA NSCLC. There is unanimous consensus among the guideline panel that close collaboration among medical oncologists, radiation oncologists, thoracic surgeons, radiologists, and pathologists will ensure the best possible outcome for every patient with a resected NSCLC. # HEALTH DISPARITIES Although ASCO clinical practice guidelines represent expert recommendations on the best practices in disease management to provide the highest level of cancer care, it is important to note that many patients have limited access to medical care. Racial and ethnic disparities in health care contribute significantly to this problem in the United States. Patients with cancer who are members of racial/ ethnic minorities suffer disproportionately from comorbidities, experience more substantial obstacles to receiving care, are more likely to be uninsured, and are at greater risk of receiving care of poor quality than other Americans. Many other patients lack access to care because of their geographic location and distance from appropriate treatment facilities. Awareness of these disparities in access to care should be considered in the context of this clinical practice guideline, and health care providers should strive to deliver the highest level of cancer care to these vulnerable populations. # MULTIPLE CHRONIC CONDITIONS Creating evidence-based recommendations to inform treatment of patients with additional chronic conditions, a situation in which the patient may have two or more such conditions-referred to as multiple chronic conditions (MCCs)-is challenging. Patients with MCCs are a complex and heterogeneous population, making it difficult to account for all of the possible permutations to develop specific recommendations for care. In addition, the best available evidence for treating index conditions, such as cancer, is often from clinical trials whose study selection criteria may exclude these patients to avoid potential interaction effects or confounding of results associated with MCCs. As a result, the reliability of outcome data from these studies may be limited, thereby creating constraints for expert groups to make recommendations for care in this heterogeneous patient population. As many patients for whom guideline recommendations apply present with MCCs, any treatment plan needs to take into account the complexity and uncertainty created by the presence of MCCs; this highlights the importance of shared decision making regarding guideline use and implementation. Therefore, in consideration of recommended care for the target index condition, clinicians should review all other chronic conditions present in the patient and take those conditions into account when formulating the treatment and follow-up plan. In light of the above considerations, practice guidelines should provide information on how to apply the recommendations for patients with MCCs, perhaps as a qualifying statement for recommended care. This may mean that some or all of the recommended care options are modified or not applied, as determined by best practice in consideration of any MCC. # GUIDELINE IMPLEMENTATION ASCO guidelines are developed for implementation across health settings. Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners and survivors of cancer and caregivers, providing adequate services in the face of limited resources, as well as the challenge of discriminating between multiple guideline products from various sources. The guideline Bottom Line Box was designed to facilitate implementation of recommendations. This guideline will be distributed widely through the ASCO Practice Guideline Implementation Network. ASCO guidelines are posted on the ASCO Web site and most often published in Journal of Clinical Oncology and Journal of Oncology Practice. ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate. # AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors # AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non-Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. The expert panel thanks Neelima Denduluri, Loretta Nastoupil, the American Society of Clinical Oncology Clinical Practice Guidelines Committee, the Cancer Care Ontario Report Approval Panel, and target audience clinicians in Ontario for their thoughtful reviews and insightful comments on this guideline.

New evidence added to Section 1 and new data found in Section 4 Updated web publication 2012 recommendations ENDORSED Update of version 2 August 2018 NA MSLT-II trial added to Section 1 only Updated web publication Recommendation 1b updated with the data from the MSLT-II trial. For details see Appendix 3# - What is the optimal surgical management of patients with biopsy-proven clinically palpable or biopsy-proven radiologically detected lymph nodes from cutaneous melanoma of the trunk or extremities with respect to: a. Extent of nodal dissection # OUTCOMES OF INTEREST The outcomes of interest for these guideline recommendations are local and regional recurrence, distant recurrence, overall survival (OS), and disease-free survival (DFS). # TARGET POPULATION These recommendations apply to adult patients with truncal or extremity cutaneous melanoma with nodal metastases. # INTENDED USERS These guidelines are intended for use by clinicians and healthcare providers involved in the management or referral of patients with nodal metastases from truncal or extremity cutaneous melanoma. # DEFINITIONS - Completion Lymph Node Dissection (CLND) - The surgical removal of the remaining lymph nodes within an axillary or inguinal nodal basin after the identification of metastatic melanoma within a previously removed sentinel lymph node (SLN) from that same nodal basin. The axillary nodal basin is divided into three levels: level 1 nodes lie below, level 2 nodes lie behind, and level 3 nodes lie above the pectoralis minor muscle. The inguinal nodal basin includes the nodes from below/superficial to the inguinal ligament to the apex of the femoral triangle. The nodes above the inguinal ligament in the pelvis along the iliac vessels up to the common iliac bifurcation can also be considered a part of the inguinal nodal basin. If they are also removed, this is an ilioinguinal dissection. - Therapeutic Lymph Node Dissection (TLND) -The surgical removal of all lymph nodes within an axillary or inguinal nodal basin in the presence of biopsy-proven clinically palpable, or biopsy-proven radiologically detected lymph nodes. - Radiologically Detected Lymph Node -A node that was not clinically palpable but that was biopsied under radiologic guidance after appearing abnormal on radiologic imaging. - Cloquet's node -The node medial to the femoral vein at the level of the inguinal ligament. # RECOMMENDATIONS AND KEY EVIDENCE 1. Patients with a positive sentinel lymph node a. Prognostic factors for predicting non-sentinel lymph node involvement Thirty-nine studies, mainly retrospective, have looked at many factors that might predict further node positivity at CLND. However, no core set of features among the studies is consistently examined nor does a core set of features consistently predict further nodal positivity at CLND. # New 2018 b. Completion lymph node dissection at the time of SLN positivity versus observation # Qualifying Statements for Recommendation 1b - In MSLT-II one third of patients had metastases greater than 1 mm in diameter and 72% of patients had one sentinel node with metastases. A subgroup evaluation of patients with a greater disease burden (maximal tumour diameter >1 mm) did not indicate that a benefit No consistent set of factors reliably predicts non-sentinel lymph node positivity in those patients with a positive SLN. Patients with sentinel node metastasis should be considered for nodal observation with ultrasonography rather than CLND. Monitoring with ultrasonography of the affected nodal basin and clinical exam will be required, at minimum, every 4 to 6 months for the first 2 years and every 6 months from 3-5 years. Suspicions of a nodal recurrence in a lymph node basin include any two of the following: lymph node length:depth ratio <2, hypoechoic centre, failure to identify a nodal hilar vessel and/or focal rounded area of low level echoes with increased vascularity in that area. Suspicions of nodal recurrence via ultrasound should be confirmed with a biopsy of the basin. For certain patients, a CLND may still be the best option for local control but should be discussed by a multi-disciplinary team (MDT). from completion lymph-node dissection was more likely in high-risk groups than in low-risk groups. - Patients in whom CLND would be a better option than nodal observation with ultrasonography are: o patients with extensive sentinel node metastasis in which CLND would be the only option for local control o patients unlikely to be compliant with an intensive surveillance protocol - While this guideline is specific to the trunk and extremities, this recommendation can be applied to melanomas of the head and neck and their respective drainage basins. # Key Evidence Added in the 2018 Update of Recommendation 1b One randomized trial, MSLT-II evaluated the utility of CLND compared to observation with frequent nodal ultrasonography and dissection only in melanoma patients with positive sentinel lymph node metastasis. The majority of patients in MSLT-II had low-volume nodal tumour burden (1 positive sentinel lymph node, longest diameter of the largest tumor deposit measured and the mean diameter of nodal metastasis 1.1mm). Three year MSS for the CLND and the observation group was the same, 86±1.3% and 86±1.2% (p=0.42), respectively. The 3-year DFS rate was slightly higher in the CLND group (p=0.05) but the investigators caution the significance of this result based on the lack of significance of the MSS, which was the primary outcome. The DFS rate may be explained by the lower rate of nodal failure in the CLND group as compared to the observation group at 3 years (92±1% vs. 77±1.5%; p=0.001). Adverse events occurred with more frequency among the CLND patients than the observation group with lymphedema being the most common (24.1% of patients vs. 6.3% at last follow-up, p<0.001). Non sentinel-node metastases, which was identified in 11.5% of the patients in the CLND group was found to be an independent prognostic factor for melanoma related death. Overall, some regional control and prognostic value can be derived from CLND; however, this is at the expense of increased adverse events. The non-significant difference in MSS and increase in adverse events of the CLND group indicates that CLND may not be optimal for patients and does not offer a survival benefit. Although the majority of patients had low volume tumor metastases, sub set analysis did not demonstrate a benefit for any groups of patient receiving CLND. As a result of the publication of the MSLT-II trial, the original recommendation has been altered to reflect this new high-quality evidence. # Key Evidence added in the 2016 Endorsement The literature search conducted in 2016 to assess the validity of the current recommendations identified one randomized controlled trial that evaluated the benefit of CLND. The DeCOG-SLT trial found no difference in distant metastasis-free survival, overall survival, or recurrence-free survival when SLN positive patients who received CLND were compared to patients who were observed. In this study, the majority (68% of patients) had sentinel node metastasis of <1mm). Although this study indicates no benefit for CLND, the study was small (n=240 CLND; n=233 observation) and included a short median follow-up time of 35 months. Due to the limitations of this study, the current recommendation was not altered. # Original Key Evidence from 2012 There are three small non-randomized studies that have evaluated the benefit of CLND versus observation. Three papers compared CLDN at time of positive SLN to those patients having a TLND for clinically palpable nodes. The largest of these (n=2633), a metaanalysis does demonstrate a survival advantage for upfront CLND at the time of a positive SLN (Risk of Death for TLND, hazard ratio 1.60; 95% confidence interval 1.28 to 2.00; p<0.0001). This recommendation is based on this limited evidence and expert opinion. Likewise, the few studies that evaluate the benefit of CLND over either observation or TLND with respect to recurrence are not randomized. No studies identified have reported significant differences in recurrence between CLND and observation or CLND and TLND. # c. Extent of nodal dissection for sentinel node positive disease if being undertaken No studies addressing this question were identified, resulting in no evidence to support or refute the extent of axillary dissection being found. This recommendation is based on n. There is no clear advantage to ilioinguinal dissection or the evaluation of Cloquet's node with respect to survival or morbidity in the small dataset that is available. This recommendation is based on expert opinion. # Patients with biopsy-proven clinically or biopsy-proven radiologically detected positive nodes # Extent of nodal dissection No studies addressing this question were identified, resulting in no evidence to support or refute the extent of axillary dissection being found. However, these patients are more likely to have multiple positive nodes than those patients identified by a SLN biopsy. This recommendation is based on expert opinion. In the small dataset currently available there is no clear advantage to ilioinguinal dissection or the evaluation of Cloquet's node with respect to survival or morbidity. Decisions regarding iliac dissection should be made on a case-by-case basis. This recommendation is based on expert opinion. # FUTURE RESEARCH The development of more consistency among studies of factors to predict additional disease in non-sentinel lymph nodes would be invaluable, not only in the selection of variables, An inguinal dissection is recommended for patients with a positive SLN in the groin, pending the emergence of good quality randomized data. The routine examination of Cloquet's node and the addition of iliac dissection are more controversial, and any decision regarding these procedures should be made on a case-by-case basis. A complete Level 1, 2 and 3 dissection in the axilla is recommended for patients with a positive SLN, pending the emergence of good quality randomized data. Inguinal dissection is recommended for patients with biopsy-proven clinically or biopsyproven radiologically detected positive inguinal lymph nodes, pending the emergence of good quality randomized data. Because there is a greater likelihood of positive ilioinguinal nodes in this clinical situation, Cloquet's node could be examined and ilioinguinal dissection undertaken if the node is positive. A Level 1, 2 and 3 dissection in the axilla is recommended for patients with biopsy-proven clinically or biopsy-proven radiologically detected positive nodes, pending the emergence of good quality randomized data. but also in the strict definition of the variables selected. Standardized synoptic reporting of the SLN would help bring consistency to these types of studies. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED GUIDELINES

October 2015 placed Evidence-based Series (EBS) 2-12 Version 2 in the EDUCATION AND INFORMATION section. This means that the recommendations will no longer be maintained but may still be useful for academic or other information purposes. The PEBC has a formal and standardize process to ensure the currency of each document (PEBC Assessment & Review Protocol) Evidence-based Series (EBS) 2-12 Version 2, the full review report, consists of the following 4 parts: 1. Guideline Overview 2. Summary 3. Full Report 4. Document Assessment and Review Tool# FULL REPORT I. QUESTION Does combined modality radiotherapy and chemotherapy improve survival compared with radiotherapy alone in patients with localized carcinoma of the esophagus for whom a non-surgical approach is used? # II. CHOICE OF TOPIC AND RATIONALE Carcinoma of the esophagus has a poor overall prognosis. The extent of disease at the time of presentation and a patient's performance status are the most powerful predictors of the potential for cure (1,2). The opportunity exists to eradicate the disease that is localized at presentation through therapy given with curative intent. The current TNM (Tumour Node Metastases) staging system (6 th edition 2002) (3) incorporated major prognostic factors, including the extent of esophageal wall involvement (T1-4) and whether local regional nodes are involved (N1). The extent of disease that oncologists consider amenable to curative intent is evolving. The changes in the precision and accuracy of diagnostic modalities, including the use of tools such as minimally invasive staging techniques, are improving the accuracy of clinical staging. Within this context, most would consider patients with T4 disease and extensive nodal involvement incurable. There is increasing evidence that patients with less than five nodes involved may have a better outcome than those with more extensive disease (4). Furthermore, the definition of nodal stations that are considered regional and still amenable to potentially curative therapies is also evolving. For the purpose of this guideline, patients with T1-3, small volume N1, M0 are considered potential candidates for curative therapy. Both primary surgery and radiotherapy (RT) are offered as treatment options to suitable candidates. In cervical tumours, the desire to avoid a laryngoesophagectomy, together with the retrospective data supporting a better prognosis with cervical esophageal tumours, has resulted in the general acceptance of an organ-preserving approach for these patients. For patients with thoracic esophageal tumours, the recommendation for a primary surgical approach versus a primary radiotherapy approach had predominantly been based on the patient's medical operability, the patient's preference, and the treating physician's estimation of the relative morbidity of the outcomes. A well-known attempt in the United Kingdom to compare surgery and radiotherapy through a randomized study failed through the inability to accrue patients (5). Two randomized studies compared surgery alone versus radiotherapy alone (6,7). In 1994, Fok et al (6) reported a four-arm study comparing surgery alone, preoperative radiotherapy and surgery, postoperative radiotherapy and surgery, and radiotherapy alone. The study was conducted in Hong Kong and included 156 patients. Median survival for surgery versus radiotherapy was 21.6 months versus 8.2 months (p<0.001). Similarly, in 1999 Badwe et al (7) reported a randomized study comparing surgery alone versus radiotherapy alone. A total of 99 patients participated in this study. Overall survival was significantly superior in the surgery arm versus the radiotherapy arm (p=0.002). The generalizability of these results to contemporary surgical and radiotherapy techniques and practices and the selection factors that need to be considered when choosing between these two treatment modalities will be discussed in a separate guideline for the overall management of esophageal cancer that would be produced in due course. Studies of the patterns of care of esophageal cancer in North America have shown an increase in the use of combined chemoradiotherapy (RTCT). Daly et al (8) analyzed patterns of care using the U.S. National Cancer Database and found that the treatment modality most commonly employed for esophageal cancer is combined radiotherapy and chemotherapy (30.2%), followed by surgery alone (18%). The most common chemotherapy regimen used in combination with radiation is 5-fluorouracil (5FU) and cisplatin. In the Patterns of Care Study (9), the chemotherapy agents most frequently used were 5FU (84%), cisplatin (64%), and mitomycin (9%). Youssef et al (10) compared management and outcome of carcinoma of the esophagus in Ontario and the United States. Controlling for age, sex, histology, and sub-site, the rate of esophagectomy was similar, but the rate of primary RT was lower in Ontario. Practice patterns for the use of RT versus combined RTCT, and the types of chemotherapy that are being used, have not been described for Ontario or Canada. This practice guideline report addresses the question of whether the addition of chemotherapy to a primary radiotherapy approach improves patient outcomes. A separate guideline is being prepared on the use of neoadjuvant or adjuvant therapy for resectable esophageal cancer when surgery is the primary modality (PG2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer). Eventually, the Gastrointestinal Cancer Disease Site Group (DSG) will consolidate both guidelines to produce a comprehensive recommendation for patients with localized carcinoma of the esophagus who are treated with curative intent. # III. METHODS Guideline Development This practice guideline report was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-based Care (PEBC), using the methods of the Practice Guidelines Development Cycle (11). Evidence was selected and reviewed by two members of the PGI's Gastrointestinal Cancer Disease Site Group and methodologists. Members of the Gastrointestinal Cancer DSG disclosed potential conflict of interest information. The practice guideline report is a convenient and up-to-date source of the best available evidence on combined modality radiotherapy and chemotherapy in the non-surgical management of localized esophageal cancer, developed through systematic reviews, evidence synthesis, and input from practitioners in Ontario. The body of evidence in this report is primarily comprised of mature randomized controlled trial data; therefore, recommendations by the DSG are offered. The report is intended to promote evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations, and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee. The PGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. The systematic review component of this guideline report has been published as a Cochrane Review (12). MEDLINE (1966to December 2001, CANCERLIT (1983to October 2001, and the Cochrane Library (2001, Issue 4) were searched with no language restrictions. Medical subject heading (MeSH) terms employed included "esophageal neoplasms" with subheadings "drug therapy", "radiotherapy", or "therapy". The terms used to capture randomized trials included the use of "randomized controlled trials", "controlled clinical trials", "random allocation", "exp clinical trials", and the text word "random". The proceedings of the 1999, 2000, and 2001 annual meetings of the American Society of Clinical Oncology (ASCO) and the American Society for Therapeutic Radiology and Oncology (ASTRO) were also searched. Ongoing trials were identified through the Physician Data Query (PDQ) database (/). # Literature Search Strategy The literature search was updated on February 10, 2005 using the following databases: MEDLINE (through February week 1, 2005), EMBASE (through week 6, 2005), and the Cochrane Library's dB of Systematic Reviews (through Issue 4, 2004). Abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology through 2004 were also searched for relevant evidence. The National Cancer Institute's (NCI) clinical trials database was also searched on February 10, 2005 for listings of ongoing clinical trials. # Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma. # Exclusion Criteria - Esophagectomy as a planned intervention 2. Use of pure radiosensitizer (e.g. misonidazole) with radiotherapy # Study Endpoints The primary endpoint of interest was overall survival. Data were examined for one-to five-year overall mortality rates. Secondary endpoints included local recurrence and adverse effects. While disease-specific survival and quality-of-life data would be useful endpoints to consider, they were not reported by the primary authors of the eligible trials and could not be evaluated. The data in this report are based on the intention-to-treat (ITT) principle unless data for only evaluable patients were reported and there was insufficient information to allow for an ITT analysis. # Synthesizing the Evidence Studies of combined modality radiotherapy and chemotherapy can generally be categorized as using a concomitant or sequential approach based on the relative timing of the radiotherapy and chemotherapy, with different biological bases behind their designs. In this report, the trials that used a concomitant approach were described and analyzed separately from trials using a sequential approach. When data from trials of sequential and concomitant approaches were examined together, the pooled data were heterogeneous, suggesting that the studies are different in nature. Thus, a combined analysis of both approaches was rejected. Data on survival and local recurrence were pooled and the results were examined for statistical heterogeneity. For each meta-analysis, data were pooled at a common time-point (e.g., mortality at one-year). The time point selected for meta-analyses must be clinically credible and relevant but not so far along the survival curve that wide confidence intervals result from fewer patients contributing to the estimate. Since time points prior to the median will generally ensure that there is sufficient data to be credible, the median survival times, weighted by the size of the treatment arms, were calculated to determine an appropriate time point for each meta-analysis. Pooling was conducted using one-year mortality data for all meta-analyses because the weighted median survival time was less than one year for both the concomitant and sequential groups (13). The study results were pooled using Review Manager 4.0.3 (Metaview© Update Software), which is available through the Cochrane Collaboration. The random effects model was used as the more conservative estimate of effect (14). Results were expressed as odds ratios (OR) with 95% confidence intervals (CI). An OR less than 1.0 favours the experimental treatment (i.e., RTCT) and an OR greater than 1.0 favours the control (i.e., RT alone). In addition, the absolute difference is presented as percent difference in outcome, calculated from the pooled event rates. The number of patients that need to be treated with RTCT for one additional patient to benefit (NNT) was also calculated. Results for adverse effects were not pooled because the primary authors of eligible trials reported data on adverse effects using different scoring systems and symptom categories. The presentation of the incidence of adverse effects (as opposed to the numbers of patients affected within each toxicity grade) makes a quantitative summary statistic difficult. The results were summarized in a descriptive fashion for this review based on the incidence of grade of toxicity for acute and late adverse effects, where available across the studies, to allow for a qualitative comparison. Data extraction was performed independently by two members of the Gastrointestinal Cancer DSG. Discrepancies were resolved through consensus. # Subgroup Analysis It was hypothesized a priori that the use of cisplatin versus non-cisplatin chemotherapy would have an impact on the effectiveness of treatment, and a subgroup analysis was planned to examine this hypothesis. The two most commonly employed chemotherapy regimens in Canada are 5FU/mitomycin and 5FU/cisplatin, and one of the major decisions facing clinicians is what type of chemotherapy to use if the combined modality approach is adopted. Furthermore, cisplatin-based chemotherapy has been used in combination with radiotherapy in many other disease systems resulting in significant improvement in outcome (15)(16)(17)(18)(19)(20). It is, therefore, important to explore the impact of cisplatin versus non-cisplatin chemotherapy within the context of combined modality. # Potential Sources of Heterogeneity and Sensitivity Analysis The following factors were postulated a priori to be potential sources of heterogeneity: study quality using scores on the Jadad scale (21) (>2 versus 2); dose of radiotherapy (BED 2 >60 versus BED 60); and type of chemotherapy (cisplatin-containing versus others). These factors were used to explore any significant heterogeneity of results across the trials. Heterogeneity of study results was assessed using a visual plot (22) and by calculating the Breslow-Day statistic using a planned cut-off for significance of p<0.05. The robustness of our conclusions was examined through subsequent sensitivity analyses using these factors. # IV. RESULTS # Literature Search Results No fully published reports of meta-analyses were identified, although the pooling of data presented in this guideline report was published in abstract form in 1999 (23). This abstract will not be discussed further because the meta-analysis has been updated for this guideline report. A related study by Smith et al (24) was excluded due to surgery being a planned option within the study design. Ten randomized trials of concomitant RTCT met the inclusion criteria (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). After a careful evaluation of the methodology, it was decided to include only eight of these trials (25)(26)(27)(28)(29)(30)(31)(32) in the analysis. The trial by Hukku et al (33) was excluded because of concerns about the adequacy of the randomization procedure. Between 1990 and 1992, Kolaric et al reported five identical abstracts (34)(35)(36)(37)(38) for the same trial. This trial was excluded because there is sufficient uncertainty and absence of appropriate data for the clinical question we were trying to answer. Of the eight trials of concomitant RTCT that were included in the analysis, all but one trial (29) have been fully published. In addition to the report of long-term follow-up of the trial by the Radiation Therapy Oncology Group (RTOG) (32), five prior reports of this trial were identified and reviewed for data extraction (39)(40)(41)(42)(43). Five fully published, randomized trials of sequential RTCT met the inclusion criteria and were included in this review (44)(45)(46)(47)(48). Update Updating activities found an RCT by Savani and Jani reported in abstract form (1u). This trial compared RTCT to RT alone in a sample of 48 patients diagnosed with squamous cell carcinoma. There were insufficient details in the abstract regarding the intervention (dose regimen of chemotherapy and radiotherapy employed, timing of radiotherapy and chemotherapy), adequacy of the randomization process, and outcomes of interest (duration of follow up, overall survival, local recurrence rates, or late toxicities). Available study characteristics are included in Table 1-2. The investigators provided information on complete response post treatment, dysphagia relief, and acute toxicities in the abstract. The authors concluded that multimodal therapy with RTCT is a better therapeutic option, with acceptable (acute) toxicity profile and good response rate. Due to insufficient detail to permit optimal assessment of the study, the available outcome data (response rate, dysphagia relief, or acute toxicities) were NOT incorporated into the current review. Additional data from this trial will be incorporated in this review as full results become available. # Outcomes Study Characteristics Tables 1 and 2 outline the pertinent study characteristics and the treatment regimens. Patients with squamous cell carcinoma were included in all trials, with six trials devoted exclusively to this pathology (25,27,28,31,44,46). All of the other trials included both squamous cell carcinoma and adenocarcinomas. The extent of the primary disease was variable, with the majority of patients suffering from locally advanced disease. All trials excluded patients with distant metastases although this was done without the benefit of any abdominal imaging in all but three trials (31,32,44). It is highly probable that a substantial proportion of included patients had nonlocalized disease. Patients with disease spread to the supraclavicular lymph nodes were accepted in three trials (26,32,44). The presence or absence of disease spread to the mediastinal lymph nodes was not specified in any of the published eligibility criteria. Most trials used specified criteria to exclude patients in poor general condition. The chemotherapy regimens varied across the trials and included methotrexate (44), bleomycin (25)(26)(27), cisplatin (29,30), cisplatin and bleomycin (47), 5FU, mitomycin and bleomycin (28), 5FU and cisplatin (31,32,45), oral futrafur (46), and intraarterial adriamycin, 5FU and cisplatin (48). In general, the duration of follow up was short with only one-and two-year mortality data available for comparison. Table 3 provides survival data for the randomized trials. Five-year survival data were available for only three trials (28,32,44). For trials of concomitant RTCT, data on mortality were available at one year for seven trials (25,26,(28)(29)(30)(31)(32). There was no statistically significant heterogeneity among the trials of concomitant RTCT when one-year mortality data was considered (p=0.49). Pooling across the seven trials involving 687 patients at one year resulted in an OR of 0.61 (95% CI, 0.44 to 0.84; p<0.00001) in favour of concomitant RTCT (Figure 1). When expressed as an absolute mortality rate, the one-year mortality rate for RTCT versus RT alone was 56% versus 67%. This is an absolute difference of 11% and a NNT of 9. The pooled analysis of five trials involving 440 patients of sequential RTCT versus RT (44-48) revealed no significant difference in survival between the treatment groups at one year (Figure 2). There was significant heterogeneity across the trials (p=0.03), but there were too few studies to allow for a meaningful exploration of the potential sources of heterogeneity. # Subgroup analysis It was hypothesized a priori that the use of cisplatin versus non-cisplatin chemotherapy would have an impact on the effectiveness of treatment. When only concomitant RTCT trials using cisplatin-containing chemotherapy were included (29)(30)(31)(32), a statistically significant survival benefit was detected at one year (OR, 0.54; 95% CI, 0.36 to 0.82; p=0.003) (Figure 3). # Sensitivity analysis Sensitivity analyses were conducted to test the robustness of the results of the pooled analyses. The two variables that were examined by additional analyses were study quality and radiation dose in combined RTCT. The exclusion of lower quality studies and studies reported only in abstract form did not have a significant impact on the conclusion. The radiotherapy dose fractionation employed, especially as it was used in the control arm, has important implications on whether the study was optimally designed to evaluate the use of combined concomitant RTCT as a potentially curative therapy. Sensitivity analysis using one-year mortality data (Figure 4) was performed for studies using a BED of  60Gy-1 and <60Gy-1. In this analysis, no statistically significant survival benefit was detected for studies using BED  60Gy-1 (OR, 0.76; 95% CI, 0.46 to1.25; p=0.3), and significant benefits were observed in only the two studies that employed BED of <60Gy-1 (OR, 0.54; 95% CI, 0.32 to 0.90; p=0.02). This observation infers that the survival benefit observed may be due to chemotherapy compensating for suboptimal radiotherapy dosing rather than augmenting survival beyond what optimal radiotherapy alone could provide. # Local recurrence Data on local recurrence were available for only three trials of concomitant RTCT (28,29,32). The trial by the RTOG (32) was the only one for which local recurrence rates for years one to three was reported. Pooling of the data detected a significant reduction in local recurrence in patients treated with concomitant RTCT compared with RT alone (OR, 0.52; 95% CI, 0.31 to 0.89; p=0.004) and no statistically significant heterogeneity (p=0.23) (Figure 5). When expressed as probabilities, the recurrence rates were 55% versus 69%, with an absolute difference of 14% and a NNT of 7. There was also no significant heterogeneity among results for trials of sequential RTCT (p=0.26). The pooled OR was 1.05 (95% CI, 0.59 to 1.87; p=0.20), indicating no significant difference in local recurrence for sequential RTCT compared with RT alone (Figure 6). # Adverse Effects The adverse effects experienced by patients in trials of concomitant RTCT are summarized in Table 4. No information on adverse effects was available for the trial reported by Andersen et al (27). In four trials, acute adverse effects were reported using a grading system (29-32) while a narrative description of the intensity of the severity was provided instead of grading toxicity in three trials (25,26,28). Earle et al (25) described one patient with severe nausea and vomiting, one with severe stomatitis, one with severe dermatitis requiring discontinuation of chemotherapy, and one patient with white cell counts less than 2.9X10 9 /l in the combined modality arm. In the radiotherapy alone arm, two patients had leucopenia with white cell counts less than 2.9 X10 9 /l. Araujo et al (28) described three patients with severe esophagitis in the combined modality arm and no adverse effects corresponding to grade 3-4 criteria in the radiotherapy alone arm. These descriptions of toxicity intensity correspond to grade 3-4 toxicity (according to RTOG toxicity criteria). In order to facilitate presentation of the data, they are included in Table 4 under the column for acute grade 3-4 toxicity. As grade 1-2 adverse effects were not reported consistently, only grade 3-4 and toxic deaths (acute and late) are presented for comparison. Acute adverse effects, particularly gastrointestinal and hematological toxicities, were more frequent among patients treated with concomitant RTCT compared with RT alone (Table 4). Concomitant RTCT was associated with more grade 3-4 acute adverse effects compared with RT alone. There was no difference in late toxicity between the two treatment groups. Toxic deaths were rare. Zhang (26) reported that 3/48 patients in the RTCT arm died with extensive pulmonary infiltrate which was attributed to the combination of high dose RT and bleomycin compared to 0/51 in the radiotherapy alone arm. Slabber et al (31) described 2/34 versus 2/36 patients in the RTCT versus RT who died following perforation after dilatation. In the trial by the RTOG (32), there was 1/61 deaths in the RTCT arm secondary to renal and bone marrow failure compared to 0/62 in the radiotherapy alone arm. In the two trials of sequential RTCT for which data on adverse effects were reported (44,45), no toxicity grading system for intensity of adverse effects was used (Table 5). Roussel et al (44) observed more adverse effects with sequential RTCT, with predominantly hematological toxicity and mucositis. In addition, there was one death with myelopathy occurring in the RT alone arm, and one from severe pancytopenia in the RTCT arm. Nausea and vomiting and hematological toxicities were more common among patients in the sequential RTCT arm of the study by Zhou (45). # V. INTERPRETIVE SUMMARY Based on the pooled analyses, concomitant RTCT compared with RT alone was associated with an absolute reduction of one-year mortality from 67% to 56%, with a NNT of 9. The recurrence rate was reduced from 69% with RT alone to 55% with concomitant RTCT, with a NNT of 7. These benefits, while relatively modest, are not trivial considering the generally poor survival rates and the morbidity associated with an uncontrolled primary tumour. However, these advantages are associated with a significant increase in potentially life-threatening and severe adverse effects (grade 3-4). While quality of life was not evaluated in any of these trials, this aspect also demands consideration within the context of the magnitude of the survival advantage and expected survival rate based on disease and patient status. An appreciation of the primary conclusions of the studies and their impact on clinical practice patterns over time would help to put the current review in perspective. All of the published studies, with the exception of Zhang (26) (which was published only in the Chinese literature, and therefore has received very little attention), have suggested that RTCT is ineffective, until the results published by the RTOG (32). Despite the long history of negative studies, this one positive RTOG study has, for several reasons, resulted in substantial changes to clinical practice since its publication. The RTOG study supports the findings of many phase II studies suggesting a favourable outcome, but perhaps more importantly, the results are consistent with similar benefits observed in other solid tumours, such as head and neck, lung, and cervical cancer, when concomitant cisplatin was used with radical radiotherapy (15)(16)(17)(18)(19)(20). In a disease where the general outcome is uniformly poor, a single positive study conducted by a large collaborative group was sufficient to motivate the adoption of this approach in standard clinical practice. How strong is the evidence in support of combined modality? Given the methods employed to evaluate the literature, this quantitative review represents a comprehensive search of the existing data from randomized studies, and as such, represents the best available data for any evidence-based conclusions. However, three major factors will continue to limit the strength of our conclusions. First, many different types of chemotherapy regimen were tested among the studies identified. Second, long-term data are lacking for many of the included studies. Third, the sensitivity analysis raised the possibility that the observed survival benefit at one year may be explained by chemotherapy compensating for suboptimal radiotherapy doses in some studies, rather than combined chemotherapy/radiotherapy being able to improve outcome beyond what could be achieved by optimal radiotherapy alone. Despite these limitations, it is unlikely that further clinical trials using radiotherapy alone as a control arm will be undertaken to provide additional evidence to address this question, given the current practice patterns in North America. The current review illustrates a benefit in local control and survival with the use of concomitant RTCT. This result in turn supports the common clinical practice of employing combined RTCT when offering a non-surgical approach with a curative intent for the management of esophageal cancer. In patients with favourable performance status and who have a reasonable chance of completing concomitant RTCT, this approach is a reasonable option compared with radiotherapy alone. Participation in clinical trials is strongly encouraged to further define the optimal strategy needed to minimize adverse effects and further enhance treatment outcomes within the context of combined RTCT. There was no evidence to suggest any survival or local control benefit using sequential RTCT compared with RT alone. Given these results and the increased adverse effects associated with sequential RTCT, this approach should not be recommended in standard practice. # VI. ONGOING TRIALS No ongoing trials were found that addressed the guideline question and met the inclusion criteria for this review of the evidence. Clinical trials designed to reduce toxicity and further augment the outcome of this approach are ongoing, and participation in these trials should be encouraged. # VII. DISEASE SITE GROUP CONSENSUS PROCESS The Gastrointestinal Cancer DSG readily agreed upon and approved the contents of the practice guideline report. The committee felt, however, that it was important to highlight the following issues. The meta-analysis of survival benefit was based on one-year data only; therefore, caution must be used when interpreting the results, especially when long-term survival benefit is considered. The Gastrointestinal Cancer DSG members debated how to address the issue of what type of chemotherapy to recommend in the context of a combined radiotherapy and chemotherapy approach. The current review was undertaken to address the general question of whether a combined approach is superior to radiotherapy alone and, therefore, was not designed to answer the question of what specific type of chemotherapy-radiotherapy regimen is superior to others. To address the latter question, we would need to review randomized studies comparing a standard type of combined radiotherapy and chemotherapy versus an experimental one, but these studies are not available. In the current review, it was hypothesized that whether or not cisplatin-based chemotherapy was used would have an impact on the conclusion of the review, and the subgroup analysis in fact did support this. The current clinical practice in North America in this area has been heavily shaped by the results of the RTOG study (32). There has been a substantial increase in the use of combined radiotherapy and chemotherapy in recent years (8), and when it is used, 5FU and cisplatin are the chemotherapy agents most commonly employed (9). The DSG felt that given the results of the meta-analysis and the current practice pattern, the use of a cisplatin-containing regimen should be the treatment of choice when concomitant radiotherapy and chemotherapy is used. For patients with poor performance status, radiotherapy alone or optimal palliative therapy should be considered. The DSG also felt that it is important to point out the significant risk of toxicity associated with concomitant radiotherapy and chemotherapy. This fact may indeed outweigh the potential benefits in survival and local control, depending on the patient's general condition. The decision to adopt a combined radiotherapy and chemotherapy approach over radiotherapy alone for the curative management of carcinoma of the esophagus should be undertaken only after due consideration of these factors and in consultation with the patient. The group also felt it should be made clear that there are no randomized trials of chemoradiation alone versus surgery alone as the primary modality for patients with curable esophageal cancer who are suitable for both (surgical and non-surgical) approaches. # VIII. EXTERNAL REVIEW OF THE PRACTICE GUIDELINE REPORT This section describes the external review activities undertaken for the original guideline report. # Draft Recommendations Based on the evidence described in the original report above 3 the Gastrointestinal Cancer DSG drafted the following recommendations: # Target Population These recommendations apply to adult patients with localized carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist. # Draft Recommendations - Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, the use of a cisplatin-based chemotherapy regimen is recommended when concomitant radiotherapy and chemotherapy is used. - Patients should be aware of the increased acute toxicity associated with this approach. The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits and the patient's general condition. Sequential radiotherapy and chemotherapy should not be recommended as standard practice. # Qualifying Statements - Localized esophageal cancer has been managed surgically or with radiotherapy. There are no randomized trials comparing these treatments, so it is unclear whether a surgical or a nonsurgical approach is superior in patients who are suitable for both approaches. # Related Guideline Practice Guideline Initiative's Practice Guideline #2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer. # Practitioner Feedback Based on the evidence contained in the original report and the draft recommendations presented above, feedback was sought from Ontario clinicians. Practitioner feedback was obtained through a mailed survey of 163 practitioners in Ontario (28 medical oncologists, 21 radiation oncologists, 111 surgeons and three gastroenterologists). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations outlined and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer DSG reviewed the results of the survey. Key results of the practitioner feedback survey are summarized in Table 6. Seventy-nine surveys (53%) were returned. Twenty-nine respondents (37%) (10 medical oncologists, seven radiation oncologists, and 12 surgeons) indicated that the practice-guideline-in-progress report was relevant to their clinical practice and completed the survey. # Strongly disagree or disagree The rationale for developing a clinical practice guideline, as stated in the "Choice of Topic" section of the report, is clear. There is a need for a clinical practice guideline on this topic. The literature search is relevant and complete. 25 (86%) 2 (7%) 2 (7%) The results of the trials described in the report are interpreted according to my understanding of the data. The draft recommendations in this report are clear. 27 (93%) 1 (3%) 1 (3%) I agree with the draft recommendations as stated. 27 (93%) 1 (3%) 1 (3%) This report should be approved as a practice guideline. 21 (72%) 5 (17%) 1 (3%) If this report were to become a practice guideline, how likely would you be to make use of it in your own practice? # Very likely or likely Unsure Not at all likely or unlikely 21 (72%) 7 (24%) 0 Percentages may not total 100% due to missing data. # Summary of Written Comments Eight respondents (28%) provided written comments. Five of the eight respondents expressed concern that the recommendation for cisplatin-based chemotherapy versus non-cisplatin-based chemotherapy goes beyond that suggested by the available evidence. A medical oncologist who disagreed with the recommendations indicated that it would be imprudent to advise concomitant radiotherapy and cisplatin-based chemotherapy for all patients until it is determined that patients with adenocarcinoma do better with radiotherapy plus cisplatin-based chemotherapy and patients with squamous cell carcinoma do better with COP (cyclophosphamide, vincristine, prednisone). This practitioner also questioned the use of odds ratios rather than absolute risk reduction and number needed to treat. Another respondent requested an algorithm to help in deciding between surgical and non-surgical treatment. The same respondent commented on the limited discussion on quality of life. One respondent wondered why a European Cooperative Oncology Group (ECOG) study of chemoradiation was not included, although this respondent also acknowledged that surgery was a planned intervention for some patients in this ECOG study. The Gastrointestinal Cancer DSG acknowledged the comments from the practitioner feedback survey that highlighted the limitations of the evidence in support of a cisplatin-containing regimen. These comments were forthcoming despite the fact that the limitations of the data were already discussed in the interpretive summary in the original draft. The DSG, therefore, felt it was appropriate to reword the recommendation to read "a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used." Instead of the original wording of "a cisplatin-based chemotherapy regimen is recommended when concomitant radiotherapy and chemotherapy is used." The utility of other novel regimens will be incorporated into the guideline report through our guideline update process when relevant studies are completed and reported. Two respondents felt that the literature identified was incomplete, although only one additional reference was cited, i.e. the ECOG study reported by Smith et al (24). This study did not satisfy our inclusion criteria because surgery was an optional but planned intervention. # Practice Guidelines Coordinating Committee Approval Process The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval. All 11 members of the PGCC returned ballots. Ten PGCC members approved the practice guideline report as written and one member approved the guideline conditional on the GI DSG addressing specific concerns. The PGCC member requested that the following issues be addressed prior to the approval of the guideline report: One member thought that the first bullet under key evidence should end with, "at conventional radiation dose fractionation schedules", or "at the doses and fractionation of radiation used in the control arms of trials" because increasing the radiation dose or fractionation schedule could achieve improved results (but which would also increase radiation toxicity). For this reason, the same member thought there should have been an exclusion criterion for trials that used inadequate doses of radiotherapy because they give a false impression of the value of the experimental arm. Another member stated that there should be a recommendation regarding placing patients on trials to better define concurrent chemoradiotherapy combinations that will improve outcomes with less toxicity, as this item appeared in the guideline text. Modifications/Actions 1. Sensitivity analysis using one-year mortality data (Figure 4) was performed for studies using a BED of  60Gy-1 and <60Gy-1. In this analysis, no statistically significant survival benefit was detected for studies using BED  60Gy-1 (OR, 0.76; 95% CI, 0.46 to1.25; p=0.3); and significant benefits were observed in only the two studies that employed BED of <60Gy-1 (OR, 0.54; 95% CI, 0.32 to 0.90; p=0.02). This observation infers that the survival benefit observed may be due to chemotherapy compensating for suboptimal radiotherapy dosing rather than augmenting survival beyond what optimal radiotherapy alone could provide. Although the meta-analysis detected an outcome that was not as strong as expected, supporting the use of combined RTCT in non-surgical therapy for esophageal cancer is still a reasonable recommendation. 2. A bullet providing suggestions for future clinical trials was added to the recommendations. 3. All necessary editing changes were also made. # Approved Practice Guideline Recommendations These practice guideline recommendations reflect the integration of the draft recommendations with feedback obtained from the external review process. They have been approved by the Gastrointestinal Cancer DSG and the Practice Guidelines Coordinating Committee. - Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used. Patients should be made aware of the increased acute toxicity associated with this approach. The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits, and the patient's general condition. Sequential radiotherapy and chemotherapy is not recommended as standard practice. Future clinical trials to better define the optimal chemoradiotherapy combination that would improve outcomes while limiting toxicities are strongly encouraged. # IX. PRACTICE GUIDELINE This practice guideline reflects the most current information reviewed by the Gastrointestinal Cancer DSG. # Target Population These recommendations apply to adult patients with localized (T1-3, small volume N1, M0) carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist. patients with localized carcinoma of the esophagus for whom a non-surgical approach is used? # Target Population: These recommendations apply to adult patients with localized (T1-3, small volume N1, M0) carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist. 5b. List below any changes to the selection criteria in the original version made necessary by new questions, changes to existing questions, or changes in available evidence (e.g., limit a search to randomized trials that originally included non-randomized evidence). - Both phase 2 and 3 RCTs are of interest. No changes to the inclusion or exclusion criteria, or study endpoints # Inclusion Criteria: Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma. - Esophagectomy as a planned intervention 2. Use of pure radiosensitizer (e.g., misonidazole) with radiotherapy # Study Endpoints: The primary endpoint of interest was overall survival. Data were examined for one-to five-year overall mortality rates. Secondary endpoints included local recurrence and adverse effects. While disease-specific survival and quality-of-life data would be useful endpoints to consider, they were not reported by the primary authors of the eligible trials and could not be evaluated. The data in this report are based on the intention-to-treat (ITT) principle unless data for only evaluable patients were reported and there was insufficient information to allow for an ITT analysis. 5c. Conduct an updated literature search based on that done for the current version and modified by 5a and 5b above. Report the results below. Full Selection Criteria, including types of evidence (e.g., randomized, non-randomized, etc.): Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma. - Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used. Patients should be made aware of the increased acute toxicity associated with this approach. The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits, and the patient's general condition. Sequential radiotherapy and chemotherapy is not recommended as standard practice. Future clinical trials to better define the optimal chemoradiotherapy combination that would improve outcomes while limiting toxicities are strongly encouraged. # Related Guidelines Practice Guideline Initiative's Practice Guideline #2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer. We also don't expect that stronger evidence will be published in the near future that would change the current recommendations Therefore, guideline 2-12 can be ENDORSED. If Yes, the document can be ENDORSED. If No, go to 8. # X. JOURNAL REFERENCE - Does any of the newly identified evidence, on initial review, contradict the current recommendations, such that the current recommendations may cause harm or lead to unnecessary or improper treatment if followed? Answer Yes or No, and explain if necessary, citing newly identified references: # not applicable If Yes, a WARNING note will be placed on the web site. If No, go to 9. 9. Is there a good reason (e.g., new stronger evidence will be published soon, changes to current recommendations are trivial or address very limited situations) to postpone updating the guideline? Answer Yes or No, and explain if necessary: # not applicable If Yes, the document update will be DEFERRED, indicating that the document can be used for decision making and the update will be deferred until the expected evidence becomes available. If No, go to 10. - An update should be initiated as soon as possible. List the expected date of completion of the update: # not applicable An UPDATE 4 subject area so fully that it would be very surprising to identify any contradictory or clarifying evidence. § SUFFICIENT RECOMMENDATIONS -Sufficient means that the current recommendations are based on consensus, opinion and/or limited evidence, and the likelihood of finding any further evidence of any variety is very small (e.g., in rare or poorly studied disease). ¶ WARNING -A warning indicates that, although the topic is still relevant, there may be, or is, new evidence that may contradict the guideline recommendations or otherwise make the document suspect as a guide to clinical decision making. The document is removed from the Web site, and a warning is put in its place. A new literature search may be needed, depending on the clinical priority and resources. # Document Assessment and Review Outcomes - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of the Web site and each page is watermarked with the phrase "ARCHIVED". - ENDORSED -An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. - DEFERRAL -A Deferral means that the clinical reviewers feel that the document is still useful and the decision has been made to postpone further action for a number of reasons. The reasons for the deferral are in the Document Assessment and Review Tool. - UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.

A practice guideline report on adjuvant RT following prostatectomy in patients with pT3 or margin-positive prostate cancer was originally completed by the Program in Evidence-Based Care Genitourinary Disease Site Group (PEBC GU DSG) in February 2008. The systematic review, as originally published in February 2008, can be found in Section 2B of this Evidencebased Series. A systematic review manuscript based on that report was published in July 2008 (1). With the availability of new evidence, the GU DSG chose to conduct an update of the evidence and recommendations in the fall of 2009. A review of the evidence published since February 2008 is presented here, Section 2A, of this report. The evidence-based series guidelines developed by Cancer Care Ontario's PEBC use the methods of the Practice Guidelines Development Cycle (2). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by two members of the GU DSG and methodologists. This systematic review is a convenient and up-to-date source of the best available evidence on the role of adjuvant RT following prostatectomy in patients with pathologic T3 or margin-positive prostate cancer. The body of evidence in this review is primarily comprised of randomized controlled trial (RCT) data; therefore, recommendations by the DSG are offered. That evidence, along with the original evidence reviewed in Section 2B, forms the basis of a clinical practice guideline developed by the GU DSG found in Section 1 of this evidence-based series. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. # Literature Search Strategy Relevant articles published since February 2008 were identified by searches of MEDLINE (2008 -September 2009 week 1), EMBASE (2008 -2009 week 37), and the Cochrane Library (2009, Issue 4). The updated MEDLINE and EMBASE search strategies are detailed in Appendix 1. The conference proceedings of the 2008 and 2009 annual meetings of the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Urological Association, and the European Association of Urology were also searched for relevant trials. # Study Selection Criteria The study selection criteria used in the original systematic review (See Section 2B) were adopted for the 2010 update. This included RCTs, systematic reviews, or clinical practice guidelines in which adjuvant RT in the immediate postoperative period after radical prostatectomy was compared to observation, with other therapies including RT and ADT held in reserve for salvage. The patients had prostate cancer and were found at prostatectomy to have either extracapsular extension (now more commonly referred to as extraprostatic extension), seminal vesicle invasion, positive surgical resection margins, or more than one of these features. # Synthesizing the Evidence Assessment of study quality followed the same procedure as in the original systematic review (See Section 2B). OS, prostate cancer-specific survival, metastasis-free survival, bPFS, locoregional recurrence-free survival, time to initiation of ADT, acute and late toxicity, and quality of life were the outcomes of interest, as in the original systematic review. When data were available on these outcomes from two or more trials, meta-analysis of the trial data was planned using the Review Manager software (RevMan 5.0.22) provided by the Cochrane Collaboration. 1 # Literature Search Results In the original search, a total of 14 reports (3-16) representing three randomized trials satisfied the eligibility criteria. The main reports of the two trials were published as full articles (6,10) and the other trial was published as an abstract (14). A literature search update was conducted in September 2009. New reports of two RCTs contributed to the evidence base: longer term follow-up of the Southwest Oncology Group (SWOG) 8794 trial (17), and the full publication of the German Cancer Society ARO 96-02/AUO AP 09/95 trial (18), previously available only as a meeting abstract. Post-hoc analyses of the SWOG trial were also identified (19,20). Three systematic reviews (21)(22)(23) and a practice guideline (24) met the selection criteria, but did not contain any new trials. A Cochrane review protocol (25) was identified, but the systematic review is not yet available. # Trial Characteristics No new results from the European Organization for the Research and Treatment of Cancer (EORTC) 22911 trial (6) have been published since the original version of the systematic review was completed. The GU DSG contacted the EORTC trial committee in October 2009 and at that time there was no definite timeline in place for an updated trial report. While the initial report of SWOG 8794 (10) was based on analysis at a median followup of 10.6 years, the updated report published in 2009 (17) extends median follow-up to 12.6 years. The ARO/AUO trial was published in a full report in 2009 (18). Study characteristics in the updated reports remained the same as the original reports. Major characteristics of the three trials (6,17,18) are summarized in Table 1. The updated trial data are shown in italics. # Trial Quality The results of the trial quality assessment are summarized in Table 2. The three trials met all of the trial quality criteria. The updated report on the SWOG trial (17) presented new data for the outcomes of OS and metastasis-free survival. The ARO/AUO trial (18) did not provide new time-to-event analyses beyond those reported in the 2007 abstract. Trial results are summarized in Table 3, and proceeding text only addresses outcomes with updated results. # Overall Survival While the original 2006 report of the SWOG trial (10) showed no difference between treatment groups for OS, the updated report in 2009 (17) showed a significant improvement in overall survival with adjuvant RT (hazard ratio 0.72; 95% confidence interval 0.55 to 0.96; p=0.023). At the time of the update, 88 of 214 men randomized to adjuvant RT had died versus 110 of 211 men randomized to observation. Ten-year OS was 74% and 66% for those randomized to adjuvant RT and observation, respectively. Median survival was 15.2 years with adjuvant RT and 13.3 years with observation. No new results from the EORTC 22911 trial have been published since the initial version of this review was completed. Only short term (five-year) results from the 2005 trial publication are available (6). At the time of publication, 43 deaths had occurred in the observation arm and 46 deaths in the adjuvant RT arm (HR, 1.09; 98% CI, 0.67 to 1.79; p=0.6796). This represents an event rate for death of only 8.9%. In view of the immaturity of these results, the GU DSG felt that inclusion of these data in a meta-analysis was inappropriate and no such meta-analysis has therefore been undertaken. Longer term results from the EORTC trial are awaited and once available will be incorporated into a meta-analysis with the SWOG 8794 results. # Metastasis-Free Survival Only the SWOG trial (17) provided data on this outcome. In the updated report, adjuvant RT reduced death or metastatic disease by 29% compared with observation (HR, 0.71; 95% CI, 0.54 to 0.94; p=0.016). Ten-year metastasis-free survival was 71% in those randomized to adjuvant RT and 61% in those randomized to observation. # Acute and Late Toxicity The full report of the ARO/AUO trial (18) did not report early and late toxicity data separately; instead, cumulative rates of toxicity over the entire follow-up period were reported. In the adjuvant RT group, one patient experienced grade 3 GU (bladder) adverse effects, three patients (2%) experienced grade 2 GU adverse events, and two patients (1.4%) experienced grade 2 gastrointestinal adverse effects. No adverse effects ≥ grade 2 were experienced by the observation group. Overall, the cumulative rate of adverse effects for bladder and rectum ≥ grade 1 was 21.9% in the adjuvant RT group and 3.7% in the observation group (p<0.0001). The updated report of the SWOG trial (17) did not include toxicity outcomes. # Subgroup Analyses The three trials included in this review enrolled patients with positive surgical margins, extracapsular extension, or seminal vesicle invasion. (Strictly speaking, it should be noted that a positive margin alone was not sufficient for entry into the ARO/AUO trial if unaccompanied by pathologic T3 disease.) It is therefore of interest to assess the relative benefit of adjuvant RT in subgroups defined by the presence or absence of these characteristics. Exploratory analyses across these pathologic subgroups have been published for each of the three trials. Two subgroup analyses of the EORTC trial (8,26) were considered in the initial version of this systematic review, and no further analyses have since been published. The first report (26) included all patients enrolled in the trial and used local pathology data while the second report (8) was limited to approximately half of study patients (n=552) in whom a central pathology review was performed. In each report, bPFS was the outcome of interest and analysis was performed at a median follow-up of five years. Two subgroup analyses of the SWOG trial (one published report considering those patients enrolled in the trial with seminal vesicle invasion (19) and the other an abstract considering those free of seminal vesicle invasion (20)) have appeared since February 2008. Finally, the published ARO/AUO trial report included a subgroup analysis of all trial participants performed at a median follow-up of 4.5 years (18). The outcome of interest was bPFS. The analysis took account of a central pathology review in 85% of cases, while local pathology review was employed for the remaining 15% of cases. In each of the three trials, randomization was stratified with respect to these pathologic characteristics, whether considered singly or in combination (see Table 1). Hence, the adjuvant RT and observation arms in each trial are likely to be well balanced with respect to these characteristics. In addition, the definitions of bPFS employed across the three trials were similar. In view of this, meta-analysis of the bPFS subgroup data was performed by members of the GU DSG and is to be presented at the 2010 annual meetings of the Canadian Association of Radiation Oncology (27) and the American Society for Radiation Oncology (28). It should be noted that, of the two published post-hoc analyses of the EORTC trial (8,26), results of the one that included all trial patients (26) were included in the meta-analysis. The analysis included previously unpublished data provided by the SWOG trial investigators. These data included subgroup analyses of bPFS and OS by pathologic subgroup. Results of the pooled analysis of bPFS outcomes are summarized in Table 4, with the OS outcome data provided by the SWOG trial investigators. It is remarkable that the OS benefit of adjuvant RT observed in the overall SWOG trial population also extends to the subgroup of patients with positive surgical margins (HR, 0.68; 95% CI, 0.49 to 0.94); the subgroup with extracapsular extension (HR, 0.62; 95% CI, 0.46 to 0.84); and the subgroup with seminal vesicle invasion (HR, 0.57; 95% CI, 0.35 to 0.93). Stated alternatively, each of the three constituent pathologic subgroups included in these trials experienced a significant survival benefit from adjuvant RT that was independent of the others. An additional comment is necessary regarding the group free of extracapsular extension. This is the only subgroup in which the HR for OS favoured observation. Absence of extracapsular extension in this context should not be assumed to be synonymous with pT2 R1 disease. As pathologic variables were coded independently in the SWOG trial database, the extracapsular extension-absent subgroup is a collection of patients with either pT2 R1 disease or pT3b R0-1 disease without coexisting capsular extension. As such, this is a very heterogeneous group, that is not representative of the population at large with organconfined, margin-positive disease, and the result is therefore not generalizable to it. It is also a small subgroup (n=85), as evidenced by the broad confidence interval. Finally, the possibility exists that this is a spurious result that has arisen from an exploratory analysis involving multiple comparisons. For these reasons, the GU DSG cautions against overinterpretation of the outlying result seen in this subgroup. It is noteworthy that in all six subgroups examined (positive and negative surgical margins, presence and absence of extracapsular extension, and presence and absence of seminal vesicle invasion), adjuvant RT conferred a statistically significant benefit in terms of bPFS. The magnitude of benefit was broadly similar across all groups, with the pooled HR ranging from 0.45 (in the case of patients with positive margins) to 0.61 (in the case of patients with negative margins). The finding of benefit across all subgroups conflicts with both the EORTC subgroup analysis based on central pathologic review (8) and the ARO/AUO subgroup analysis (18), in which the margin-negative population did not benefit from adjuvant RT. It should be acknowledged finally that the population of patients enrolled in these trials with positive surgical margins may not be representative of the general population at large with positive margins following prostatectomy. While a positive margin alone was sufficient for entry into the EORTC and SWOG trials (pT3 disease was a requirement for entry into the ARO/AUO trial), relatively few patients whose only adverse feature was a positive margin were enrolled. For example, in the EORTC trial, 629 of the 1005 enrolled patients possessed positive surgical margins. Among these, in only 163 cases (26%) was the positive margin the only adverse feature present (i.e., pT2 R1 disease), while in the remaining 466 cases (74%) the positive margin occurred in the presence of either extracapsular extension of seminal vesicle invasion (i.e., pT3 R1 disease). Additional study of the impact of adjuvant radiotherapy in patients with organ-confined, margin-positive disease is therefore warranted. # INTERPRETATION AND DISCUSSION Since the initial publication of this systematic review in 2008, updated results from one of the three included RCTs (17) are now available. At a median follow-up of 12.6 years, adjuvant RT has now been shown to confer a significant benefit in terms of both OS and metastasis-free survival. The significance of these findings warrants re-statement; for the first time, a largescale RCT has shown that an adjuvant therapy given after prostatectomy improves longevity and reduces distant failure compared to a policy of observation and salvage therapy. The magnitude of the observed benefit is substantial; median survival is prolonged by 1.9 years with adjuvant RT. A number-needed-to-treat analysis reveals that, compared to the observation and salvage strategy employed in the trial, nine courses of adjuvant RT are required to prevent one death by 12.6 years of median follow-up. Placed in context, this is similar to the magnitude of benefit seen with post-mastectomy RT given for node-positive breast cancer (29)(30)(31). Results from the EORTC trial are not sufficiently mature to draw conclusions regarding the effect of adjuvant RT on OS in this trial. At a median follow-up of five years, only 8.9% of trial participants had died at the time of the most recent report (6). Longer term results from this trial and from the ARO/AUO trial-in which only 4% of patients have died to date-are awaited. Updates of this systematic review, and the clinical practice guideline of which it forms the basis, will be undertaken once new survival data are available. In terms of pathologic findings, a fairly heterogeneous population of patients was enrolled in each of the three trials. They included men with positive resection margins, capsular breach, or seminal vesicle invasion, and no limitations were placed on Gleason score. The results of subgroup analysis of the SWOG trial with OS as primary endpoint are striking; the benefit in OS conferred by adjuvant RT applies not only to the trial population as a whole, but also to the individual populations of patients with a positive surgical margin, extracapsular extension, or seminal vesicle invasion when considered separately. Further, the pooled subgroup analysis of the three trials with bPFS as primary endpoint demonstrates a clear and statistically significant benefit for adjuvant RT in all subgroups. This is a new finding and is at odds with previously published post-hoc analyses of the EORTC ( 8) and ARO/AUO ( 18) trials wherein no significant bPFS benefit was seen in patients with pathologic T3 disease but negative surgical margins. On the basis of the overall trial findings as well as these subgroup analyses, it can be concluded that men found at radical prostatectomy to have any of positive surgical margins, extracapsular extension, or seminal vesicle invasion benefit from adjuvant RT. As noted above, further study of those patients with organconfined, margin-positive disease is warranted to better define the impact of adjuvant radiotherapy in this setting. # ONGOING TRIALS While updated results from the SWOG trial ( 17) indicate the clear superiority of adjuvant RT over the observation and salvage therapy policy employed in the trial, it remains uncertain whether the superiority of adjuvant RT would remain if it were compared to a strict policy of close surveillance with salvage RT initiated at the earliest sign of biochemical recurrence. The latter approach holds the potential advantage of avoiding RT, and its side effects, in those that do not ultimately recur biochemically following surgery. Determining which of these approaches is optimal requires well-designed phase III trials. Fortunately, three such RCTs comparing adjuvant and early salvage approaches to postoperative RT are now underway. Features of these trials, which were identified on a search of the National Cancer Institute trials registry at clinicaltrials.gov, are summarized below. The GU DSG will monitor the progress of the trials and review reported results when they become available. # Protocol ID Title and details of trial MRC/NCIC-RADICALS-PR10 NCT00541047 Phase III randomized study of immediate vs. early salvage radiotherapy (RT) and short-vs. long-term androgen deprivation therapy in patients who have undergone local surgery for non-metastatic adenocarcinoma of the prostate. 1) RT timing randomization Arm I -immediate RT; Arm II -early salvage RT in case of PSA failure. In both arms, RT is delivered, according to clinician preference, either to 66 Gy in 33 fractions or 52.5 Gy in 20 fractions to the prostate bed. 2) Hormonal therapy during randomization Arm I -0 months; Arm II -6 months; Arm III -24 months. During the pilot phase, patients may elect to be randomized between only 2 of these 3 arms. In the only RCT for which long-term follow-up data are available, adjuvant RT following radical prostatectomy in patients with pathologic T3 or margin-positive prostate cancer has been shown to improve OS and reduce distant metastases compared to observation. The OS benefit extends individually to the subgroups with positive surgical margins, extracapsular extension, and seminal vesicle invasion. Longer follow-up from the other two completed RCTs is awaited and this review will be updated once new data become available. # CONFLICT OF INTEREST There are no known conflicts of interest. # Funding The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# Guideline Document History # Qualifying Statement -Added to the 2017 Endorsement: The recommendations for pathology were updated to align with the most recent CAP protocol released in February 2017 (2), based on the International Society of Urological Pathology (ISUP) consensus conferences in 2009 (3-8) and 2014 (9,10), the (2016) WHO/IARC classification of urological tumours (11) and the seventh edition AJCC cancer staging manual. The eighth edition of the AJCC (12) will come into effect January 1, 2018 and a corresponding version of the CAP protocol was released June 2017 (13) in preparation for this change. The current documents may be obtained from the CAP website: # See Section 4, for additional information. # SURGICAL RECOMMENDATIONS The main goals of RP are (a) complete eradication of the cancer-containing organ with negative surgical margins, (b) preservation of urinary function, and (c) preservation of erectile function, where appropriate, but, in some cases, it is not possible to achieve all three. Positive surgical margins are associated with higher rates of cancer recurrence, but techniques for the preservation of urinary and erectile function may result in positive margins. The consensus opinion of the expert panel is that the following techniques and objectives form the basis for good surgical management during RP. In Ontario currently, most RPs are performed via the open retropubic route, but other methods are acceptable. # Radical Prostatectomy - RP should be offered to low-risk and intermediate-risk patients for whom surgery is the preferred option after full discussion with patient and taking into account patient preferences. - The decision to offer surgery to high-risk patients should be made with careful consideration. High-risk patients should be offered a referral for radiation consultation or review at a Multidisciplinary Cancer Conference (MCC). The intent of the MCC is to ensure that all appropriate diagnostic tests, all suitable treatment options, and the most appropriate treatment recommendations are generated for each cancer patient and discussed prospectively with a multidisciplinary team with the knowledge and tools to provide a full array of surgical interventions, systemic and radiation treatments, and supportive and palliative care. The incidence of positive margins in this patient group is expected to be higher than in that for pT2 disease. - Sparing of the neurovascular bundles should be considered the "standard approach" except for high-risk patients. - In patients with otherwise low or intermediate risk, where there is an increased likelihood of positive margins, based on clinical evidence, or the likelihood of extracapsular tumour extension and risk categorization, wide excision of the neurovascular bundles would be warranted in order to avoid compromising cancer control. - The panel consensus was that the goals are to achieve rates of <1% mortality, <1% for rectal injury and <10% for blood transfusion in non-anemic patients. - Radical Prostatectomy should aim at achieving a negative margin, while ensuring a balance between margin rates and functional outcomes # Qualifying Statements -Added to the 2017 Endorsement: The original 2008 recommendation on positive margin rates was modified in 2017 by the Expert Panel, removing the reference to a specific target and not limiting that patient population to pT2 cases. See Section 4 for additional information. The original and the revision to the positive margin rate recommendations are based on the expert opinion of the guideline panels. In the updated literature review (to May 2016) no new data were identified to directly inform this recommendation. # Pelvic Lymph Node Dissection - Standard PLND should be mandatory in high-risk patients and is recommended for the intermediate group. PLND is optional for low-risk patients. (Standard PLND should include all lymphatic tissue along the external iliac vein from the lymph node of Cloquet distally to the bifurcation of the common iliac vein proximally and includes all lymphatic tissue in the obturator fossa.) - Evidence and opinions on the role of extended PLND in high-risk patients are divided. (An extended PLND entails the removal of lymph nodes medial and lateral to the internal iliac vessels up to and around the bifurcation of the common iliac artery, with the genitofemoral nerve as the lateral limit.) # Technical Considerations for Radical Prostatectomy - For additional specific details concerning technical considerations for RP refer to Section 2: Appendix 4.a) of this document. # PATHOLOGICAL RECOMMENDATIONS Handling of the Radical Prostatectomy Specimen in the Operating Room - Frozen section analysis of the radical prostatectomy specimen (RPS) for margin status is not recommended. - For routine handling, the RPS should be fixed in 10% neutral buffered formalin or other appropriate fixative. The specimen should be put in an appropriately sized container with a minimum formalin/tissue ratio of 10:1 (i.e., 500 cc formalin for a 50 cc prostate). # Pathology Requisition Information - The surgical specimen should be accompanied by an appropriate pathology requisition that includes demographic and other identifying information, relevant clinical data (e.g., serum PSA, DRE findings Gleason score on biopsy), and the history of neoadjuvant therapy (e.g., hormones # Pathology Report - The surgical pathology report should include the relevant diagnostic and prognostic information as outlined in the CAP Cancer Protocol for Carcinomas of the Prostate Gland (2,13). CCO has recommended as a minimum standard that all required (core) elements on the CAP checklist be included in the RPS pathology report. # Added to the 2017 Endorsement: See Section 4, Appendix 2 for the updated checklist. - It is recommended that the diagnostic and prognostic factors be presented as a synopsis as opposed to a narrative or paragraph form. Data from CCO indicates that synopses are more likely to be complete. # Technical Considerations for Handling and Processing the Radical Prostatectomy Specimen in the Pathology Laboratory - For additional specific details concerning technical considerations for handling and processing, refer to Section 2: Appendix 4.b) of this document. - In the Pathology Laboratory, the RPS (with or without lymph nodes) is accessioned in the usual fashion. - The RPS should be fixed in neutral buffered formalin (minimum 10:1 ratio) for a minimum of 18-24 hours prior to sectioning. A microwave-assisted technique may be used to reduce fixation time. - The prostate gland should be weighed and measured in three dimensions; seminal vesicles should be measured; accompanying lymph node specimens should also be measured and a record made of the number and size of grossly identified nodes. - The outer aspects of the RPS should be carefully inked to identify the surgical margins, prior to tissue banking. - After appropriate fixation and inking, the distal apical segment is transected and then serially sectioned, perpendicular to the inked surface. An en face (shave) technique is to be discouraged at the apex, as this approach can result in false-positive margin interpretation. - The basal (bladder neck) aspect is commonly doughnut shaped and irregular. It is transected from the main specimen and should also be submitted in a perpendicular fashion to minimize the possibility of a false-positive margin at this location. - The intervening transverse sections can be either totally or subtotally submitted using regular-sized blocks. The submission protocol should be documented with an appropriate diagramatic or written block legend. - For subtotal submissions, a systematic approach to include the posterolateral peripheral zone should be used. - All lymph nodes accompanying the RPS should be submitted for histological analysis. It is not necessary to submit all perinodal fat, although it is often difficult to distinguish between adipose tissue and fatty lymph nodes. - Updated in the 2017 Endorsement: The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

PDT is a local treatment. It utilizes the local, selective, cytotoxic reaction produced by photosensitizers when activated by red nonthermal laser light of a specific wavelength. This cytotoxic effect is achieved through the generation of free radicals, the production of singlet oxygen via energy transfer from light to triplet oxygen, or by ischemic necrosis through neovascular shutdown partly mediated by thromboxane A2 release (anti-angiogenic effect). For a period after administration, photosensitizers are selectively retained in higher concentrations in tumours than in surrounding tissue. The goal of PDT is to exploit this selectivity by exposing tumours to laser light of an appropriate wavelength during this time, typically two to four days after systemic administration of the photosensitizer (1). Although treatment protocols may vary, PDT is a two-stage process that involves the administration of a photosensitizer via the intravenous route, typically at a dose of 2mg/kg of body weight for porfimer sodium (Photofrin®), and laser light irradiation two to four days later. A flexible bronchoscope is used to position a fiberoptic diffuser, either within or at the surface of the tumour, and the tumour is irradiated using a laser light source capable of producing the required wavelength (630nm ± 3nm for porfimer sodium). The choice of the fiberoptic diffuser tip depends on the indication, tumour location, and size of the tumour. For endobronchial tumours, the usual total light energy is 200 joules/cm of tumour length. Topical or local anesthesia is generally administered prior to PDT, and toilet bronchoscopies are performed within a few days of each treatment for debridement of the necrotic tumour to clear the airway of mucous plugging and prevent airway obstruction, atelectasis, dyspnea, or airway infection. Where required, laser light can be re-applied within 4 to 5 days of the photosensitizing drug being administered. The PDT process can be repeated once or twice, with a minimum of 30 days between injections of the photosensitizer (1). The development of new photosensitizers and more compact, powerful laser systems is continuing and may allow for the treatment of tumours of greater depth with fewer side effects. PDT using porfimer sodium as a photosensitizer has been used in Europe since the 1980's for treatment of lung cancer, esophageal cancer, bladder cancer, brain tumours, and head and neck tumours. It was first approved in Canada in 1993 for bladder cancer. By 1998, QLT Phototherapeutics Inc. (Vancouver) had received U.S. FDA approval for the use of porfimer sodium for treatment of early stage lung cancer and Axcan Pharma Inc. now produces the compound. The use of PDT and porfimer sodium in lung cancer in Canada is still very limited, although there is increasing use of PDT worldwide. The Lung Cancer Disease Site Group (Lung DSG) felt that conducting a systematic review and evaluating the evidence for PDT was appropriate. This systematic review was developed by Cancer Care Ontario's Program in Evidencebased Care (PEBC). Evidence was selected and reviewed by one member of the PEBC's Lung DSG and methodologists. This systematic review is a convenient and up-to-date source of the best available evidence on PDT. The body of evidence in this review is primarily comprised of nonrandomized controlled trial data. This precludes the development of definitive recommendations and instead, opinions of the DSG are offered. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. # Literature Search Strategy MEDLINE (1966 through June 2005), CANCERLIT (1975 through June 2002), EMBASE (1988 through 2005, week 23) and the Cochrane Library (2005, Issue 4) databases were searched. "Lung neoplasms" (Medical subject heading (MeSH)) was combined with "bronchial neoplasms" (MeSH), "dihematoporphyrin ether" (MeSH), "hematoporphyrins" (MeSH), "hematoporphyrin photoradiation" (MeSH), "phototherapy" (MeSH) and each of the following phrases used as text words: "lung cancer", "lung carcinoma", "lung malignancy", "bronchogenic cancer", "bronchial cancer", "bronchogenic carcinoma", "bronchial carcinoma", "bronchogenic malignancy", "bronchial malignancy", "photofrin", "porphrin", "porphyrin", "hematoporphyrin", "dihematoporphyrin ether", "porfimer sodium". These terms were then combined with the search terms for the following study designs: practice guidelines, systematic or quantitative reviews, meta-analyses, randomized controlled trials, controlled clinical trials, clinical trials phase ii and phase iii, and multicenter studies. In addition, conference proceedings of the American Society of Clinical Oncology (ASCO) were searched for abstracts of relevant trials published between 1997 through 2005. The Physician Data Query (PDQ) clinical trials database on the Internet (/) was searched for reports of new or ongoing trials. The Canadian Medical Association Infobase () and the National Guidelines Clearinghouse () were searched for existing evidence-based practice guidelines. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from those sources were searched for additional trials, as were the reference lists from relevant review articles. # Inclusion Criteria Fully published reports or abstracts that met the following criteria were selected for inclusion: 1. Systematic reviews, practice guidelines, randomized controlled trials (RCTs) or noncontrolled prospective studies of PDT using porfimer sodium (Photofrin®), alone or in combination with other therapies, for the treatment of stages I through IV primary, non-small cell lung cancers. 2. Outcomes of survival, response rate, or toxicity were reported, or for locally advanced lung cancer, the outcome of symptom palliation was reported. Exclusion Criteria 1. Studies with less than ten patients 2. Studies in which PDT was used for the detection of lung cancer. - Individual case reports, pilot studies and retrospective studies. 4. Letters and editorials. 5. Papers published in a language other than English. # Synthesizing the Evidence The three randomized trials identified in the literature search did not have similar treatment comparisons; therefore, a meta-analysis of this data was not considered appropriate. In addition, the other prospective trials identified in the literature search were non-comparative and were not suitable for meta-analysis. # Literature Search Results # Practice Guidelines Two evidence-based guidelines, developed by the American College of Chest Physicians (ACCP) (2) and the Scottish Intercollegiate Guidelines Network (SIGN) (3), have provided recommendations for the treatment of lung cancer and included a section on the use of PDT. The SIGN guideline was based on the systematic review examining PDT developed by the Lung DSG previously published (4), and its recommendations were consistent with the Lung DSG's conclusions (3). The ACCP searched a variety of literature sources (including MEDLINE and the Cochrane Library) until July 2001, however the methods of study selection were not clearly described (5). This guideline was funded through an unrestricted educational group from Bristol-Myers Squibb (5). The ACCP recommended photodynamic therapy as a treatment option for early stage superficial squamous cell carcinoma patients who are not surgical candidates. For early stage patients who are surgical candidates, they recognized that PDT appears to be a promising treatment, but that evidence comparing PDT to surgical outcomes remains limited (2). # Clinical Trials Three RCTs in patients with late stage lung cancer were eligible for inclusion. Two trials (reported in a single abstract) compared PDT with Nd:YAG laser treatment (6) and one trial compared external beam radiotherapy plus PDT with external beam radiotherapy alone (7). Eleven non-controlled studies reporting for early stage lung cancer (three reported in a single abstract) (8)(9)(10)(11)(12)(13)(14)(15)(16), one summary paper reporting the cumulative results of PDT studies in early stage disease conducted in Japan over 19 years (17), one non-controlled study that included a mix of stages (18), and four non-controlled studies of PDT in late stage disease (19-22) also met the inclusion criteria. In abstracts where the results of several trials were reported (6,8), the method of pooling data were not provided. Where the same data were reported in more than one publication, the most recently available data are used. Moghissi et al recently reported the results of the Yorkshire Laser Centre experience with PDT for lung cancer (16). Some of the advanced disease-stage patients in that study were subjects of previous publications included in this review, and it was unclear if that trial included any advanced patients that had not been previously reported (6,21). To avoid repetition of results, only the early-disease stage results from that study are included. Two early studies were excluded because of limited data on lung cancer and the use of inadequate power density in laser treatment (23) and limited data on outcomes (24). One additional study was excluded as no information was provided on the stage of the patients and the data for primary and recurrent cancer patients were not reported separately (25). The research to date has mostly consisted of small studies that describe clinical experience with the use of PDT at a single centre (9,10,(12)(13)(14)(15)(16)(19)(20)(21) or study summaries (17). For many of those studies, it is unclear if all eligible patients received treatment or whether the authors selected or reported on a subset of patients. In addition, three trials are in abstract format, and one is a summary paper, which provides limited detail on trial methodology. Overall, the quality of the published research is relatively poor. # Early Stage Lung Cancer Tables 1a and 1b summarize the 11 non-controlled prospective studies and the one summary paper of PDT in the treatment of early stage lung cancer. The results of three studies, conducted in Europe and Canada, are reported in one abstract by Lam et al (8). In the summary paper, Kato reported the cumulative results of PDT studies conducted over 19 years at the Tokyo Medical College in Japan (17). Most patients were considered medically inoperable or had refused surgery (8)(9)(10)12,15). In one study, patients were oncologically operable but ineligible for surgery due to inadequate cardiorespiratory function or poor general fitness (16). In contract, another study included only patients who were considered candidates for surgery (13). It is also of note that where gender was reported, the overwhelming majority of patients were male (84% to 97%) (9)(10)(11)(12)(13)16). The method of response assessment varied across studies, and it is, therefore, difficult to directly compare the response rates between studies. In some cases, assessment included a combination of chest x-ray, bronchial biopsy or brushings, or sputum cytology (9,16). Other studies determined response from (12,13) endoscopic or histologic tests alone (8,15), and some studies did not report the definition of a complete response or the method of response assessment (14,17). Similarly, the timing of response assessment was variable, with some studies requiring an absence of tumour for at least four weeks post-treatment (11,12,15), some assessing response at a three-month follow-up (13), and others not providing the exact timing of response assessment (8)(9)(10)14,17). For the 14 cancers with a complete response post-PDT, median follow-up was 29 mos (3-53 mos). † Staging data were inconsistently reported by Furuse et al (11). For the 61 carcinomas assessable for toxicity, table 1 indicated that 17 were Tis and 44 were T1s and the text indicated that 14 were Tis and 47 were T1s. ‡ Fifty-one patients with 61 carcinomas were assessable for toxicity and 49 patients with 59 carcinomas were assessable for response. § The Imamura et al study (12) was conducted at one of the institutions and with many of the same authors as reported for the Furuse et al study (11). The time period and patient population also overlapped. ║ Abstract report of three trials conducted in Canada and Europe. Of 20 patients receiving radiation therapy in combination with PDT, 18 had no evidence of local recurrence at last follow-up or on autopsy and the five-yr survival rate for these patients was 41.2%. † Data from a multicentre trial reported by Kato (17) appear to update the Furuse et al data (11), with CR obtained two months after the final treatment in 58 of 64 early stage lesions (90.6%). ‡ Estimated by reviewer from survival curve for 51 eligible patients. § When death due to other diseases was excluded, the five-year survival rate was 94.8%. ║ Abstract report of three trials conducted in Canada and Europe. ¶ One patient died 1 month after PDT from myocardial infarction and a bronchoscopic check was not conducted # Toxicity data was not reported separately for early stage patients Overall, the response rate associated with PDT in patients with early-stage lung cancer varied considerably, from 30.8% of 39 lesions (10) to 100% for 15 patients (16). One study found a response rate of 84.8% for 59 lesions, and that study involved only tumours that were roentographically occult or had clearly visible margins at bronchoscopy (11). The response rate for patients with operable disease ( 13) was comparable to that of studies mainly including patients considered medically inoperable or refusing surgery (69.6% compared with 30.8% to 79%). In five studies, the response rates reported were determined after the initial PDT treatment (11)(12)(13)(14)16) and varied from 64.1% to 100%, while in three studies, the response rate was assessed after PDT was repeated up to three times (9,10,15) and varied from 30.8% to 61.5%. The number of PDT treatments per patient was not provided in the three studies reported by Lam et al (8) or in the summary paper by Kato (17). In those studies where response was assessed after a number of PDT treatments were administered, the reasons for the variation in the response rates are unclear but could include variation in the method of administering PDT, differences in the extent of disease, and differences in the timing or method of assessment of response. Four of the studies also conducted subgroup analyses of response to PDT according to tumour length or surface area. Kato (17) reported complete responses in almost 100% of superficial lesions with a maximum dimension of 1cm in length (44 of 45 tumours, 97.8%, versus 6 of 14 tumours, 42.9%, p=0.00001). In a multivariate logistic regression analysis, the same investigators found that estimated length of longitudinal tumour extent was the only significant, independent prognostic factor for complete response (p=0.0021). The other factors included in the regression analysis were tumour location, clarity of distal tumour margin, bronchoscopic findings of superficial versus nonsuperficial tumour, and light source of argon dye versus excimer dye laser. For a subset of tumours with a surface area of ≤ 3cm2, Imamura et al (12) obtained complete responses in 71.9% (23 of 32 tumours) compared to a complete response rate of 64.1% for all tumours. Edell and Cortese (9) reported a complete response rate of 48% for a similar subset (14 of 29 tumours) compared to 35% for all tumours. A comparison of response rates for carcinomas in situ and T1 cancers was available from data reported by Furuse et al (11) and Imamura et al (12), although it is not clear that the two data sets were entirely independent. Both obtained higher response rates with the carcinomas in situ (15 of 15 TiN0M0 versus 35 of 44 T1N0M0 and 17 of 21 carcinoma in situ versus 8 of 18 T1N0M0, respectively). The differences in response rates, however, were not significant. Five-year survival rates were reported for five non-controlled studies of early stage disease (10,(12)(13)(14)17) and varied from 43% among 36 patients with poor pulmonary or cardiac function (10) to 72% among 21 patients who were surgical candidates (13). Those rates are difficult to interpret because the studies all include the use of other modalities at some point, e.g., surgery, radiation, and/or brachytherapy. Of the eight studies that provided data on adverse effects (8-13), all reported reactions relating to photosensitivity. Between 8% of 38 patients (9) and 41% of 29 patients (12) experienced sunburn, with reactions typically described as mild to moderate. Edell and Cortese (9) reported fatal hemoptysis within one month of treatment in 8% of 38 patients. In two of those cases, the tumours were large, obstructing a major airway, and the authors suggested that the events were likely related to tumour necrosis and bleeding as a result of PDT. The most frequent side effects identified by Furuse et al (11) were pulmonary-related, including exertional dyspnea, bronchitis, and obstructive pneumonitis, which occurred at World Health Organization (WHO) grades one and two in 75% and eight percent of 51 patients, respectively. Lam et al ( 8) also indicated that mild to moderate pulmonary effects were common, occurring in 7% to 22% of 102 patients. Productive expectoration or cough was reported as a mainly shortterm side effect of treatment in two studies (9,13). The related side effect of temporary airway stenosis or obstruction was reported to be common by Imamura et al (12) and was found in 13% of 38 patients receiving PDT by Edell and Cortese (9). In the two latter studies, hypercapnic respiratory failure requiring mechanical ventilation occurred in one of 29 and two of 38 patients, respectively. One of those patients had a previous right pneumonectomy and subsequently died due to tension pneumothorax, and one patient had a previous left pneumonectomy and a right upper lobectomy (9). The third patient may have died as a result of respiratory insufficiency three weeks after a repeat PDT and 33 months after the first PDT, although this association is not clearly reported (12). Transient elevations in serum transamines have been reported (11), as well as transient grade one liver dysfunction ( 12) and WHO grade one and two allergic reactions (11). An anaphylactic reaction was also reported in 1 of 29 patients (11,12,12). In the study by Patelli et al (15), the adverse effects were not described in detail but the author did indicate that airway edema, hemorrhage, and necrobiotic features were common within the first 48 hours after PDT. # Mixed Stages of Lung Cancer There was only one non-controlled study with mixed stages of lung cancer. McCaughan and Williams (18) reported the results of a large series of 175 patients treated with PDT over 14 years (Table 2). Response rates were not reported for all patients. The longest median survival was obtained for patients with the earliest stage disease, and, in a mulitvariate analysis, the factors found to influence survival were disease stage (p=0.0001) and performance status (p=0.013). The length of palliation for patients with incurable disease was reported as equal to, or better than, historical controls. Of the eight deaths that occurred within 30 days of first PDT treatment, four were due to pulmonary hemorrhage (one stage IIIA, two stage IIIB and one stage IV), two to pneumonia (both stage IIIA), one to stroke (stage IIIB), and one to lung cancer (stage IIIA). All of the patients with fatal pulmonary hemorrhage experienced hemoptysis with clots prior to treatment. One patient had a tracheoesophageal fistula within one week of treatment, and, after several treatments, some patients had strictures due to scar tissue that completely obstructed the bronchi. McCaughan and Williams (18) detected that airway obstruction can occur due to edema and exudates resulting from PDT, and they emphasized the importance of posttreatment toilet bronchoscopies. Skin photosensitivity was described as lasting for up to eight weeks following injection of the photosensitizer. # Late Stage Lung Cancer Table 3 summarizes the two RCTs (both reported in a single abstract) comparing PDT with Nd:YAG laser therapy, one RCT comparing PDT plus external beam radiotherapy with external beam radiotherapy alone, and four non-controlled prospective studies of PDT for the treatment of late-stage lung cancer. All studies reported that disease was advanced or late stage, although one RCT did not detail the methods used to determine stage of disease (6,22). The remainder assessed disease stage histologically, bronchoscopically, or radiologically. The majority of the patients were male for the one RCT and two non-controlled studies that reported gender composition (7,19,21). Median follow-up data were not available for the late stage disease studies. Wieman et al (6) reported the results of two randomized trials, one conducted in Europe and one in North America, comparing PDT with Nd:YAG laser treatment in 211 patients. The baseline characteristics of the patients in both groups were comparable. Objective response was assessed one month after treatment and the response rate was significantly higher for patients treated with PDT (55% versus 30%, p=0.00029). However, the definition of complete and partial response and the method of response assessment were not provided, and it is, therefore, difficult to compare these response rates with those obtained in other studies. In the randomized trial by Lam et al (7), a standard definition of response was not used; however, bronchial obstruction was estimated from bronchoscopy as the point of maximum narrowing of the most central airway. The bronchial lumen was completely opened and post-treatment bronchoscopy revealed no gross, visible tumour in 14 of 20 patients receiving PDT plus radiotherapy compared with two of 21 patients receiving radiotherapy alone. In total, treatment failures were reported to be zero and four, respectively, although the timing of response assessment was not clearly stated. Neither study reported if assessment of response was blinded. In a non-controlled study, Hugh-Jones and Gardner (19) treated nine patients and assessed response visually and radiologically after one treatment. With the stated aim of palliation, a complete response was broadly defined as the enlargement of the diseased airway to at least 90% of normal and a partial response was considered as an enlargement of 50 to 90% of normal. The use of this broad definition resulted in an objective response rate of 100%. An independent radiologist subsequently reclassified one of the responses from 'complete' to 'partial'. Interestingly, this study was the only one that reported an independent assessment of response. In the two randomized trials reported by Wieman et al (6), overall survival was reported to be similar for both the PDT and Nd:YAG laser treatment groups; however, detailed survival data were not provided. Lam et al (7) found that median survival was similar for patients randomly allocated to radiotherapy alone or to PDT with radiotherapy, although the 20 patients in the PDT group remained recurrence free for significantly longer than the 21 patients in the radiotherapy alone group. In all three randomized trials, it was unclear if patients whose initial treatment was unsuccessful subsequently received additional treatments, a situation that could influence the results. Radiotherapy dosed at 3000 cGy in 10 fractions over 2 weeks using a linear accelerator. † CR and PR not defined. Reported no gross visible tumour post-treatment for 70% (PDT+XRT) and 10% (XRT) of patients. ‡ Abstract report of two trials conducted in North America and Europe. § Number of patients in each group obtained from the 1998 ASCO poster presentation provided by the author. ║ Reviewer calculated chi-square = 13.103, df = 1, p = 0.00029. ¶ Response rate was provided for 9 of 10 patients that were treated and evaluable; one was untreated due to laser failure. An additional five patients were treated as part of a pilot study. # Pathological response reported as partial for all patients, although 'partial' is not defined. Two patients were not treated with PDT as one has intraperitoneal disease and one had unsuspected intrapericardial disease. # † † Median Three of the four non-controlled studies reported median survival. Locicero et al (20) administered PDT to 10 patients and achieved a median survival of four months. Six of the 10 patients subsequently received external beam radiation averaging 60 Gy, three patients were retreated with PDT an average of nine months after the initial treatment, and one patient was later treated with Nd:YAG laser. In a study involving 100 patients receiving multiple treatments of PDT (21), the results of a multivariate analysis indicated that performance status had a significant effect on survival. Patients with a WHO performance status rating less than or equal to two survived longer than those with a rating greater than two (median: 14 months versus four months, p<0.0001). Histology, disease stage, age, and sex did not significantly influence survival. In a study of combined modality therapy, including PDT, Friedberg et al ( 22) reported a median survival of 21.7 months, considerably longer than the two other studies. Twenty patients in that study underwent surgery and received PDT intra-operatively. Chemotherapy or radiotherapy was also administered pre-or post-surgery. In the trial by Lam et al (7), respiratory symptoms were measured on a scale of 0 (no symptom) to 4 (unbearable), although no data were provided on the reliability or validity of the scale. Compared to radiotherapy alone, PDT with radiotherapy produced a significant improvement in hemoptysis and shortness of breath at three months post-treatment (p<0.05), although both groups improved from baseline. In the PDT group, coughing was also significantly reduced at one month and three months post-treatment compared to baseline (p<0.05). Additional palliation of symptoms was not reported for radiotherapy alone. Comparing PDT with Nd:YAG laser therapy, Wieman et al (6) found that more patients showed an improvement in dyspnea grade one month after PDT when assessed on an unspecified symptom severity scale (17% versus 30% of patients, p-value not reported), although the PDT group had a greater number of adverse events related to photosensitivity, dyspnea, hemoptysis, and bronchitis. Neither study reported if assessment of symptoms was blinded. Among the non-controlled studies, Hugh-Jones and Gardner (19) used a self-report analogue scale and reported improvement from baseline in breathing for all nine evaluable patients and a cessation of hemoptysis in six patients. In the study by Locicero et al (20), all 10 patients experienced a reduction in coughing from baseline and most experienced reduced dyspnea, although the methods of evaluation were not provided. Average bronchial obstruction, estimated by comparing the widest projected area of the tumour with a measure of the area of the bronchus obtained from transbronchoscopic photography, decreased from 86% (± 2%) to 57% (± 3%) following PDT; however, obstruction remained > 70% for half of the patients. There were no significant post-treatment changes in measures of pulmonary function. Moghissi et al (21) also reported a decrease in mean percentage bronchial obstruction, assessed bronchoscopically six to eight weeks after PDT, from 85.8% (± 19.6%) to 18.5% (± 17.3%). In that study, pulmonary function as measured by forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) did improve following PDT from 2.07L (± 0.78) to 2.50L (± 0.74) for FVC and from 1.38L (± 0.56) to 1.66L (± 0.57) for FEV1. Three of 20 patients randomized to PDT in the study by Lam et al ( 7) experienced massive and fatal hemoptysis at 67, 187, and 567 days after treatment. It was suggested that those events could be the result of either disease progression or weakening of the bronchial wall as a result of PDT. In the same study, of 21 patients who received radiotherapy alone, one died of respiratory failure and two of pneumonia, while one patient receiving both PDT and radiotherapy died of pneumonia. Wieman et al ( 6) also found that hemoptysis, dyspnea, and bronchitis occurred more frequently in patients who received PDT compared to those who received Nd:YAG laser therapy. However, many of the events reported by Wieman et al (6) occurred more than 30 days after treatment, suggesting that they were not directly attributable to the therapy. Photosensitivity associated with PDT occurred in 20% of patients in both the Lam et al (7) and the Wieman et al ( 6) studies. Three of the four non-controlled studies also reported adverse effects associated with photosensitivity for patients receiving PDT, mainly in the form of mild sunburn. However, in the study by Locicero et al (20), one of 10 patients had a severe second-degree burn as a result of prolonged exposure to the sun post-PDT, and one patient experienced mild anasarca. Transient worsening of breathlessness was reported by Hugh-Jones and Gardner (19) for two of nine patients receiving PDT. In one case, that led to mechanical ventilation, and the patient subsequently died one month after treatment, although it was unclear if the patient remained on a ventilator until death. In the same study, two patients also experienced post-treatment infection. Friedberg et al ( 22) reported a wide range of toxicities. The most common toxicities included elevation in transaminases and creatinine, edema, hypotension, acidosis, thrombocytopenia, increased protime, and increased partial thromboplastin time. The operative mortality from surgery and PDT was 9% (two of 22 patients), with one death due to pneumonia resulting in sepsis and respiratory failure and the other death due to acute respiratory distress syndrome. PDT is relatively easy to administer, can be performed on an outpatient basis, and can be repeated. For early-stage lung cancers, the published data from non-controlled prospective studies, which mainly included patients with medically inoperable disease, showed a varied response rate from 30.8% to as high as 100%. Three of four studies that reported subgroup analyses according to tumour length or surface area found a tendency towards improved response rates for smaller tumours. In one of those studies, patients with small tumours of ≤ 1 cm experienced a significantly better response rate than patients with tumours > 1 cm in length (97.8% versus 42.9%, respectively). The five-year survival rate varied from 43.4% to 72%, although for most studies this outcome reflected the effects of a combination of treatments rather than PDT alone. Overall, the data suggest that PDT can produce moderate response rates in early-stage lung cancer, particularly where the tumour is small. The effect of PDT on survival for patients with early-stage lung cancer is less clear. For treatment of late-stage lung cancers, there were three RCTs: two studies involved PDT versus Nd:YAG laser therapy and the third study involved external beam radiotherapy plus PDT versus external beam radiotherapy alone. None of the RCTs detected a survival advantage for PDT, but there was an advantage for PDT with radiotherapy over radiotherapy alone with respect to symptom control, although the validity of the symptom measurement scale was unclear. In comparison to Nd:YAG laser therapy, PDT did improve dyspnea grade but that was offset by the higher number of adverse events in the PDT group. Three of the noncontrolled studies also resulted in post-PDT reductions in dyspnea, hemoptysis, cough, or bronchial obstruction in these palliative patients. The palliative effect of PDT in late-stage lung cancer is promising, although its effectiveness in comparison to traditional therapies requires further study. Most treatment side effects were considered mild to moderate, with photosensitivity being evident in most studies and pulmonary side effects occurring commonly. There were three cases of hypercapnic respiratory failure requiring mechanical ventilation among 67 patients with early stage lung cancer. One RCT in locally advanced disease reported improvement in hemoptysis after treatment with PDT plus radiotherapy compared to radiotherapy alone. However, in the same study, three of the 20 patients receiving PDT had fatal hemoptysis at two, nine, and 18 months post-treatment. In two non-controlled studies, seven of 213 patients died from hemoptysis or pulmonary hemorrhage within one month of treatment (three with early stage disease and four with locally advanced lung cancer). The data on toxicity emphasize the need to ensure that patients understand the risks of exposure to sunlight in the period following treatment. The product monograph for Photofrin® indicates that the most common side effect in patients who have received Photofrin® is photosensitivity for 30 days or more, even up to 90 days. Patients must avoid exposure of eyes and skin to direct sunlight or brightly focused indoor light. The risk for serious adverse events should be taken into consideration in light of the patient's history and clinical condition. Toilet bronchoscopies should always be completed following endobronchial PDT to minimize the risk of bronchial obstruction, and the risk of hemoptysis should be considered prior to therapy and monitored post therapy. There are a number of contraindications for the use of PDT in patients with lung cancer. These include porphyria or known allergies to porphyrins, tumours that erode into a major blood vessel, and existing tracheoesophageal fistulas. To date, drug-to-drug interactions involving Photofrin® have not been documented. Its use in pregnant women, nursing women, and children has not been established, and, therefore, Photofrin® is not recommended for use in those cases (1). Much current research is of limited quality and is mainly obtained from non-controlled prospective studies with small sample sizes and, at times, it is difficult to compare results between studies as the endpoints, and their definitions vary. There is a need to fully assess the effectiveness of PDT through RCTs comparing PDT to surgery, chemotherapy, radiation therapy, and brachytherapy, in both early-and late-stage lung cancers. # ONGOING TRIALS PDT could be considered as a treatment option for patients with medically inoperable early-stage disease that is accessible by bronchoscopy. Evidence to date suggests that PDT may be most effective with small, superficial airway lesions, 1cm or less in length. The relative safety and effectiveness of PDT compared to radiotherapy, an alternative treatment for patients with inoperable early-stage disease, remains undefined. In locally advanced and symptomatic lung cancer PDT, with or without radiotherapy, can contribute to the relief of airway obstruction and hemoptysis, but it has not shown a survival advantage when compared with current treatments such as Nd:YAG laser therapy or radiotherapy alone. There is a role for PDT in the palliation of advanced lung cancer; however, this is not well defined in relation to other modalities of palliation. Serious adverse effects including fatal hemoptysis and respiratory failure can occur; therefore, the suitability of patients for this treatment should be carefully assessed. Since tumour necrosis can result in post-treatment airway obstruction, patients should be closely monitored after undergoing the procedure and toilet bronchoscopies repeated as indicated. for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each clinical practice guideline report, through the routine periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original clinical practice guideline information. The Evidence-based Series: A New Look to the PEBC Practice Guidelines Each Evidence-based Series is comprised of three sections. Section 1: Clinical Practice Guideline. This section contains the clinical recommendations derived from a systematic review of the clinical and scientific literature and its interpretation by the DSG or GDG involved and a formalized external review by Ontario practitioners. Section 2: Systematic Review. This section presents the comprehensive systematic review of the clinical and scientific research on the topic and the conclusions reached by the DSG or GDG. Section 3: Guideline Development and External Review: Methods and Results. This section summarizes the guideline development process and the results of the formal external review by Ontario practitioners of the draft version of the clinical practice guideline and systematic review. # DEVELOPMENT OF THIS EVIDENCE-BASED SERIES Development and Internal Review This evidence-based series was developed by the Lung Cancer DSG of CCO's PEBC. The series is a convenient and up-to-date source of the best available evidence on the role of PDT in patients with NSCLC, developed through systematic review, evidence synthesis, and input from practitioners in Ontario. The systematic review on this topic is reported in Section 2 of the Series and describes the body of relevant clinical evidence and the interpretation of this evidence by members of the DSG. The final recommendations developed by the Lung DSG and approved by the DSG and the Practice Guidelines Coordinating Committee (PGCC) are summarized in Section 1 of the Series. # External Review by Ontario Clinicians An earlier version of this practice guideline and systematic review, dated February 26, 2002, was circulated to 114 Ontario clinicians for feedback. Box 1 summarizes the draft clinical recommendations and supporting evidence that was circulated to clinicians from the earlier version. # BOX 1: DRAFT RECOMMENDATIONS (approved for external review February 26, 2002) Target Population These recommendations apply to adult patients with primary, non-small cell lung tumours. The lack of sufficient high quality evidence precludes definitive recommendations. Instead, the Lung Cancer DSG offers the following opinions based on the evidence reviewed Photodynamic therapy could be considered as an option for the treatment of early stage lung cancer in patients with medically inoperable disease that is accessible by bronchoscopy. Evidence to date suggests that photodynamic therapy may be most effective with small superficial airway lesions, 1cm or less in length. The relative safety and effectiveness of photodynamic therapy compared to radiotherapy, an alternative treatment for patients with inoperable early stage disease, remains undefined. In locally advanced and symptomatic lung cancer, photodynamic therapy can contribute to the relief of airway obstruction and hemoptysis, but its role is, as yet, not well defined in relation to other modalities of palliation. Serious adverse effects including fatal hemoptysis and respiratory failure can occur; therefore, the suitability of patients for this treatment should be carefully assessed. Since tumour necrosis can result in post-treatment airway obstruction, patients should be closely monitored after undergoing the procedure and toilet bronchoscopies repeated as indicated. Key Evidence Ten non-controlled studies and one summary paper reporting on the use of photodynamic therapy in early stage lung cancer patients, who generally could not tolerate surgery or refused surgery, showed that photodynamic therapy commonly leads to tumour regression. The reported five-year survival rates in these patients varied from 43.4% to 72%. In patients with late stage lung cancer, three randomized controlled trials and four noncontrolled studies showed that photodynamic therapy could contribute to the palliation of local cancer-related symptoms. Of the three randomized trials, two comparing photodynamic therapy with Nd:YAG laser therapy and one comparing photodynamic therapy plus external beam radiotherapy with external beam radiotherapy alone, none detected a survival advantage for photodynamic therapy; however, photodynamic therapy did produce improved pulmonary symptom control. There was a significant improvement in the control of hemoptysis and the relief of dyspnea for patients receiving photodynamic therapy plus radiotherapy compared with those receiving radiotherapy alone. The most common adverse effect reported in all studies was photosensitivity, which consisted mostly of sunburn. The most serious adverse effects reported were respiratory failure and hemoptysis. The former, resulting from airway edema and tumour necrosis, led to mechanical ventilation in three of 67 patients with early stage lung cancer (two studies). Fatal hemoptysis occurred within one month of treatment in seven of 213 patients (two studies), three with early stage disease and four with locally advanced lung cancer. Three of 20 patients with locally advanced lung cancer also suffered from fatal hemoptysis between two and 18 months post-treatment. The role of photodynamic therapy in producing late fatal hemoptysis is uncertain. Contraindications for photodynamic therapy include porphyria or known allergies to porphyrins, tumours that impact on major blood vessels, and existing tracheoesophageal fistulas. Feedback was obtained through a mailed survey of 114 practitioners in Ontario (37 medical oncologists, 22 radiation oncologists, 29 surgeons, 25 respirologists, and one hematologist). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed out on February 26,2002. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Lung DSG reviewed the results of the survey. Sixty-five responses were received out of the 114 surveys sent (57% response rate). Responses include returned completed surveys as well as phone, fax, and email responses. Of the practitioners who responded, 47 indicated that the report was relevant to their clinical practice, and they completed the survey. Key results of the practitioner feedback survey are summarized in Table 5. # Missin g The rationale for developing an evidence summary, as stated in the "Choice of Topic" section of the report, is clear. There is a need for an evidence summary on this topic. 31 (66%) 10 (21%) 5 (11%) 1 (2%) The literature search is relevant and complete in this evidence summary. I agree with the methodology used to summarize the evidence. I agree with the overall interpretation of the evidence in the evidence summary. 41 (87%) 3 (6%) 1 (2%) 2 (4%) The Opinions of the Disease Site Group section of this evidence summary is useful. # Summary of Written Comments Thirteen respondents (28%) provided written comments. The main points contained in the written comments were: 1. Evidence for the use of PDT in lung cancer is limited. 2. This technique is not currently widely available and, unless funding for the photosensitizer and laser equipment is provided, it will not be possible to use the information contained in this evidence summary. 3. Evidence for the use of PDT as standard care for patients with early inoperable lung cancer or advanced lung cancer is unconvincing. Modifications/Actions 1. The Lung DSG agreed that the current evidence for the use of PDT is limited; however, the Lung DSG felt that it was appropriate to summarize the available evidence on this procedure to date. 2. The Lung DSG acknowledged the current, limited availability of PDT as a treatment option and noted the following: a) This evidence summary could have an impact on the provincial decision regarding funding for Photofrin ®. b) The establishment of PDT centres in the province is currently under consideration. 3. Although the current evidence for the use of PDT is limited, the Lung DSG felt that it was sufficient to support this procedure as one of several treatment options for inoperable lung cancer. # Practice Guidelines Coordinating Committee Approval Process The evidence summary report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval. All 11 members of the PGCC returned ballots. Six PGCC members approved the evidence summary report as written, three members approved the report as written and provided suggestions for consideration by the Lung DSG, and two members approved the report conditional on the Lung DSG addressing specific concerns. The Lung DSG responded to the PGCC concerns as detailed below and the evidence summary was subsequently approved. The PGCC noted that the evidence for PDT appears to be of a preliminary nature. They asked if response to radiotherapy was comparable to that obtained with PDT and questioned whether PDT as a treatment option should routinely be considered in early stage lung cancer. The PGCC indicated that the evidence for PDT in advanced disease was limited with only one small published RCT and one abstract report of an RCT available. They felt that substantial critical appraisal of this evidence was lacking. The PGCC also suggested that the very severe toxicities that occurred in a small number of patients were understated. The Lung DSG agreed that the evidence for PDT is generally not of high quality and indicated that it did not propose PDT as a treatment option to be routinely used in early stage lung cancer. However, the five-year survival data obtained in studies of early stage disease (43% to 72%) rivals that generally obtained using external beam radiotherapy in medically inoperable patients. In patients with poor respiratory function and early stage disease that is treated with surgery or external beam radiotherapy, lung tissue is lost and this may preclude definitive interventions. For these reasons, PDT could be considered as the treatment option of choice in a small population of patients. The Lung DSG believes the data do support the fact that PDT can relieve airway obstruction in a significant proportion of patients with late stage lung cancer. Although PDT is only one of a number of treatment options for bronchial obstruction, it may be the most useful approach to symptom palliation in some circumstances, e.g., where tumours have become resistant to external beam radiotherapy or where the bronchial lumen is completely blocked and the tumour cannot be accessed for brachytherapy or Nd:YAG laser therapy. The Lung DSG acknowledged the serious toxicities experienced by some patients but felt that these were clearly indicated in the evidence summary, particularly in the Opinions section of the document SUMMARY. # Peer-Review Feedback When the Evidence Summary Report was submitted to a journal for publication, one reviewer questioned the inclusion of the study by Friedberg et al because it involved intraoperative pleural PDT rather than endobronchial PDT. The authors acknowledged that PDT is generally administered endobronchially; however, other forms of PDT administration are considered of interest for treatment of patients with NSCLC and these were not excluded from the Evidence Summary Report. patients in the radiotherapy alone group. # RELATED PRINT AND ELECTRONIC PUBLICATIONS - One trial reported a significantly longer survival time for PDT (265 days vs. 95 days, p=0.007). - One trial reported similar response rates between the two treatment groups. Another trial found significant differences in response rate at 1 month between PDT (61%) and Nd:YAG laser resection (35%, p<0.05). The same trial also found a significantly longer time elapsed to failure in favor of PDT (50 days vs. 38 days, p=0.03). - One trial found that both FVC (mean difference=0.47 vs. - The 5-year OS rates of patients with <1.0 and ≥1.0 cm lesions were 57.9% and 59.3%, respectively. The difference was not significant (p=0.207). - The overall complete response rate was 83.3% (95 of 114 lesions). The complete response rates were 92.8% (77 of 83 lesions) for patients with lesions <1.0 cm and 58.1% for patients with lesions ≥1.0 cm (18 of 31 lesions). The difference was significant (p<0.001). Local Recurrences after complete response were observed in 9 of 77 lesions <1.0 cm (11.7%) and 3 of 18 lesions ≥1.0 cm (16.7%). # CONFLICT OF INTEREST The primary authors of this guideline report declared no potential conflicts of interest. # JOURNAL REFERENCES # THE PROGRAM IN EVIDENCE-BASED CARE The Program in Evidence-based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO) (1). The PEBC mandate is to improve the lives of Ontarians affected by cancer, through the development, dissemination, implementation, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer care. The PEBC supports a network of disease-specific panels, called Disease Site Groups (DSGs) and Guideline Development Groups (GDGs), mandated to develop the PEBC products. These panels are comprised of clinicians, methodologists, and community representatives from across the province. The PEBC is well known for producing evidence-based practice guideline reports, using the methods of the Practice Guidelines Development Cycle (1,2). The PEBC reports consist of a comprehensive systematic review of the clinical evidence on a specific cancer care topic, an interpretation of and consensus agreement on that evidence by our DSGs and GDGs, the resulting clinical recommendations, and an external review by Ontario clinicians in the province # DOCUMENT ASSESSMENT AND REVIEW RESULTS # Question Considered - What is the role for PDT in the management of early stage lung cancer? 2. What is the role for PDT in the palliation of patients with symptomatic, locally advanced lung cancer? The outcomes of interest were response rate, survival, and toxicity. Palliation of symptoms was also of interest for locally advanced lung cancer. # Literature Search and New Evidence The new search (June 2005 to October 2013) yielded 2 practice guidelines, 1 systematic review, and 4 full text publications of non-controlled prospective studies. Additional searches on clinicaltrials.gov, ASCO, the Cochrane Library, the Canadian Medical Association Infobase, and the National Guidelines Clearinghouse yielded no results. Brief results of these publications are shown in the Document Review Summary and Tool. # Impact on Guidelines and Its Recommendations The The outcomes of interest were response rate, survival, and toxicity. Palliation of symptoms was also of interest for locally advanced lung cancer. Target Population: This evidence-based series applies to adult patients with primary, non-small cell lung tumours. # Study Section Criteria: Inclusion Criteria Fully published reports or abstracts that met the following criteria were selected for inclusion: 1. Systematic reviews, practice guidelines, randomized controlled trials (RCTs) or noncontrolled prospective studies of PDT using porfimer sodium (Photofrin®), alone or in combination with other therapies, for the treatment of stages I through IV primary, nonsmall cell lung cancers. - Outcomes of survival, response rate, or toxicity were reported, or for locally advanced lung cancer, the outcome of symptom palliation was reported. # Guidelines Working Group Recommendations References German Respiratory Society and the German Cancer Society - The use of photodynamic therapy (PDT) in palliative treatment of lung cancer is only slightly superior to conventional laser. With the currently available sensitizers, the quality of life of patients is disproportionately affected by skin sensitization. As a result, PDT can hardly be recommended for palliation. (Grade of recommendation: Weak) - PDT is the most effective method for eradication of early tumors that are limited to the mucosa and less than 1 cm in diameter. (Grade of recommendation: Weak) - One trial reported no differences in mortality rates or survival times between PDT + radiotherapy (444 days) and radiotherapy alone (445 days). - One trial reported a significantly greater reduction of haemoptysis and shortness of breath, and cough at 1 and 3 months for PDT + radiotherapy (p<0.05). There was also a significant difference in the median interval between treatment and local recurrence (PDT + radiotherapy=233 days vs. radiotherapy=107 days, p=0.005). There were 14 of 20 patients in the PDT + radiotherapy group achieving complete bronchial lumen re-opening vs. 2 of 21 Fayter et al., # OUTCOMES DEFINITION - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of our website, each page is watermarked with the word "ARCHIVED". - ENDORSED -An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. # DELAY - A delay means that there is reason to believe new, important evidence will be released within the next year that should be considered before taking further action. # UPDATE - An update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.

What is the optimal post-orchidectomy management strategy for stage I testicular seminoma? Outcomes of interest include cancer-specific survival, long-term toxicity (including second malignancy), and quality of life. # TARGET POPULATION Adult patients with stage I testicular seminoma. # RECOMMENDATIONS AND KEY EVIDENCE The DSG recommends surveillance as the preferred option, because adjuvant therapy is associated with important short and long-term toxicities and second malignancy risks with no evidence of improved survival. - Surveillance or adjuvant therapy (radiation therapy ultimately yields equivalent disease control in stage I seminoma. - Patients should be informed of all treatment options, including the potential benefits and side effects of each treatment. A table of benefits and risks associated with each management option is available in Section 1: Appendix A. - A treatment plan should be developed that includes the patient's preferences and clinical judgement of that specific case. # Qualifying Statements - The minimum surveillance program should be a physical examination every three to four months, chest X-ray every six to twelve months, and computerised tomography (CT) of the abdomen and pelvis every three to four months in the first three years and then less often thereafter. - In addition, follow-up should include appropriate investigations of sites at risk of relapse. This approach can be based on the risk of relapse with the frequency as suggested in the evidence-based guidelines outlined by Martin et al. (1). - When a primary surveillance approach is adopted, patients should be informed of their estimated risk of recurrence and the need for frequent surveillance as described above. - Prognostic factors for relapse on surveillance have been identified (tumour size, rete testis invasion) and low, intermediate, and high-risk groups for disease progression defined. This has led to the introduction of a risk-adapted approach by some groups. However, the prognostic model underlying this risk-adapted strategy has not been prospectively validated. In addition, the risk stratification provided is limited, as even in the highest risk group over 65% of patients do not require additional therapy after orchidectomy. Thus, a risk-adapted approach cannot be recommended at this time. - Due to the low incidence of testicular cancers, management is best performed in a multidisciplinary environment within centres familiar with the management of the disease. # Key Evidence - Data from large prospective randomized controlled trials (RCTs) and large prospective cohorts of stage I seminoma patients identified in a systematic review of the evidence indicate that overall survival at five years is greater than 95%, regardless of the initial treatment strategy adopted. The challenge remains to define the optimal management approach to minimize toxicity while maintaining excellent results. - Data from large prospective cohorts of primary surveillance identified in a systematic review of the evidence indicate that surveillance is safe and that 80-85% of patients do not require any post-orchidectomy treatment. In addition, when a policy of routine radiation therapy (RT) for relapse is utilised, there is no increase in the proportion of patients requiring systemic chemotherapy compared to those treated with adjuvant RT. For patients who prefer immediate treatment, or who are unsuitable for primary surveillance, adjuvant RT is the recommended option. - When adjuvant RT is the preferred option, a radiation dose of at least 20 Gy and no more than 30 Gy is recommended. - When adjuvant RT is the preferred option, para-aortic and extended-field (i.e., "dogleg") RT are equivalent in prevention of para-aortic recurrence, but are different in terms of short-and long-term toxicity and follow-up requirements. - In patients treated with adjuvant therapy, post treatment monitoring for disease relapse is still necessary. Except in the specific case of extended-field radiotherapy, the follow-up after adjuvant therapy should be as thorough as the surveillance conducted in the absence of adjuvant therapy. # Qualifying Statements - If adjuvant therapy is planned, sperm banking (and scrotal shielding with RT) should be offered if future fertility is of concern to the patient. - With extended-field RT, there is evidence from RCTs and non-randomized trials (2)(3)(4)(5)(6)(7) that the risk of pelvic recurrence is greatly reduced, and therefore regular abdominal/pelvic computerized tomography (CT) is not necessary as part of the ongoing surveillance/follow-up program. - With para-aortic RT, the continuation of pelvic CT scanning on a routine basis is necessary. However, there is also evidence that short-term toxicity is reduced with paraaortic RT compared to extended-field RT. This trade-off should be discussed with the patient as part of the decision-making process. - The main concern with adjuvant RT is the potential for the induction of second nontesticular malignancies. In addition, long-term survivors of testicular seminoma treated with adjuvant RT are at an excess risk of death as a result of cardiac disease. These toxicities should be discussed fully with the patient. # Key Evidence - An RCT (2) compared 20 Gy to 30 Gy in a non-inferiority design and found no difference in relapse-free survival between the methods (hazard ratio for relapse, 1.11; 90% confidence interval 0.54 to 2.28; log rank p=0.81). - An RCT (3) compared para-aortic to "dogleg" radiotherapy in a non-inferiority design, and found no difference in three-year relapse-free survival. - Evidence from RCTs (2,3) supports the conclusion that para-aortic RT leads to a greater risk of pelvic recurrence but also less short-term toxicity than does extended-field RT. This has also been confirmed in non-randomized trials (8-10). - Twelve population-based studies (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) demonstrated a consistent increase in the risk of second malignancy associated with RT compared to population expected rates. The largest of these (18,19) combined fourteen population-based registries including 10,534 patients with seminoma (all stages) treated with RT and no chemotherapy who had at least 10 years follow-up. Compared with matched cohorts from corresponding registries, the overall relative risk for a second non-testicular malignancy was 2.0 (95% CI, 1.8-2.2). For a 35-year-old patient with seminoma (most treated with RT), the cumulative 40-year risk of a second malignancy was 36%, compared with 23% in the normal population. Another study compared 5,265 stage I seminoma patients treated with adjuvant RT against 1,499 patients managed with surveillance and found a second malignancy observed-to-expected ratio of 1.93 (p<0.05) (1, 21). - Two studies addressed the cardiac toxicity associated with RT. In the MD Anderson series (23), 453 patients treated between 1951 and 1999 had a standardized cardiac mortality ratio of 1.80 (95% CI, 1.01-2.98) after 15 years if only infradiaphragmatic and no mediastinal RT was used. A similar increase in cardiac events (risk ratio, 2.4 was reported in a cohort of 992 patients treated at the Royal Marsden Hospital (2,24). The etiology of this effect is currently unclear. When neither surveillance nor RT is suitable, adjuvant chemotherapy is the preferred option. Single-agent carboplatin is typically used. - In patients treated with adjuvant therapy, post-treatment monitoring for disease relapse is still necessary. The follow-up after adjuvant therapy should be as thorough as the surveillance conducted in the absence of adjuvant therapy. # Qualifying Statements The follow-up of patients treated with carboplatin in a randomized trial ( 4) is still relatively short, and the long-term toxic effects of carboplatin are not yet fully known. Additionally, evidence from the randomized trial suggests that the risk of para-aortic recurrence is sufficiently high to warrant abdominal/pelvic CT on a regular basis. The use of carboplatin may be restricted to specific situations outside a clinical trial, for instance where adjuvant therapy is preferred and there is a contraindication to RT. Patients should be informed of these possible risks in order to fully consider their options, particularly in comparison to surveillance. - The authors suggest that the optimal dose is not yet known and may be higher than that used in the trial. # Key Evidence - An RCT ( 4) compared RT at 20 Gy or 30 Gy with a single cycle of carboplatin (area under curve =7) in a non-inferiority design, and found no difference in three-year relapse-free survival (HR, 1.28; 90% CI, 0.85-1.93; p=0.32). Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Guideline Questions a) What is the optimal chemotherapy for patients with multiple myeloma? b) In terms of survival, is peripheral blood stem cell or autologous bone marrow transplantation better than conventional chemotherapy? c) What is the relative efficacy of autologous and allogeneic transplantation? d) What specifics of the transplant manoeuvre can be recommended? e) When should transplantation be performed? f) Who should (should not) be transplanted?These recommendations apply to adult patients with advanced-stage multiple myeloma and good performance status.Update Autologous transplantation is recommended for patients with advanced-stage myeloma and good performance status. The evidence is strongest for patients under 65 years of age without significant renal dysfunction following hydration and remission-induction chemotherapy. Physicians must use their clinical judgement in recommending transplantation to patients over 65 years of age or those with renal impairment.There is insufficient evidence to recommend allogeneic transplantation as routine therapy for multiple myeloma. Patients who are potentially eligible for transplantation should be referred for transplant assessment early after diagnosis and should not be given extensive exposure to alkylating agents such as melphalan prior to the collection of stem cells. High-dose EBS 6-6 VERSION 2 vi glucocorticoid-based regimens such as vincristine, doxorubicin (Adriamycin), dexamethasone (VAD) are preferable for such patients. Harvesting of autologous peripheral blood stem cells or bone marrow should be performed early in the patient's treatment course. The best available data demonstrate that transplantation is most advantageous when performed as part of the initial therapy.No conclusions can be reached about the role of interferon alpha following transplantation at this time.For patients undergoing autologous stem cell transplantation as part of standard therapy, it is recommended that the transplantation regimen include melphalan 200 mg/m 2 without total body radiation. There is insufficient evidence to recommend a treatment plan that includes two transplants performed in succession (tandem transplantation) outside of a clinical trial.# 4. What specifics of the transplant manoeuvre can be recommended? 5. When should transplantation be performed? 6. Who should (should not) be transplanted? # Literature Search and New Evidence The new search (2003 to September 2010) yielded 37 relevant new publications. Brief results of these publications are shown in the Document Assessment and Review Tool (Appendix 1) at the end of this report. # Impact on Guidelines and Its Recommendations The newly identified evidence supports the existing recommendations. Hence, the Hematology DSG ENDORSED the 2003 guideline and recommendations on optimal therapy for patients diagnosed with multiple myeloma and the role of high-dose chemotherapy and stem cell support. It was noted that the new search yielded a substantial amount of new evidence that informs the questions of optimal induction therapy prior to transplantation that may warrant further discussion/revision of the document. melphalan did not find a difference in terms of response and two-year event-free survival, but toxicity was significantly greater for patients receiving the total body regimen; two RCTs in abstract form of single versus double bone marrow transplantation did not find a significant difference in progression-free survival or overall survival between the two groups; An RCT on interferon following transplantation found that there was a non-significant trend towards longer median progression-free survival in the patients given interferon (46 months vs. 27 months; p=0.11); however, there was no difference in overall survival. One randomized controlled trial on early versus late transplantation found the median survival was 64.6 months for early transplant, and 64 months for late transplantation (p=0.92). The quality of life measure, TWISTT (time-without symptoms, treatment and treatment toxicity) was 27.8 months (95% CI, 23.8 to 31.8) in the early transplant group versus 22.3 months (95% CI, 16.0 to 28.6) in the late transplant group. Three non-randomized comparisons of autologous and allogeneic transplantation found autologous transplantation to be less toxic and associated with at least equivalent survival. # Update In an updated report of the randomized trial comparing combination therapy with melphalan 140 mg/m 2 and total body radiation with melphalan 200 mg/m 2 as a single modality, survival at 45 months was superior in the group assigned to receive melphalan 200 mg/m 2 (65.8% vs. 45.5%; p=0.05). In addition, patients assigned to receive melphalan 200 mg/m 2 experienced less severe mucositis, required fewer transfusions, and had shorter durations of hospitalization and intravenous antibiotics administration. In addition to the single RCT comparing high-dose therapy and stem cell transplantation with conventional chemotherapy identified in the original document, three more RCTs have been published. Two of the four studies reported a survival benefit for patients randomized to receive high-dose therapy and autologous stem cell transplantation. For further information about this practice guideline report, please contact Dr. What is the optimal chemotherapy for patients with multiple myeloma? b) In terms of survival, is peripheral blood stem cell or autologous bone marrow transplantation better than conventional chemotherapy? c) What is the relative efficacy of autologous and allogeneic transplantation? d) What specifics of the transplant manoeuvre can be recommended? e) When should transplantation be performed? f) Who should (should not) be transplanted? Problem/Scenario A 58 year old man presents with fatigue, back pain, and weight loss and is diagnosed with multiple myeloma with multiple lytic bone lesions. He is in good general health with normal renal function. He has two living siblings. # II. CHOICE OF TOPIC AND RATIONALE Multiple myeloma is an aggressive cancer with a median survival time of three years (1). Median survival varies from one year to over five years, depending on the stage of disease. Conventional chemotherapy with oral melphalan and prednisone or multi-agent intravenous chemotherapy can provide effective palliation, but is not curative (2). Peripheral blood stem cell and bone marrow transplantation have established roles in a number of hematologic malignancies including Hodgkin's disease and non-Hodgkin's lymphoma (3). Case series reports have described encouraging results when patients with myeloma are treated with allogeneic (alloBMT) or autologous bone marrow transplantation (ABMT) (4). These data suggest that transplantation may have an important role in treating patients with myeloma. Stronger evidence evaluating transplantation, including a recently published randomized trial, is emerging (5,6). It was the impression of members of the Hematology Disease Site Group (DSG) that there are widely disparate practices regarding the use of transplantation for multiple myeloma in different parts of the province. This impression was reinforced by differing availability of transplantation throughout the province. The variability in practice together with emerging evidence of higher quality made the assessment of this topic a priority for the Hematology DSG. # III. METHODS Guideline Development This practice guideline report was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-Based Care, using the methods of the Practice Guidelines Development Cycle 1. Evidence was selected and reviewed by one member of the PGI's Hematology DSG and methodologists. The practice guideline report is a convenient and up-to-date source of the best available evidence on multiple myeloma, developed through systematic reviews, evidence synthesis and input from practitioners in Ontario. The body of evidence in this report is primarily comprised of mature randomized controlled trial data; therefore, recommendations by the DSG are offered. The report is intended to promote evidence-based practice. The PGI is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. External review by Ontario practitioners was obtained through a mailed survey for the original practice guideline dated August 10, 1999. The survey consisted of items asking for ratings on the quality of the draft practice guideline and whether the draft recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC). The PGI has a formal standardized process to ensure the currency of each guideline report. This process consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. This guideline was subsequently updated and reviewed by the PGCC in October 2000. # Guideline History This practice guideline report was originally completed on December 22, 2000 # Literature Search Strategy MEDLINE, CANCERLIT and the Cochrane Library databases were searched from 1992 to December 1997. This search was updated in October 1998, June 1999, and April 2000. "Multiple myeloma" (MeSH and text word) was combined with "bone marrow transplantation" (MeSH and text word) and drug therapy (MeSH). These terms were then combined with the search terms for the following study designs: practice guidelines, systematic reviews or meta-analyses, reviews, randomized controlled trials, controlled clinical trials and comparative studies. In addition, Pubmed, the Physician Data Query (PDQ) database (), relevant conference proceedings (American Society of Hematology, 1997Hematology, 1998Hematology, 1999 and American Society of Clinical Oncology, 1999), article bibliographies and personal files were reviewed. To address the issue of optimal chemotherapy, an additional search was performed of the same databases using "multiple myeloma" (MeSH) combined with "randomized controlled trials" (MeSH) and the text word "random:" in the title. The original literature search has been updated using MEDLINE (Ovid) (through March 2003), Medline® In-Process & Other Non-Indexed Citations (formerly known as PreMedline) (PREM) ( March 13, 2003), CANCERLIT (Ovid) (through October 2002), the Cochrane Library (2003, Issue 1), the proceedings of the annual meetings of the American Society of Clinical Oncology (2000 to 2002) and the American Society of Hematology (2001 and # Inclusion Criteria Articles were selected based on the following criteria: 1. Randomized controlled trials (RCTs) of patients with multiple myeloma that reported on the outcomes of survival and/or quality of life. 2. Non-randomized trials were included if they had appropriate contemporaneous control groups and reported on the outcomes of survival and/or quality of life. Study results were used to estimate both the potential efficacy and appropriate timing of autologous and allogeneic transplantation. Meta-analyses, systematic reviews and economic analyses were also included. Because of insufficient data addressing the specifics of the transplant manoeuvre and which patients would be most likely to benefit from transplantation, a second literature search was performed to include data from single-arm studies. As of the June 2003 guideline update, only RCT data will be included except for the questions addressing the relative efficacy of autologous and allogeneic transplantation and pretransplant chemotherapy. In addition, updated data for nonrandomized trials already included in the guideline will be reported. # Synthesizing the Evidence As the nine randomized controlled trials on transplantation addressed different questions, statistical pooling of data was not attempted. The DSG recognizes that the pooling of data comparing standard-dose therapy with highdose therapy and autologous transplantation may be feasible. The DSG will review whether conducting a published data meta-analysis is appropriate when the results of recently reported abstract publications are reported in article form. # IV. RESULTS # Literature Search Results Sixty-nine papers met the criteria for inclusion (Table 1). Four meta-analyses, one comparing multi-agent chemotherapy to melphalan and prednisone (2), the second individual patient data meta-analysis of 27 trials that compared combination chemotherapy versus melphalan and prednisone (7), and two evaluating the role of interferon were identified (8,9). Thirty randomized controlled trials comparing multi-agent chemotherapy to melphalan and prednisone were identified. Twenty-seven of these were included in the individual patient data meta-analysis (7). Three economic analyses were also found (47,63,64). Nine additional randomized controlled trials were identified (5,44,(51)(52)(53)(54)(55)(56)65). Two RCTs (5,44), one of which was an abstract (44), compared ABMT versus conventional chemotherapy and addressed the question of who should be transplanted. Six RCTs addressed the question of specifics of the manoeuvre (51)(52)(53)(54)(55)(56), five of which were in abstract form (51)(52)(53)(54)(55). Of these six, one compared bone marrow to peripheral blood as a source of stem cells (51), one compared CD34+ selected versus unselected autologous peripheral blood progenitor cells (52), one assessed the role of total body irradiation (53), two trials compared single versus double autologous transplants (54,55), and one trial addressed the role of interferon following transplantation therapy (56). One RCT compared bone marrow versus peripheral blood stem cell transplantation published in abstract form (65). Nineteen non-randomized comparative studies were found: three studies on autologous transplantation versus conventional chemotherapy (6,45,46), three studies on the relative place of allogeneic and autologous transplantation (48)(49)(50), four studies on age of patients and transplantation (57)(58)(59)(60), one of which is published in abstract form (60), one study of melphalan and stem cell support (66) and one comparing early versus delayed autologous transplantation published in abstract form (67), and seven studies (68)(69)(70)(71)(72)(73)(74) addressing the issue of age or renal function in autologous transplantation, five of which are published in abstract form (69,70,(72)(73)(74). Four single-arm studies were found: two addressed the effect of prior chemotherapy on the yield of stem cell collection (61,62) and the other two, published in abstract form (75,76), addressed the upper age limit for transplantation. In each section below, we describe the studies, summarize the results and provide an interpretative summary. From the updating process, 26 relevant reports were identified and included 22 reports of results from randomized trials (16 published in abstract form (1u-15u,16u) and seven published in article form (17u-23u)), two retrospective cohort comparisons published in article form (24u,25u), and one cohort study (26u). The cohort study was included because it updated results from a nonrandomized comparison reported in the original guideline. The article by Attal and Harousseau (19u), considered a full report but is published in a non-peer-reviewed journal, contains results of four randomized trials included in this guideline. Also included are studies that were originally identified as ongoing trials but now have available data (1u,4u,5u,8u,9u,13u-16u,18u,19u,22u,23u) All included studies are categorized by study question and are referenced in Table 1. The present version of the guideline consolidates the original and update tables in each section, seen in previous updates of this guideline, into one table for that section. # Quality Assessment Update Of the RCTs located in the June 2003 guideline update (14u-19u,23u), one trial (23u) indicated that a minimization algorithm was used for randomization, but no other trials reported information on the randomization method or procedure. No trials provided any, or adequate, information on allocation concealment or any information on blinding. Seven trials (15u,17u,19u) indicate that patient characteristics were similar or listed the similar characteristics between randomized groups, two trials (18u,23u) provided the baseline characteristics without indicating whether the groups were similar, one trial (16u, abstract) only provided information on median age and gender, and one trial (14u, abstract) did not provide information on patient characteristics between groups. Use of a power calculation was stated in two trials (18u,23u), but the studies may not have been sufficiently powered for the analysis of those outcomes. Five trials (14u,17u,18u, 19u,23u) provided enough information to indicate that an intention-to-treat analysis was used, but only two trials (17u,19u) indicated that all randomized patients were analyzed for at least one outcome. Information on withdrawals, patient exclusions, and protocol adherence was more extensively reported in some trials (17u,18u,23u); three trials that provided minimal (e.g., reasons for inevaluable patients for one outcome) or no information were in abstract form (14u-16u). One report of four trials (19u) provided some information (e.g., eligibility for randomization or patients who received allocated therapy). One trial (23u) was funded in part by a pharmaceutical company, three trials (14u,17u,18u) had funding from non-pharmaceutical agencies, and five trials (15u,16u,19u) did not report funding information. Of all those trials, five (14u,17u,19u) were updated reports of trials reported in the original guideline. # (a) What is the optimal chemotherapy for patients with multiple myeloma? To properly compare transplantation to conventional chemotherapy, we have attempted to define the optimal conventional chemotherapy. Melphalan plus prednisone has been standard therapy for myeloma for over 25 years (1). Patients treated with this regimen have a median survival time of about three years. In an effort to improve outcome, more aggressive multi-drug regimens have been developed. These regimens generally consist of a combination of one or more alkylating agents (usually melphalan, BCNU, or cyclophosphamide) in combination with vincristine, and an anthracycline. Evidence from one individual patient data meta-analysis of 27 trials, one metaanalysis of 18 trials, an overview on interferon, and one meta-analysis on the role of maintenance treatment with interferon are discussed below. # Chemotherapy meta-analyses An individual patient data meta-analysis of 27 trials comparing combination chemotherapy versus melphalan and prednisone was recently published by the Myeloma Trialists' Collaborative Group (7). Individual patient data were supplied from 20 of the trials (4930 patients) (10,11,15,16,20,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), including one unpublished trial (IMMSG M-80). Published data were abstracted from reports of seven of the trials (1703 patients) (12)(13)(14)(17)(18)(19)23). Data could not be obtained from three trials (553 patients) (20,21,40). Overall, there was no significant difference in survival between patients allocated to combination chemotherapy versus melphalan and prednisone. The proportional reduction in the annual odds of death was 1.5% in favour of combination chemotherapy (95% CI, -8% to 5%; p=0.6). This translated into an odds ratio (OR) of 0.99 (95% Confidence Interval (CI), 0.93 to 1.05-reviewer's calculations). There was also no difference between the results of trials with individual patient data (OR=0.98; 95% CI, 0.92 to 1.04) and those for which published data were used (OR=1.03; 95% CI, 0.83 to 1.25,  2 for interaction=0.2; p=0.7). The test for heterogeneity was not significant (27 trials,  2 =31.9 with 26 degrees of freedom; p=0.2). The response rates were significantly higher with combination chemotherapy than with melphalan and prednisone (60.0% versus 53.2%; p<0.00001). A literature-based meta-analysis of 18 trials comparing melphalan and prednisone to combination chemotherapy was published by Gregory et al (2). That meta-analysis found that more aggressive multi-drug combination chemotherapy results in similar survival to melphalan and prednisone (OR=1.04; 95% CI, 0.90 to 1.19; p=0.61). # Interferon meta-analyses In an overview of 24 randomized trials published in abstract form (8), interferon increased recurrence-free survival by six months. The improvement in three-year survival was modest (4%). However, this slight clinical benefit must be weighed against cost (both financial and quality of life). In a meta-analysis by Trippoli et al (9), survival was measured by a unique measure called the 'mean lifetime survival'. Its method of analysis and interpretation is available in the paper (8). Using this survival endpoint, there was no significant improvement in survival between treated patients and controls (IFN=3.9 years vs. Control=3.4 years; p=0.095). # Interpretive summary No compelling evidence exists to indicate that a specific chemotherapy regimen is associated with a survival advantage in patients with myeloma. It is unlikely that melphalan plus prednisone is superior to multi-agent chemotherapy, particularly for patients with poor prognosis disease. For the purpose of assessing trials of transplantation, we consider multi-agent chemotherapy and melphalan and prednisone to be equivalent and that either regimen is an appropriate control group for randomized trials. There is no significant improvement in survival with the use of interferon. # Chemotherapy trials This topic was evaluated in the June 2003 update. Poenisch et al (15u) report in abstract form the results of the East German Study Group for Hematology/Oncology trial where 136 patients with myeloma in stage II in progression or stage III were randomized to bendamustine plus prednisone (BP) or melphalan plus prednisone (MP). No differences in probability of survival at 60 months post-diagnosis (BP, 28%, vs. MP, 23%, p=0.72) or response rates (75% vs. 68%, p=not provided; n=131) were detected between groups, but complete remissions were higher in the BP arm (32% vs. 11%, p<0.003). Data to October 31, 1998 for surviving patients from an RCT included in the individual patient meta-analysis in the original guideline report (38) were updated in a subsequent full report (17u); median survival was 32 versus 25 months and partial response was 45% versus 31.5% for the combination chemotherapy and melphalan plus prednisone groups, respectively (no p values between groups provided). # Interpretive Summary The original interpretation remains current. # (b) In terms of survival, is peripheral blood stem cell or autologous bone marrow transplantation (ABMT) better than conventional chemotherapy? # Randomized controlled trials The IFN 90 randomized trial published by Attal et al (5) compared conventional chemotherapy (n=100) with ABMT (n=100) in 200 previously untreated patients less than 65 years of age with clinical stage II and III myeloma. Those with another malignancy, poor cardiac, hepatic, or respiratory function, or psychiatric disease were excluded. Poor performance status and renal dysfunction were not reasons for exclusion at study entry, but did preclude transplantation if these did not improve after the fourth cycle of chemotherapy. Randomization occurred prior to any therapy. Conventional therapy consisted of 12 months of multi-agent chemotherapy with VMCP/BVAP (vincristine, melphalan, cyclophosphamide, and prednisone/ vincristine, carmustine, doxorubicin and prednisone) with interferon alpha three million units/m 2 three times weekly starting at cycle nine of chemotherapy and continuing until relapse. Patients randomized to transplantation received four to six cycles of VMCP/BVAP chemotherapy. Patients with a good performance status, serum creatinine of less than 150 μmol/L and an adequate bone marrow harvest collected after the fourth cycle of chemotherapy received a preparation regimen of melphalan 140 mg/kg and total body irradiation consisting of a total of 800 cGy in daily fractions over four days followed by re-infusion of autologous bone marrow. Interferon alpha three million units three times weekly was administered following hematologic recovery. The data were analysed according to an intention-to-treat model. Quality of life data were not presented. Seventy-four of the 100 patients assigned to transplantation completed therapy. Reasons for non-completion were insufficient bone marrow harvest (n=10), poor performance status (n=6), abnormal renal function (n=5), and premature death (n=5). Overall survival, median survival and response-to-treatment were all significantly better with ABMT (Table 2). A multivariate analysis showed that event-free survival correlated significantly with the pre-treatment -2 microglobulin (p<0.001) level and with treatment assignment (p=0.01). Survival correlated only with the pretreatment -2 microglobulin level (p<0.001). In patients under the age of 60 years, survival was correlated with both treatment assignment and -2 microglobulin level. In patients over the age of 60, this correlation was not found. In a randomized controlled trial published in abstract form (44), with a median follow-up of 56 months, median event-free survival and overall median survival were not significantly different for patients aged 55-65 with multiple myeloma who received high-dose therapy and autologous blood stem cell transplantation versus conventional treatment (VMCP regimen) (Table 2). # Non-randomized comparisons (NRCs) Three non-randomized studies (6,45,46) were identified which compared ABMT or peripheral blood stem cell transplant with controls or conventional therapy. All three found that survival was superior for patients who received autologous bone marrow or peripheral blood stem cell transplantation compared with controls (Table 2). # Economic analysis A cost-effectiveness analysis using survival data reported in five large published randomized controlled trials on induction treatment evaluated the incremental cost-effectiveness ratio (47). The mean lifetime duration of survival was 3.47 years for melphalan at conventional doses without interferon, 3.74 years for melphalan at conventional doses with interferon and 7.28 years for ABMT. Survival was significantly better for patients undergoing ABMT versus melphalan treatment (Relative risk reduction=54%, 95% Confidence Interval, 46% to 59%; p0.05). The marginal costeffectiveness ratio of autologous transplantation was approximately an additional $26 000 per life year gained compared with conventional treatment with melphalan. Economic analyses based on trials that collect data on cost as part of their primary data collection are less susceptible to methodological errors. This economic analysis collected and pooled data from information available in the published literature. Based on the critical appraisal done by the Guidelines Initiative, we have determined it to be methodologically rigorous (77). Therefore, the impact of ABMT compared with conventional treatment with melphalan can be considered to be favourable in terms of cost-effectiveness ratio. # Interpretive summary Based on the results from the two RCTs (5,44), ABMT results in prolonged progression-free survival and overall survival compared with conventional chemotherapy for newly diagnosed patients under the age of 65 with advanced stage myeloma. However, a subset analysis conducted on data from Attal's randomized controlled trial showed that the survival benefit was confined to patients < 60 years of age. The second randomized controlled trial (44) did not show a benefit for high-dose therapy and ABMT in older patients, however longer follow-up is needed. The impact of autologous transplantation on quality of life remains unclear. The DSG recognized that the conclusion to recommend autologous transplantation was based on one RCT. The results of the second RCT, presented in abstract form, required that this conclusion be reconsidered. The DSG concluded that assessment of more mature results of the Fermand study, presented in full article form for more comprehensive evaluation, are needed before modifying the current recommendation. Five abstracts (1u-5u) and three full reports (18u,19u,23u) of four RCTs comparing transplantation with standard-dose chemotherapy were identified (Table 2). One full report of a cohort study (26u) was identified; this study updates data of a previously published non-randomized comparison included in the original guideline. # Randomized controlled trials Child et al conducted the MRC Myeloma VII randomized trial comparing C-VAMP plus highdose melphalan and peripheral blood stem cell support (intensive treatment) with ABCM (standard treatment); interferon-alpha maintenance therapy was planned in both groups. Two abstracts (4u,5u) and one full paper (23u) report data from this trial; only data from the full report (23u) will be presented. Four hundred and seven previously untreated patients less than 65 years of age were randomized; the stage of myeloma was not provided. Fifty patients in the intensive treatment group did not receive high-dose melphalan and transplantation, some because of early disease progression; before the transplantation, eight patients in that group received total body irradiation plus melphalan in lieu of high-dose melphalan. Thirty-four patients in the standard treatment arm received an autograft or allograft. Four hundred and one patients were included in the intention-totreat analysis. The study was powered for 10% absolute increase in survival, which was not reached: absolute improvement was 9% (94 deaths vs. 122 deaths. The median progression-free survival (n=395) and the median overall survival were significantly longer in the intensive treatment group (Table 2). No data were provided on whether age was a prognostic factor, and the authors did not analyze outcomes in age subgroups. Blade et al (3u) reported in abstract form the results of a randomized trial conducted by the Spanish Cooperative Group, PETHEMA, comparing high-dose therapy and autologous transplantation with conventional chemotherapy. Previously untreated patients with stage II or III myeloma and an ECOG performance status of less than 3 initially received four courses of alternating BVMCP/VBAD. The median age of the enrolled patients was 56 years. Responding patients were then randomized to receive eight additional courses of that chemotherapy, or to a transplantation strategy consisting of either melphalan 140 mg/m 2 and total body radiation (12 Gy) or melphalan 200 mg/m 2. Maintenance therapy consisting of interferon alpha and dexamethasone was administered in both arms. From the initial cohort of 216 patients, 185 responded to initial chemotherapy and 164 were randomized (83 to the chemotherapy arm and 81 to autologous transplantation). Results are shown in Table 2; no differences in median progression-free or overall survival were detected. Attal and Harousseau (19u) updated the results from the IFM 90 trial reported in the original guideline (5). Patients allocated to ABMT had significantly better response rates than those allocated to conventional chemotherapy (Table 2). Seven-year event-free and overall survival rates for treatment versus control were 16% versus 8% and 43% versus 25%, respectively. Median eventfree and median overall survivals were also provided (Table 2). Event-free (p=0.01) and overall (p=0.03) survivals were significantly better with ABMT, but it is not clear whether the p values correspond to the median survival or the seven-year analyses or both. Segeren et al (1u,2u,18u) randomized 268 previously untreated, stage II or III patients to melphalan without stem cell support or a "myeloablative" strategy (cyclophosphamide, melphalan, total body radiation and autologous stem cell transplantation) in a HOVON group trial (Table 2). Median age of enrolled patients (n=379) was 55 years. By intention-to-treat analysis (n=261), no differences in median overall or median event-free survival were detected between groups, but the myeloablative group had significantly better complete response (Table 2) (18u). The analysis may not have been sufficiently powered to detect a difference in event-free survival because only one of two factors used in the power calculation was met. # Cohort study Barlogie et al (26u) provided updated results of their previously published non-randomized trial; however, no comparison group was included in the updated report. Of 231 patients (median age 51 years and 53% stage III), 195 received at least one autologous transplantation and 151 in sustained partial remission or complete remission received a second autologous transplantation, while 14 received an allotransplantation after the autotransplantation. In all 231 patients, median overall survival was 68 months, and median time to relapse/progression was 52 months. Complete and partial remission was 83%. # Interpretive Summary In the two RCTs published in full paper form comparing ASCT to conventional therapy (19u, 23u), survival was superior with transplantation. Two RCTs in abstract form (44, 3u) did not demonstrate a survival benefit, and one study (18u) was not felt to contribute to the analysis as it compared high-dose therapy plus stem cell support with high-dose therapy alone. # (c) What is the relative efficacy of autologous and allogeneic transplantation? Randomized trials comparing autologous and allogeneic transplantation have not been published. Three non-randomized comparisons have been found (Table 3). # Non-randomized comparisons One retrospective study with a matched case-control design compared the outcome of allogeneic and autologous transplants reported to the European Bone Marrow Transplant Registry (EBMTR) (48). Among cases reported to the Registry, 189 allogeneic sibling donor transplants were matched for gender and extent of prior chemotherapy with an equal number of autologous stem cell transplants. The allogeneic bone marrow transplants (alloBMT) took place between 1983 and 1994, while the autologous transplants were done between 1986 and 1994. The alloBMT patients were significantly younger than patients who underwent autologous stem cell transplantation (ASCT) (median 43 vs. 49 years; p=0.0001). Several different high-dose therapy regimens and graft-versus-host disease prophylaxis protocols were used. Alpha interferon was given to 96 (51%) ASCT patients but only nine (5%) alloBMT patients. The median survival was significantly longer for ASCT compared with alloBMT (34 months vs. 18 months; p=0.001). The overall survival at 24 months was 70% vs. 47% and at 72 months was 34% vs. 30% (estimated from curves). Treatment-related mortality for alloBMT was 41% compared with 13% for ASCT (p=0.0001) while the relapse rate was higher for ASCT (70% vs. 50% at 48 months; p=0.04). Treatment-related mortality with ASCT improved over the period observed (35% in 1986-89 and 7% in 1992-94), while there was no significant improvement in treatment-related mortality for alloBMT (40% from 1983-87 and 38% 1992-94). Varterasian et al compared the outcome of 24 consecutive ASCTs performed for myeloma with 24 alloBMTs performed during the same time period in the same institutions (49). The reasons for assignment to ASCT or alloBMT were not detailed. The alloBMT patients were younger and had a shorter interval from diagnosis to transplantation. Six deaths in the allogeneic transplant group versus two deaths in the autologous transplant group occurred within 90 days of transplant. There was no difference in event-free survival (16.7 months vs. 31 months; p=0.854) or median overall survival (33.5 months vs. 38.6 months; p=0.7637). At 46 months, the overall survival was 32% vs. 44% between the two groups (estimated from curves), despite more favourable baseline characteristics in the alloBMT patients. Couban et al compared the outcome of 40 consecutive patients undergoing autologous blood or marrow transplantation with 22 consecutive patients undergoing alloBMT in the same institution (50). The reasons for assignment to autologous or allogeneic transplantation were not detailed. There were no significant differences in baseline characteristics between the two groups. Survival was significantly longer for those undergoing autologous transplantation. # Interpretive summary On the basis of the limited evidence available, overall survival following autologous transplantation is comparable to the overall survival following allogeneic transplantation and may in fact be longer. In view of the greater toxicity of allogeneic transplantation, it is reasonable to recommend autologous transplantation. Allogeneic transplantation is not recommended outside a clinical trial. The European Group for Blood and Marrow Transplantation (24u) reported the results of a retrospective cohort comparison evaluating myeloma patients who underwent allogeneic transplantation during different periods of time. As reported in our original guideline, that Group has previously conducted a similar retrospective analysis (48), which demonstrated superior overall survival in patients receiving an autologous as compared with an allogeneic transplant. The present study included a comparison of patients undergoing allogeneic bone marrow transplantation between 1983 and 1993 (group 1; 334 patients), or 1994 and 1998 (group 2; 223 patients), and a group receiving a transplantation with allogeneic peripheral blood stem cells between 1994 and 1998 (group 3; 133 patients). In comparison with group 1, patients in group 2 experienced less treatment-related mortality at six months (38% vs. 21%) and two years (46% vs 30%) and had a superior median overall survival (p < 0.0001). A comparison of groups 2 and 3 patients failed to detect differences in treatment-related mortality, median overall survival, or rate of relapse from a complete remission. Outcomes of a group undergoing autologous transplantation were not included in the analysis. # Interpretive Summary This analysis suggests that outcomes with allogeneic transplantation have improved over time. However, treatment-related mortality continues to be significant problem and no comparisons have demonstrated superior survival in comparison with a group undergoing autologous transplantation. # (d) What specifics of the transplant manoeuvre can be recommended? Autologous transplantation is a complex procedure with a number of distinct components. We attempted to evaluate the optimal pre-transplant chemotherapy, source of stem cells, role of purging or selection, high-dose therapy regimen, supportive care, single versus double transplants, and post-transplant therapy. # Pre-transplant chemotherapy Chemotherapy may adversely affect the ability to harvest bone marrow stem cells and therefore might adversely affect engraftment of autologous stem cells (78). This concern has been particularly suggested with respect to therapy with alkylating agents such as melphalan. The impact of prior chemotherapy exposure on the yield of bone marrow harvest has not been addressed in randomized controlled trials. In the randomized controlled trial discussed previously (5), four to six cycles of alkylating-agent-based chemotherapy (BVAP/VMCP) were given prior to bone marrow harvest. Ten percent of eligible patients did not have sufficient marrow collected to permit transplantation. Conclusions cannot be drawn on the effect of chemotherapy on bone marrow harvesting from this study. # Case series Two case series have addressed the effect of cumulative alkylating agent exposure on the quality of peripheral blood stem cell collection (61,62). Tricot et al performed a multivariable analysis of factors predicting engraftment in 225 patients undergoing double-autologous transplantation for myeloma (61). Three hundred and sixty-four consecutive patients with multiple myeloma were enrolled in the study of autologous transplantation at a single institution. Newly diagnosed patients (45%) and previously treated patients were included. The engraftment kinetics of the 225 patients who underwent transplantation were reported. Peripheral blood stem cells were mobilized using high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor (GM-CSF). The target cell dose was 6x10 8 mononuclear cells/kg. No minimum CD34 positive cell dose was used. Patients with marginal peripheral blood stem cell yield enrolled before July 1993 received both peripheral blood stem cells and bone marrow. High-dose therapy for transplantation consisted of melphalan (200 mg/m 2. The primary end-points of the study were time to engraftment of platelets (>50x10 9 /L) and granulocytes (>0.5 x10 9 /L). Time-to-engraftment of both granulocytes and platelets was inversely correlated with extent of alkylating agent exposure (any exposure for granulocytes, and >1 month for platelets). Prince et al evaluated the impact of extent of melphalan exposure on the ability to harvest peripheral blood stem cells (62). Fifty-four consecutive peripheral blood stem cell collections in 37 patients were reviewed. All patients had multiple myeloma and were 65 years of age or younger. Peripheral blood stem cells were collected after administration of cyclophosphamide (4 g/m 2 and either GM-CSF or sequential interleukin 3 and GM-CSF. Treatment was defined by local policies which changed over time. The primary end points were number of granulocyte macrophage colony forming units (CFU-GM) per collection and proportion of patients with a collection exceeding 10 x 10 4 CFU-GM/kg. The extent of melphalan exposure adversely affected the ability to collect stem cells. Only 32% of patients given more than four courses of melphalan had collections that met or exceeded the threshold value compared with 85% for those who had received zero to four courses (p=0.001). # Interpretive summary The effect of prior alkylating agent exposure on bone marrow harvesting is not clear. However, alkylating agent exposure adversely affects peripheral blood stem cell yield and engraftment following ASCT. If stem cell transplantation is considered, patients should not be given extensive exposure to melphalan or other alkylating agents prior to stem cell collection. High-dose glucocorticoid-based regimens such as VAD (vincristine, doxorubicin dexamethasone) may be preferable for such patients. # Source of stem cells: bone marrow versus peripheral blood Peripheral blood stem cells (PBSC) are replacing bone marrow as the principal source of stem cells for use in ABMT. The use of peripheral blood stem cells results in faster engraftment of both neutrophils and platelets (79). In myeloma it has been suggested that the use of (PBSC) could improve survival post-transplant because of reduced contamination with malignant cells of the autograft (80). # Randomized controlled trial One randomized trial comparing bone marrow to peripheral blood as a source of stem cells has been published in abstract form (51). Three hundred and thirty-three patients were randomized to receive peripheral blood stem cells (n=133) or bone marrow (n=89). Neutrophil engraftment was faster for patients receiving peripheral blood (9.7 days vs. 12.2 days; p<0.001), however, toxic death (n=1 vs. n= 3); response rates and two-year survival were not significantly different. # Non-randomized comparisons The same authors of the randomized controlled trial described above (51) published an earlier non-randomized comparison of bone marrow and PBSC which yielded similar results (57). An additional comparison of PBSC with bone marrow-derived stem cells for myeloma was conducted on 63 patients with multiple myeloma (58). Twenty-six patients received autologous bone marrow transplantation and 37 received peripheral blood stem cell transplantation. This study found a significant acceleration of engraftment (19 days vs. 33 days; p=0.0015) for PBSC as compared with autologous transplantation without improvement in transplant-related mortality or survival. A retrospective analysis of 123 patients who received transplants of either bone marrow or peripheral blood stem cells performed for multiple myeloma or breast cancer was performed (59). Patients undergoing peripheral blood stem cell transplantation had faster engraftment, the requirement for transfusions of red blood cells and platelets was reduced, and the number of days needed in the hospital was significantly lower. There was no difference in the frequency of infectious complications between the two groups, but the number of days with fever and with antibiotic treatment were significantly lower in the peripheral blood stem cell transplantation patients. # Economic analyses Two studies assessing economic endpoints have addressed this topic. Duncan et al performed a cost-minimization analysis to compare PBSC transplantation with ABMT (63) and Powles et al included costing data in a non-randomized comparison that assessed tolerance in interferon post-transplant as its primary outcome parameter (64). Both analyses demonstrated that PBSC transplantation had economic advantages when compared with ABMT. # Interpretive summary These findings are compatible with data from other diseases which suggest that while engraftment is accelerated with peripheral blood stem cells, no difference in relapse rate is observed. Bone marrow or PBSC are acceptable sources of stem cells for transplantation in myeloma. Outcomes that assess clinical efficiency, other than patient survival, should guide the choice of treatment. Based on the limited data suggesting more rapid engraftment and an economic advantage with PBSC, with no apparent loss of efficacy, the DSG favoured the use of PBSCs as the source of stem cells. Attal and Harousseau (19u) provide updated results of the IFM 9401 trial reported in the original guideline (51). Four hundred and three previously untreated patients less than 60 years of age were initially randomized at diagnosis to single or double autologous transplantation and then randomized three months after diagnosis to bone marrow (n=163) or PBSC (n=180); all patients in the second randomization (n=343) were analyzed for at least most of the outcomes. When bone marrow was compared with PBSC, no differences in response rate (data not provided), six-year event-free survival (21% vs. 26%; p=not significant), or six-year overall survival (37% vs. 50%; p=0.07) were detected. # Interpretive summary There remains relatively scant data directly comparing peripheral blood with bone marrow as a source of stem cells for transplantation. The available data is consistent with that in other diseases: there appears to be no difference in long-term outcome, but engraftment with PBSC appears to be more rapid. For that reason, PBSC remains the preferred source of stem cells for hematopoietic reconstitution following high-dose therapy. # Role of Purging or Selection The relationship between reinfusion of malignant cells in the autograft and disease relapse is unclear. Numerous different methods have been used to attempt to eliminate malignant contamination. Limited data exist on the clinical benefit of such therapy. # Randomized controlled trial Stewart et al reported preliminary results of a randomized trial of CD34 selection. This trial compared CD34+ selected (n=93) versus unselected (n=97) autologous peripheral blood progenitor cells (52). After a median follow-up of 37.2 months, 33 patients (36%) in the selected arm and 34 patients (35%) in the unselected arm had died (p=0.784). A median overall survival in the selected arm was reached at 50 months and is not reached in the unselected one. # Interpretive summary Insufficient data exist to recommend purging or selection outside a randomized controlled trial. Two articles (20u,21u) in which the results of a previously included abstract publication (52) are updated, and three new abstracts (6u,7u,9u) addressing the role of cell purging and selection were found. Preliminary results demonstrating that a process to select CD34 positive cells could reduce the number of myeloma cells contained within autologous harvests were reported in abstract form (52) and described in the original version of this guideline. The results of that trial have now been reported in two articles. In the first article, Vescio et al (20u) confirm that this processing procedure reduces myeloma cell contamination of the harvested product. Stewart et al (21u) again report this finding in the final analysis of this study in which clinical outcomes of all 190 patients are also described. Although tumour cell contamination was reduced with the selection process, when the group receiving selected stem cells was compared with those receiving unselected stem cells, no differences were detected in median disease-free survival (100 vs. 104 months; p=0.82) or overall survival (50 months vs. not reached; p=0.78) (21u). Goldschmidt et al (6u) have reported results of a randomized comparison of autologous transplantation using CD34 positive selected stem cells or unselected stem cells in 127 patients with stage II-III myeloma. No differences in response rate, event-free or overall survival were detected. More frequent serious infections were observed in the CD34 selected arm (12 vs. 1; p value not indicated). Fermand et al (7u,9u) reported results of a randomized comparison of autologous transplantation using CD34 positive selected stem cells or unselected stem cells in 230 patients; the trial included a factorial design comparing single with tandem transplantation. In that preliminary analysis in which results are reported in abstract form, no differences in the frequency of relapse (data not reported) or death (22 vs. 27; p not provided) were detected between patients receiving unselected or selected stem cells (7u). More frequent serious infections were observed in patients receiving CD34 positive selected stem cells (data not provided) (7u). # Interpretive Summary While contamination of the stem cell harvest with myeloma cells can be reduced with use of a CD34 positive selection process, these three trials all failed to detect benefits in clinically relevant outcomes. In addition, the use of selected stem cells may be associated with more frequent infections. Purging or selection of harvested stem cells is not recommended outside the setting of a clinical trial. # High-dose therapy preparative regimen and supportive care One randomized controlled trial and one non-randomized comparison, both in abstract form, have assessed the role of total body irradiation (TBI). # Randomized controlled trial Two hundred and thirty-one patients were randomized to receive either high-dose melphalan 140 mg/m 2 plus total body irradiation (n=113) versus high-dose melphalan 200 mg/m 2 (n=108) as a conditioning regimen for peripheral blood progenitor cell autologous transplantation in patients with newly diagnosed multiple myeloma (53). There was no difference in response rate and 2-year survival rate between the two groups, but the TBI containing regimen was more toxic (median duration of neutropenia 8 days vs.10 days; p<0.001, median duration of thrombocytopenia 4 days vs. 6 days; p<0.001, median number of red blood cell transfusions 1.7 vs. 3, p=0.001, mean number of platelet transfusions 1.9 vs. 3.8; p<0.001, median duration of IV antibiotics 8 days vs. 11 days; p<0.001). # Non-randomized comparison Analysis of data on 1905 patients submitted to the European Group for Blood and Marrow Transplantation (EBMT), was reported by Bjorkstrand et al (60). The analysis of pretreatment variables reported that transplants performed with preparatory regimens that included TBI were associated with inferior survival. # Interpretive summary In Section IV b), the IFN 90 randomized controlled trial was described in detail (5). This study found survival to be superior when transplantation was combined with a high-dose therapy regimen consisting of high-dose melphalan and total body irradiation. Outcomes in the preliminary abstracts reported above appear to be no worse when total body irradiation is omitted from the highdose therapy regimen and toxicity is improved. In the absence of additional data, it is reasonable to recommend a single transplant using high-dose melphalan (200mg/m 2 alone or melphalan (140mg/m 2 with total body irradiation as standard therapy outside a clinical trial. Moreau et al (8u, 22u) and Attal and Harousseau (19u) provide the final results of the Intergroupe Francophone du Myélome 9502 trial initially described in the original guideline (53); data from the more recent full report (22u) will be presented here. Newly diagnosed patients, less than 65 years of age, initially received three cycles of VAD, with responding patients then receiving a fourth cycle of that treatment followed by high-dose therapy and autologous transplantation. The transplantation procedure included the harvesting of peripheral blood stem cells and randomization to receive combined modality therapy consisting of melphalan 140 mg/m 2 and total body radiation, or melphalan 200 mg/m 2 as a single modality. A comparison of the outcomes of the 142 patients receiving melphalan as a single modality with the 140 patients receiving combined modality therapy failed to detect a difference in response rate (55% vs. 43%; p=0.06) or median event-free survival (20.5 vs. 21 months; p=0.6). Overall survival at 45 months was superior in patients receiving melphalan as a single modality (65.8% vs. 45.5%; p=0.05). Patients assigned to receive melphalan 200 mg/m 2 experienced less severe mucositis, required fewer transfusions, and had shorter durations of hospitalization and intravenous antibiotics administration (p<0.001 for all comparisons). Schneider et al (16u) randomized 56 of 116 enrolled patients in stage II or III myeloma to high dose melphalan (200 mg/m 2 (n=30, median age 55 years) or a combination regimen of idarubicin (42 mg/m 2, melphalan (200 mg/m 2, and cyclophosphamide (120 mg/kg) (n=26, median age 57 years) followed with autologous stem cell transplantation. No differences in complete or partial remission after three months or overall survival (no statistical analysis provided) were detected between the groups. # Interpretive Summary The final analysis of the IFM 9502 trial confirms superior survival and reduced toxicities in patients receiving melphalan 200 mg/m 2 in comparison with a regimen that includes total body radiation. For this reason, the Hematology DSG concluded that melphalan 200 mg/m 2 is the recommended high-dose regimen. # Single versus double transplants Two randomized controlled trials and one non-randomized comparison have compared single versus double transplants (Table 4). # Randomized controlled trials Two randomized controlled trials of a single autologous bone marrow versus tandem (double) autologous bone marrow transplantation have been presented in abstract form (54,55). Both studies found that event-free and overall survival were not significantly different between the two groups. However, in one study (55) there was a trend for a longer relapse-free and event-free survival for patients assigned to receive a double transplant. This difference was statistically significant (p=0.03) when the analysis was restricted to patients who actually completed double transplants. # Non-randomized comparison Two hundred and seventy-eight patients were included in a double transplant program versus 1252 patients received a single transplant in the study by Bjorkstrand et al (60). Progressionfree survival was significantly better in the patients treated in a double transplant program versus those who received a single transplant (data not reported). There was also a trend for improved overall survival in the double transplant group. (54). †Analyzed across all four groups. ‡At 5 years after second randomization. # Interpretive summary Based on the intent-to-treat analysis of the two randomized controlled trials, there is no clear benefit for double versus single transplantation. A survival benefit was only seen when analysis was restricted to those who completed therapy. Double transplantation should be performed only in the setting of a clinical trial. Five abstracts and one full report reporting the results of three randomized trials comparing single with double (tandem) transplantation were found (9u-14u,19u). Fermand et al (7u, 9u) have reported results of a randomized trial that included a factorial design; the trial evaluated the role of stem cell selection (see above) and single as compared with double transplantation. Among the 193 patients randomized to receive single or double transplantation, no differences were observed in total events or deaths (Table 4) (7u). Attal et al have reported updated results of the IFM 94 02 randomized trial comparing single and double autologous transplantation that was included in the original version of this guideline (54); updated data were reported in three abstracts (10u-12u), but data from the published report (19u) are presented. This trial randomized 403 previously untreated patients who were less than 60 years of age. The trial was factorial in design, with patients randomized first to single or double transplantation and then, if eligible for a transplant (n=344), randomized second to bone marrow or PBSC transplantation. Patients randomized to receive a single transplantation received melphalan (140 mg/m 2 and total body irradiation for the high-dose regimen. Those randomized to the double transplant arm were given high-dose melphalan alone (140 mg/m 2 with the first transplantation and received melphalan (140 mg/m 2 and total body irradiation with the second. An interim analysis was presented. At a median follow-up of five years post-diagnosis, a significant difference across the groups was detected for response (complete plus very good partial response) and five-year eventfree and overall survivals (Table 4) (19u). Cavo et al (13u, 14u) reported updated interim analyses of the Bologna 96 randomized trial in the original guideline (55) comparing single versus double autologous peripheral blood stem cell transplantation in previously untreated patients; results from the more mature analysis (14u; n=220) will be presented here. At a median follow-up of five years, no difference in median overall survival was detected between groups, but median event-free survival was longer in the double transplant group (Table 4). Complete remission was reported in each group (Table 4). # Interpretive Summary The benefits of double transplantation remain unclear. The Attal study (19u) is large, but the fact that for the single transplant arm the investigators used a high-dose regimen now considered inferior (melphalan, 140 mg/m 2 and total body irradiation) limits the study's interpretability. In addition, two smaller studies published in abstract form did not report a survival benefit. Definitive conclusions regarding the role of double transplantation will need to await more mature results from those studies. Because of the relatively complex design of a number of these trials, the full published form of these studies may need to be examined before firm recommendations regarding the role of double transplantation can be made. # Post-transplant therapy Interferon alpha has been used following conventional or high-dose therapy in an effort to delay recurrence. An overview of randomized trials of interferon use with conventional therapy as well as the use of interferon in maintenance therapy has been discussed in Section IV (a) (8,9). There has been interest in the use of interferon following ABMT, as an immunomodulatory effect may be more prominent in a minimal residual disease state. Interferon administration after transplantation is a commonly described practice (1). In the randomized study comparing transplantation with conventional dose chemotherapy (5) interferon alpha, three million units/m 2 was given three times weekly to both the transplant and conventional therapy groups until disease progression. It is not possible to factor out the contribution to this component of that entire treatment manoeuvre in order to comment upon the importance of interferon. The major justification of using interferon after ABMT comes from two studies which are described below. # Randomized controlled trial One randomized trial of interferon administration following transplantation has been reported (56). Eighty-four patients with myeloma were randomized to receive either three million units of interferon alpha three times weekly until progression or no maintenance therapy. There was a trend towards longer median progression-free survival in the patients given interferon (46 months vs. 27 months; p=0.11). Overall survival was not different in the two groups. # Non-randomized comparison The analysis of 1905 patients from the European Group for Blood Marrow Transplantation registry found that post-transplant alpha-interferon (IFN) maintenance treatment was associated with prolonged survival previously discussed in Section IV (c) (60). # Interpretive summary The evidence on the benefit of interferon is conflicting. One preliminary report of a cohort comparison suggests a survival benefit (60), while a small randomized trial shows no benefit (56). For this reason, the DSG was unable to reach consensus and a recommendation about using interferon was therefore not included. Bjorkstrand et al (25u) have updated, in article form, results of a cohort comparison assessing the role of post-transplant use of interferon alpha in patients whose data have been entered into the European Group for Blood and Marrow Transplantation database. An earlier analysis (60) had been published in abstract form and was included in the initial version of this guideline. The updated analysis includes 473 patients who did and 419 patients who did not receive interferon alpha; a Cox analysis was used to attempt to balance prognostic factors. Treatment with interferon alpha was associated with longer median progression-free survival (29 vs. 20 months; p=0.006) and overall survival (78 vs. 47 months; p=0.007). # Interpretive summary The new evidence supports the hypothesis that maintenance therapy with interferon alpha may improve outcomes in myeloma patients who undergo autologous transplantation. However, these data result from a non-randomized comparison, and the trial design is subject to biases, including imbalances of prognostic factors between the treatment groups. There is no change in the overall interpretation of evidence assessing this topic. # (e) When should transplantation be performed? In the IFN 90 study patients were considered for transplantation prior to any therapy (5). Bone marrow was obtained early after diagnosis and transplantation took place at a median of 5.5 months after diagnosis of myeloma. It is unclear whether transplantation has to be performed this early in the course of the disease to be of benefit. # Randomized controlled trial One randomized trial compared early (n=91) and late (n=94) autologous transplantation in patients who have had stem cells collected shortly after diagnosis (65). Patients under age 56 with symptomatic advanced stage myeloma were enrolled and had PBSC collection performed. Patients with an adequate collection and adequate organ function were randomized to early or delayed transplantation. Patients assigned to the early transplant arm received three to four courses of vincristine, doxorubicin (Adriamycin), methylprednisolone (VAMP) followed by high-dose therapy and transplantation using a high-dose regimen of lomustine, VP-16, cyclophosphamide, melphalan and total body irradiation. Patients assigned to late transplantation received monthly courses of vincristine, melphalan, cyclophosphamide and prednisone (VMCP) until a plateau phase was reached. At progression, patients who received VMCP underwent transplantation. All patients in remission in either arm received interferon alpha. Two hundred and two patients were enrolled and 185 patients were randomized. Median overall survival was similar in both arms (64.6 months in the early transplant group vs. 64 months in the late transplant group; p=0.92). Median event-free survival was superior for early transplant group compared with the late transplant group (39 months, 95% CI 29 to 48 vs. 13 months, 95% CI 9.4 to 17.6; p=not reported). Time-without-symptoms, treatment and treatment toxicity (TWISTT) was 27.8 months (95% CI, 23.8 to 31.8) for the early transplant group vs. 22.3 months (95% CI, 16.0 to 28.6) for the late transplant group. Eighty-nine of 91 (98%) patients assigned to early transplant underwent transplantation while 73 of 94 (78%) patients in the late high-dose therapy arm were transplanted. # Non-randomized comparison A non-randomized study reported on 64 patients who had stem cells harvested within 12 months of diagnosis but were not transplanted until relapse or refractory disease developed (66). The authors found that the median survival from diagnosis in patients who received delayed transplant was 51 months with a median survival of 19.3 months post-transplant. A second nonrandomized controlled trial has suggested that delaying transplantation until patients have shown evidence of progressive disease may result in loss of efficacy for this procedure (67). # Interpretive summary While delaying transplantation until progression in patients who have stem cells collected at diagnosis does not adversely affect survival, it does decrease time without symptoms and delays the need for treatment. It also increases time without treatment toxicity. Furthermore, delay is not reasonable unless stem cells have been collected prior to extensive alkylator therapy. The DSG emphasize the need for early harvest and consideration of patient preference. Furthermore, the DSG felt that unless extenuating circumstances exist, there are advantages to early treatment related to symptom control. # (f) Who should (should not) be transplanted? Age The maximum age for ABMT in any disease remains controversial. Transplantation is commonly performed in patients up to the age of 65 years. It is reasonable to expect that older patients may risk greater transplant-related mortality and therefore derive less survival benefit from transplantation. However, some centres have routinely offered this procedure to older (69)(70)(71)(72)(73)75,76). Two randomized controlled trials and six non-randomized comparisons are described below. # Randomized controlled trials The Attal study enrolled patients up to the age of 65 years (5). The authors did not report age to be an adverse prognostic factor, but 42% of patients over age 60 did not complete the transplant compared to 18% of younger patients (p=0.01). In this study, multivariate analysis found that randomization to the transplant arm was independently associated with improved outcome only for patients under the age of 60. One randomized trial comparing transplantation to conventional therapy in older patients (age 55-65) has been reported in preliminary form (44). This trial showed outcome to be no better with transplantation than conventional therapy (55.3 months vs. 50.4 months; p=0.98). However follow-up was short and a longer follow-up is required to assess the role of transplantation in this population. # Non-randomized comparisons One study reported as a full paper compared 71 patients (median age, 64 years) who received dose intensive melphalan with stem cell support with 71 matched pair mates (median age, 64 years) who received oral melphalan and prednisone (68). Median event-free survival was 34 months in the transplant arm and 17.7 months in the melphalan group (p<0.001). Median overall survival was 56+ months vs. 48 months (p<0.01), in those same groups. Numerous non-randomized studies show that transplantation can be performed in selected patients over age 65 with toxicity and survival similar to younger patients (69)(70)(71)(72)(73). # Interpretive summary Transplantation can be safely performed in older patients, however the survival benefit has only been documented for patients under age 60. Physicians must use clinical judgement when recommending transplantation to patients over the age of 60 years. # Randomized controlled trials The MRC trial (23u) compared high-dose therapy and autologous stem cell transplantation with standard therapy in patients with previously untreated myeloma younger than age 65 years. The trial reported a survival benefit for the high-dose therapy arm when compared with the standard treatment arm. Although age was included as a minimization factor in a Cox model analysis, the authors did not indicate whether it was a significant prognostic factor for survival. # Interpretive summary The Attal (5) and MRC trials (23u) both enrolled patients up to age 65 years and both demonstrated an overall survival benefit for the high-dose therapy arms. The Attal trial did not report a benefit for older patients on subgroup analysis, and the Fermand trial (44) trial, which included only patients over age 55, was negative. # Renal function The randomized controlled trial published by Attal et al (5) included patients with renal dysfunction; however, transplantation was only performed if the serum creatinine fell to less than 150 mol/L after initial chemotherapy and before transplantation. While some centres have transplanted patients with severe renal dysfunction, it is reasonable to expect that transplant-related mortality may be higher for such patients and survival may not be prolonged to the same extent as for patients with intact renal function. # Non-randomized comparison Mehta et al ( 74) compared the outcome of 42 patients with renal failure (creatinine ≥200 g/L) to 84 pair-matched controls with normal renal function. The study found that although morbidity was higher, treatment-related mortality and three-year survival rates were no different (44%, 95% CI 15 to 74 vs. 59%, 95% CI 43 to 76; p=0.15). # Interpretive summary While autologous transplantation can be performed in patients with significant renal dysfunction, it remains unclear whether such patients benefit from the transplant procedure. For this reason, transplantation cannot be routinely recommended for patients with significant renal dysfunction until randomized controlled trials demonstrate a survival benefit for these patients. Renal function may improve with chemotherapy. In the Attal study (5), patients were only excluded if serum creatinine levels were abnormal after four to six cycles of initial chemotherapy. # Dosing/Scheduling Considerations In the trial by Attal et al ( 5), the following regimen schedule was used: Four to six cycles of vincristine, melphalan, cyclophosphamide, prednisone, carmustine, and doxorubicin (VCMP/BVAP). After fourth cycle of chemotherapy, a preparative regimen of total body irradiation 200 cGy per day x 4 days (day -7 to day -4) and melphalan 140 mg/kg (day -2) followed by re-infusion of autologous bone marrow. Interferon alpha three million units/m 2 three times weekly was administered following hematologic recovery Issues regarding the details of therapy have been discussed in previous sections. # V. ONGOING TRIALS Members of the Hematology DSG are aware of the following ongoing trials. The progress of these open trials will be monitored and the reported results will be reviewed when available: - Southern England Collaborative Trials Group randomized trial of high-dose versus intermediate-dose melphalan after initial vincristine, doxorubicin, dexamethasone (VAD) or vincristine, doxorubicin, methylprednisolone (VAMP) chemotherapy in newly diagnosed stage II or III myeloma patients. 2. Français du Myélome and the Groupe Myélome-autogreffe are conducting a meta-analysis of individual patient data comparing high-dose chemotherapy supported by ASCT with conventional chemotherapy as treatment for newly diagnosed multiple myeloma patients. # Cooperative clinical study of the German Multiple Myeloma Study Group (DSMM) and the East German Study Group for Hematology/Oncology comparing bendamustine plus prednisone with standard therapy. The following trials are now closed and will be reported in future updates when data become available: - National Cancer Institute (NCI) high-priority clinical trial that randomized patients to autologous stem cell transplantation versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone (VBMCP chemotherapy with further randomization to interferon alpha or observation. - Leukemia Cooperative Group randomized trial testing the effect of bone marrow transplantation or conventional chemotherapy with or without alpha interferon for aggressive myeloma. 3. Australasian BMT Co-operative Study Group's randomized trial comparing melphalan with or without amifostine prior to autologous stem cell transplantation (ASCT) in multiple myeloma patients. # VI. DISEASE SITE GROUP CONSENSUS PROCESS The Hematology DSG was asked to develop a broad guideline on the management of patients with multiple myeloma. The DSG considered the potential of developing a more comprehensive guideline and concluded that the complexity and importance of the high-dose therapy transplant topic warranted a specific guideline; the possibility remains for subsequently merging this guideline into a document dealing with a wider range of issues in myeloma. On appraising the published literature regarding transplant therapy, there were two major issues that yielded considerable debate. The first issue related to the quality and volume of data assessing the transplant question. Specifically, debate centered on the strength of the recommendation for transplantation given that the supporting data were limited to only one wellconducted positive randomized trial (5). After careful consideration, there was unanimous agreement that patients ought to be informed about the results of this study and this was reflected in the wording of the recommendations. There was further discussion about whether there was sufficient evidence to not only offer, but to "recommend" this treatment as the preferred therapeutic option. While the DSG felt that patients should have a choice, they felt that that the current evidence is sufficient to warrant the "recommend" terminology. The second point of debate dealt with the role of interferon. Some members of the group felt that as interferon was part of the treatment maneuver in the Attal study (5), and was reported by Cunningham et al (56) to result in superior time-to-disease progression, the use of interferon should be included in transplant treatment strategies. Other members felt that in the absence of data demonstrating a survival advantage, the toxicity of this agent precludes routine use. The DSG was unable to reach consensus and a recommendation about using interferon was therefore not included. The DSG members considered whether a firm recommendation should be made regarding the timing of transplantation. Members felt that the best available evidence found a survival benefit when transplantation was used as part of the initial therapy (5). In a randomized trial of early versus delayed transplantation in patients in whom stem cells had been collected at diagnosis, delaying transplant did not shorten survival although there was a suggestion that quality of life was adversely affected; however the 95% confidence intervals overlapped. For this reason, the DSG members did not feel that a strong recommendation could be made regarding the timing of transplantation, although there was consensus that if a delayed transplant is contemplated, stem cells should be collected soon after diagnosis. The initial draft recommendations were circulated for practitioner feedback in May 1999 and received wide support. The initial Practice Guideline was approved by the Practice Guidelines Coordinating Committee in October 1999. Since the release of the initial guideline, new data emerged in abstract form that included assessment of the role of total-body irradiation (TBI) (53,60) and a further randomized trial evaluating autologous transplantation in patients over age 55 years (44). The DSG concluded that the study comparing melphalan 140 mg/m 2 plus TBI with melphalan 200 mg/m 2 required modification of the previous recommendation regarding the details of the highdose therapy regimen (bullet five) (53). The reworded recommendation now permits either option (see bullet five). There was considerable discussion regarding the results of the report by Fermand et al (44). This trial, published in abstract form, compared a transplant strategy with standard dose treatment in patients 55 years and greater and failed to detect a survival benefit. The DSG considered whether these data should lead to a rewording of the overall recommendation regarding "offering" versus "recommending" high-dose therapy and transplantation and/or whether an age restriction should be suggested. The DSG concluded that while the Fermand trial was large and appeared to be well conducted, insufficient information was provided in the abstract to change the initial recommendations. However, the wording of the new recommendation (bullet one) highlights the indication by age. The DSG acknowledges that the final results of the Fermand trial and other ongoing studies may influence the nature and wording of the recommendations in the future. The DSG did not consider these new data and the resulting modifications sufficiently different from the initial guideline to warrant another cycle of practitioner feedback. This revised guideline was circulated to the Practice Guidelines Coordinating Committee. The Hematology DSG's evaluation of new evidence resulted in extensive discussions of two topics: the role of autologous stem cell transplantation in comparison with standard-dose therapy and the nature of the high-dose therapy regimen. The publication of the MRC trial (23u) has strengthened the evidence in favor of high-dose therapy and autologous transplantation over standard dose therapy for newly diagnosed patients with myeloma. While a meta-analysis will be required to better define the magnitude of benefit, the DSG concluded that high-dose therapy should continue to be recommended for patients with myeloma and that the text of the recommendation should be amended to indicate that the evidence is strongest in patients under the age of 65 years. Given the updated evidence regarding high-dose therapy preparative regimens, the DSG unanimously concluded that melphalan 200 mg/m 2 as a single modality should be the recommended regimen for patients undergoing autologous transplantation outside a clinical trial setting. In comparison with melphalan 140 mg/m 2 and total body radiation, melphalan given as 200 mg/m 2 was associated with superior survival and less toxicity, and was less resource intensive (22u). The DSG discussed whether the publication of the Attal study (19u) should lead to a change in the recommendation regarding double (tandem) autologous transplantation. The DSG concluded that the survival benefit reported in that trial was potentially important, but noted that other trials did not report a benefit. The DSG also noted that the high-dose therapy regimen used in the single transplant arm in that trial no longer represents the standard of care, as it has been shown to be inferior to melphalan (200 mg/m 2 alone. The DSG members concluded that the recommendations should not be changed until new data are available from those studies. The DSG concluded that new evidence regarding the role of post-transplantation interferon maintenance did not warrant a change in the recommendations. # VII. EXTERNAL REVIEW OF THE PRACTICE GUIDELINE REPORT This section describes the external review activities undertaken for the original guideline report. For a description of external review activities of the new information presented in the updated sections of this report, please refer to Update below. # Draft Recommendations Based on the evidence described in the original guideline report, the Hematology DSG drafted the following recommendations in December 1998: # Target Population These recommendations apply to patients with advanced-stage multiple myeloma and good performance status. # Draft Recommendations - Autologous transplantation is recommended for patients with advanced-stage myeloma and good performance status. The evidence is strongest for patients under 60 years of age without significant renal dysfunction. Physicians must use their clinical judgement in recommending transplantation to patients over 60 years of age or those with renal impairment. There is insufficient evidence to recommend allogeneic transplantation as routine therapy for multiple myeloma. Patients who are potentially eligible for transplantation should be referred for transplant assessment early after diagnosis and should not be given extensive exposure to alkylating agents such as melphalan prior to the collection of stem cells. High-dose glucocorticoid based regimens such as vincristine, Adriamycin, dexamethasone (VAD) may be preferable for such patients. Harvesting of autologous peripheral blood stem or bone marrow should be performed early in the patient's treatment course. The best available data demonstrate that transplantation is advantageous when performed as part of the initial therapy. There are insufficient comparative data regarding the specifics of transplant process to allow for definitive recommendations. In the absence of such data, the use of a single transplant with high-dose melphalan and total body irradiation as high-dose therapy is suggested for patients who undergo transplantation outside of the setting of a clinical trial. No conclusions can be reached about the role of interferon alpha following transplantation at this time. # Practitioner Feedback Based on the evidence contained in the original guideline report and the draft recommendations presented above, feedback was sought from Ontario clinicians. Practitioner feedback was obtained through a mailed survey of 221 practitioners in Ontario (94 hematologists, 93 medical oncologists, and 24 radiation oncologists). The survey consisted of items evaluating the methods, results, and interpretative summary used to inform the draft recommendations outlined and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (postcard) and four weeks (complete package mailed again). The results of the survey have been reviewed by the Hematology DSG. - Return Rate: 71% 2. Quality of data synthesis: 91% agreed or strongly agreed that the summary of the evidence was acceptable 3. Agreement with the draft recommendations: 87% 4. Approval of the recommendations as a practice guideline: 81% # Summary of Main findings Forty-three percent (39/90) of the respondents provided written comments. The main points were: 1. Nine respondents felt that one randomized trial was insufficient evidence to "recommend" stem cell transplantation as the preferred option. These respondents felt that the publication of the guideline should be delayed until further evidence is available or that transplantation should be "offered" rather than "recommended". - There were two comments that renal function at presentation should not dictate transplant eligibility, as function may improve with initial chemotherapy. 3. There were three comments on total body irradiation (TBI) as part of the high-dose therapy regimen. Respondents indicated that it should be omitted or administered differently from the Attal et al study (5). 4. Four respondents indicated concern regarding resource availability. 5. There were two comments indicating a potential future role of allogeneic transplantation. Both respondents acknowledged the toxicity and comments short survival in published reports of allogeneic transplantation. Modifications/Actions 1. Members of the DSG acknowledged that the first recommendation is based on a single randomized trial. The DSG felt that the trial was well done and showed statistically significant differences in the important clinical outcomes. None of the nine respondents indicated weaknesses in the trial, but rather a need for further evidence. In "recommending" the treatment, the DSG realize that patient preferences should be considered. However, the group felt that rather than just being "an option", the strength of the report makes this the "preferred option". 2. Members of the DSG felt this was an appropriate comment and have inserted the following phrase in the first recommendation: "following hydration and initial chemotherapy". The following statement was also added under the renal function in section (f): "Renal function may improve with chemotherapy. In the Attal study, patients were only excluded if serum creatinine levels were abnormal after 4-6 cycles of initial chemotherapy." 3. Members of the DSG felt that while no RCTs compared high-dose therapy regimens, the only published trial showing a survival benefit for transplantation used melphalan and TBI. For this reason melphalan and TBI should be recommended as standard practice outside of a clinical trial. As a further follow-up to this, based on preliminary data (53,60), the fifth bullet of the recommendations was modified (see Section VI).There were three comments on total body irradiation (TBI) as part of the high-dose therapy regimen. Respondents indicated that it should be omitted or administered differently from the Attal et al study (5). 4. The issue of resource impact lies outside the scope of evidence-based guidelines. 5. The review of the European Bone Marrow Transplant Registry study (44) found substantially shorter survival in patients undergoing allogeneic transplantation. Members of the DSG felt that ongoing clinical trials of improved allogeneic transplantation technology should be encouraged. # Approved Practice Guideline Recommendations These practice guideline recommendations reflect the integration of the draft recommendations with feedback obtained from the external review process. They have been approved by the Hematology DSG and the Practice Guidelines Coordinating Committee. Autologous transplantation is recommended for patients with advanced-stage myeloma and good performance status. The evidence is strongest for patients under 55 years of age without significant renal dysfunction following hydration and remission-induction chemotherapy. Physicians must use their clinical judgement in recommending transplantation to patients over 55 years of age or those with renal impairment. There is insufficient evidence to recommend allogeneic transplantation as routine therapy for multiple myeloma. Patients who are potentially eligible transplantation should be referred for transplant assessment early after diagnosis and should not be given extensive exposure to alkylating agents such as melphalan prior to the collection stem cells. High-dose glucocorticoid-based regimens such as vincristine, doxorubicin (Adriamycin), dexamethasone (VAD) are preferable for such patients. Harvesting of autologous peripheral blood stem cells or bone marrow should be performed early in the patient's treatment course. The best available data demonstrate that of transplantation is most advantageous when performed as part of the initial therapy. There are insufficient comparative data regarding the specifics of the transplant process to allow for definitive recommendations. In the absence of such data, the use of a single transplant with high-dose melphalan (200 mg/m 2 alone or melphalan (140mg/m 2 with total body irradiation is suggested for patients who undergo transplantation outside of the setting of a clinical trial. No conclusions can be reached about the role of interferon alpha following transplantation at this time. The recommendations regarding autologous transplantation and high-dose regimens have been modified to reflect the updated evidence. The changes in recommendations were not sent for external review because they did not substantially deviate from the original recommendations. The new recommendations are as follows: Autologous transplantation is recommended for patients with advanced-stage myeloma and good performance status. The evidence is strongest for patients under 65 years of age without significant renal dysfunction following hydration and remission-induction chemotherapy. Physicians must use their clinical judgment in recommending transplantation to patients over 65 years of age or those with renal impairment. For patients undergoing autologous stem cell transplantation as part of standard therapy, it is recommended that the transplantation regimen include melphalan 200 mg/m 2 without total body radiation. There is insufficient evidence to recommend a treatment plan that includes two transplants performed in succession (tandem transplantation) outside of a clinical trial. # VIII. POLICY IMPLICATIONS In Ontario, myeloma treatment is provided by hematologists, medical oncologists and a number of internists in community practice as well as in larger cancer centres. For this reason there is potential for a wide variation in practice. In order to ensure that all patients have access to ideal therapy, the dissemination of this guideline is very important. Myeloma is currently an indication for transplantation in all transplant centres in Ontario. It is the perception of the Hematology DSG that rates of referral to the transplant centres vary substantially across the province. Adoption of this practice guideline is likely to increase the pressure on transplant centres, but to differing degrees for each centre. # IX. PRACTICE GUIDELINE This practice guideline reflects the most current information and integrates the new evidence with evidence from the original guideline report. # Target Population This recommendation applies to patients with advanced-stage multiple myeloma and good performance status. There is insufficient evidence to recommend a treatment plan that includes two transplants performed in succession (tandem transplantation) outside of a clinical trial. # X. JOURNAL REFERENCE 5c. Conduct an updated literature search based on that done for the current version and modified by 5a and 5b above. Report the results below. Initial chemotherapy where HDT is not planned -'conventional therapy' - VAD or a VAD-type regimen should be used as initial therapy in patients where future HDT is planned (grade B recommendation; level II a evidence). - No firm recommendation can be made on whether oral idarubicin and dexamethasone or high-dose dexamethasone alone are equivalent to VAD. - For older patients in whom HDT is not planned, either melphalan or cyclophosphamide should be used, with or without prednisolone (grade A recommendation; level Ia evidence). - Thalidomide should only be used in newly diagnosed patients in the context of a clinical trial (grade C recommendation; level IV evidence). - In all patients dose modifications may be required because of impaired renal function or cytopenia (grade C recommendation; level IV evidence). # High-dose therapy and transplantation: Autologous stem cell transplantation - HDT with ASCT should be part of the primary treatment strategy in newly diagnosed patients up to the age of 65 years with adequate performance status and organ function (grade A recommendation; level Ib evidence). - HDT with ASCT may be considered in patients aged >65 years with good performance status (grade B recommendation; level IIa evidence). - Conditioning with melphalan alone, without TBI, is recommended (grade B recommendation; level IIa evidence). The usual dose is 200 mg/m2 but the dose should be reduced in older patients (over 65-70 years) and in renal failure. - Planned double (tandem) ASCT cannot be recommended on the current evidence. However, it is recommended that enough stem cells are collected to support two high-dose procedures (grade C recommendation; level IV evidence). - Currently available methods of purging have not demonstrated clinical benefit and are not, therefore, recommended (grade A recommendation; level Ib evidence). - HDT and ASCT may be considered for patients with severe renal impairment (creatinine clearance/GFR <30 ml/min) but the dose of melphalan should be # DOCUMENT ASSESSMENT AND REVIEW DEFINITIONS # Document Assessment and Review Terms DEFINITIVE RECOMMENDATIONS -Definitive means that the current recommendations address the relevant subject area so fully that it would be very surprising to identify any contradictory or clarifying evidence. § SUFFICIENT RECOMMENDATIONS -Sufficient means that the current recommendations are based on consensus, opinion and/or limited evidence, and the likelihood of finding any further evidence of any variety is very small (e.g., in rare or poorly studied disease). ¶ WARNING -A warning indicates that, although the topic is still relevant, there may be, or is, new evidence that may contradict the guideline recommendations or otherwise make the document suspect as a guide to clinical decision making. The document is removed from the Web site, and a warning is put in its place. A new literature search may be needed, depending on the clinical priority and resources. # Document Assessment and Review Outcomes - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of the website, and each page is watermarked with the term "ARCHIVED". # ENDORSED - An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. # DEFERRAL - A Deferral means that the clinical reviewers feel that the document is still useful and the decision has been made to postpone further action for a number of reasons. The reasons for the deferral are in the Document Assessment and Review Tool. # UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making. For a complete list of the Hematology Disease Site Group members, please visit the PEBC / This section includes all references obtained from the review and updating activities. PG 6-6 Document Assessment Review Tool. Date and final results / outcomes 24 May 2011 Beginning at question 1, below, answer the questions in sequential order, following the instructions in the black boxes as you go. # Document Assessment and Review Tool - Is there still a need for a guideline covering one or more of the topics in this document? Answer Yes or No, and explain if necessary: - Yes If No, then the document should be ARCHIVED 1 with no further action; go to 11. If Yes, then go to 2. - Are all the current recommendations based on the current questions definitive or sufficient § and have less than 5 years elapsed since the latest search? Answer Yes or No, and explain if necessary: Current recommendations are sufficient. However, more than 5 years have elapsed since the last search. If Yes, the document can be ENDORSED 2 with no further action; go to 11. If No, go to 3. Is there expected or known evidence that contradicts the current recommendations, such that they may cause harm or lead to unnecessary or improper treatment if followed? Answer Yes or No, and explain if necessary, providing references of known evidence: If Yes, the document should be taken off the website as soon as possible. A WARNING ¶ should be put in its place informing a user that the document is only available by email, with a brief explanation of the reasons. If No, go to 4. 3 should be placed on the document indicating it cannot be updated at this time, but will be reviewed again on a yearly basis. If Yes, go to 5. 5a. List below any new, relevant questions that have arisen since the last version of the document. List any changes to the original research questions that now must be considered. Original Question(s): - What is the optimal chemotherapy for patients with multiple myeloma? 2. In terms of survival, is peripheral blood stem cell or autologous bone marrow transplantation better than conventional chemotherapy? 3. What is the relative efficacy of autologous and allogeneic transplantation? 4. What specifics of the transplant manoeuvre can be recommended? 5. When should transplantation be performed? 6. Who should (should not) be transplanted? 5b. List below any changes to the selection criteria in the original version made necessary by new questions, changes to existing questions, or changes in available evidence (e.g., limit a search to randomized trials that originally included non-randomized evidence Inclusion criteria: Articles were selected based on the following criteria: - Randomized controlled trials (RCTs) of patients with multiple myeloma that reported on the outcomes of survival and/or quality of life. 2. Non-randomized trials were included if they had appropriate contemporaneous control groups and reported on the outcomes of survival and/or quality of life. Study results were used to estimate both the potential efficacy and appropriate timing of autologous and allogeneic transplantation. Metaanalyses, systematic reviews and economic analyses were also included. Because of insufficient data addressing the specifics of the transplant manoeuvre and which patients would be most likely to benefit from transplantation, a second literature search was performed to include data from single-arm studies. reduced to 140 mg/m2 (grade B recommendation; level IIb evidence) and the procedure should only be carried out in a centre with special expertise (grade C recommendation; level IV evidence). # High-dose therapy and transplantation: Allogeneic stem cell transplantation Transplantation with conventional conditioning regimens - Patients up to the age of 50 years who have achieved at least a partial remission after initial therapy may be considered for HLA-matched sibling allogeneic SCT. The procedure should be performed as part of a clinical trial, where possible (grade B recommendation; level IIb evidence). - DLI should be considered for patients with persistent or progressive disease following transplantation (grade B recommendation; level IIa evidence). - SCT should be carried out in EBMT accredited centres where data are collected prospectively as part of international transplant registries (grade C recommendation; level IV evidence). - RIC allografting may be considered in patients up to the age of 70 years with an HLA-matched sibling (grade B recommendation; level IIb evidence). The procedure would usually follow an initial autograft, should be done early in the disease phase and should always be done as part of a clinical trial (grade C recommendation; level IV evidence). - Matched unrelated donor transplants using RIC may be considered within the context of a clinical trial.

# A. INTRODUCTION Guideline Objective The objective of this guideline is to provide the basis for a quality assurance program for all colonoscopy procedures done in the province of Ontario, including those conducted as part of the fecal occult blood test (FOBT)-based colorectal cancer (CRC) screening program. This guideline is intended to provide recommendations that are based on an up-to-date systematic review of the evidence on the following three key aspects of colonoscopy: training and maintenance of competency for physician endoscopists, institutional quality assurance parameters, and performance indicators for colonoscopy. Clinical practice recommendations for how to perform colonoscopy or recommendations designed to improve the skill level of individual endoscopists are beyond the scope of this guideline. This Evidence-Based Series (EBS) provides an update to the 2007 PEBC document EBS #15-5 Colonoscopy Standards (1). These recommendations are based on the best evidence currently available and are not intended to constitute absolute requirements for individual endoscopists. The recommended targets can be monitored and used to provide feedback to individuals in order to improve performance on quality indicators when necessary, and to monitor performance at the system level to improve the overall quality of colonoscopy in Ontario. A quality improvement program should document its requirements, monitor performance using established quality indicators, and then institute changes that will lead to demonstrated improvements upon reassessment. # Recommendations Development The recommendations contained in this guideline are based on evidence from a systematic review of the primary literature and an environmental scan of existing guidance documents. The guideline development group used this evidentiary base, combined with consensus opinion, to develop recommendations. Further details related to the methodology for developing the evidentiary base can be found in Section 2 of this Evidence-Based Series (EBS). Recommendations from the previous version of this guideline (1) were used as a starting point and were updated where new evidence justified a modification. The following criteria were used by the guideline development group as a guide to ensure consistency and transparency when specifying target thresholds or values: - Evidence that the target is linked to an established important outcome (e.g., adenoma detection rate, PCCRC). 2. Evidence that the target is applicable in the Ontario context. 3. Taking into account the quality of evidence, targets were identified with a preference for values that were in the middle of the range found the literature, in order to set reasonably attainable targets for Ontario. Some indicators are dependent on the underlying risk profile of the population. For example, adenoma detection rate is expected to be higher than average in populations that have been referred for colonoscopy after a positive fecal occult blood test (FOBT) or fecal immunochemical test (FIT), or in those with a family history or other risk factors such as previous polyps. # Quality Indicators and Auditable Outcomes Quality and safety indicators (p.13) for which there were sufficient evidence to recommend a specific target are called quality indicators. Important quality indicators are labelled auditable outcomes where there was insufficient evidence to recommend a specific target, but there was working group agreement that the indicator should be monitored for quality assurance purposes. These labels are consistent with those used in other guidance documents (2,3). As data accumulates, it may be possible to establish targets for these auditable indicators or to make necessary adjustments to targets that are already specified. # B. RESEARCH QUESTIONS # Physician endoscopist training and maintenance of competency - What primary training is required for physicians performing colonoscopy? What are the requirements for maintenance of competency for physicians performing colonoscopy? # Institutional quality assurance parameters What, if any, are acceptable quality assurance parameters for: Patient assessment prior to the procedure; Infection control, including colonoscope washing procedures and the use of highpowered washers; Monitoring during and after the administration of conscious sedation; Resuscitation capability; - Acceptable endoscope quality. # Colonoscopy quality indicators and auditable outcomes # C. TARGET POPULATION This guideline is intended to provide guidance on quality colonoscopy for adult patients undergoing this procedure in Ontario. # D. INTENDED USERS This guideline is intended for clinicians involved in the delivery of colonoscopy to patients in Ontario and for policy makers and program planners involved in quality assurance at Cancer Care Ontario and in hospitals and clinics. Colonoscopy may be performed for a variety of indications, specifically: follow-up to a positive fecal occult blood test, screening for those who have a family history of colorectal cancer in a first-degree relative, investigation for symptomatic patients, surveillance of those with a history of adenomatous or serrated polyps, inflammatory bowel disease or CRC, and other screening (e.g., average-risk screening). # E. RECOMMENDATIONS AND KEY EVIDENCE # I. TRAINING AND MAINTENANCE OF COMPETENCY # Primary training - To be considered for credentialing, gastroenterologists must complete a formal two-year subspecialty training program, with the option of a third year of subspecialty training, before entering full-time practice. Prior to being qualified, other physicians, including surgical residents, must acquire the necessary specific knowledge and technical training in colonoscopy over a period of at least six months. # Key Evidence The guideline development group endorses the recommendations of the Canadian Association of Gastroenterology regarding the requirements for credentialing. # Attainment of competency - To be considered competent colonoscopists, trainees should achieve an average independent cecal intubation rate (CIR) of at least 85% for all colonoscopies and are expected to have performed at least 300 colonoscopies during training. The independent CIR should be measured on a subset of colonoscopies performed at the end of training. If 300 colonoscopies are performed during training, it is anticipated that at least 50 polypectomies would have been performed. In addition to proficiency in the technical aspects of colonoscopy, proficiency in cognitive aspects of the procedure is essential, including knowledge of appropriate contraindications and indications for colonoscopy, application of appropriate screening and surveillance intervals (4), histologic classification of polyps and their significance, and knowledge of how to deal with findings encountered at the time of colonoscopy. # Key Evidence Most sources located in the review state that competent colonoscopists should be able to intubate the cecum in ≥90% of all cases (5). The consensus of the guideline development group was that a slightly lower threshold of at least 85% for new endoscopists was realistic at the completion of training, with the justification that the higher threshold stated in the next Recommendation would apply as endoscopists continue in independent practice. In determining a threshold for volumes required to attain competency, the working group assessed the relationship between volumes and cecal intubation rate. In the full-text studies found in the literature, estimates ranged from 275 colonoscopies to achieve an average CIR of 85%, and 400 colonoscopies to achieve an average CIR of 90% among 41 GI fellows (6), to 500 colonoscopies needed for all fellows in a three-year training program to achieve reliable independent completion rates of at least 90% (7). The guideline development group chose the moderate value of 300 as a minimum volume to achieve competency because of the variability of the evidence and because lower thresholds defined in the past have, in practice, been shown to be inadequate for most trainees to achieve competence (8). It is preferable to use an objective criterion of technical competence, such as the cecal intubation rate, rather than volume when granting privileges to physicians for endoscopic procedures (8). The statement that trainees will remove polyps in at least 50 patients is based on the target of 300 procedures during training. However, it is the opinion of the guideline development group that performing this volume should provide newly trained colonoscopists with sufficient experience with the basic therapeutic techniques in colonoscopy. A similar threshold has been used in other guidelines as a consensus-based recommendation (9). # Qualifying statement: - Completing recommended training period and meeting volume minimums does not ensure competence in colonoscopy; the achievement of the minimum rate of cecal intubation stated in the Recommendation above is still required as well as proficiency in the cognitive aspects of colonoscopy. # Granting, maintenance and renewal of privileges - Each institution or facility should develop and maintain guidelines for granting and renewing privileges. A physician who is requesting privileges to perform colonoscopy after having been away from practice for three or more years, or who has practised endo-colonoscopy for less than the equivalent of six months in the previous five years should undergo an individualized educational process prior to the granting of privileges (10). Detailed training requirements are provided in the College of Physicians and Surgeons of Ontario document, Expectations of physicians who have changed or plan to change their scope of practice to include endo-colonoscopy (10). Endoscopists should perform a minimum of 200 colonoscopies per year with a desired minimum cecal intubation rate for outpatient colonoscopies of 95% in patients with adequate bowel preparation and no obstructive lesions. # Key Evidence There is good evidence that proficiency in endoscopic procedures is dependent upon continued practice and performance of adequate numbers of procedures, although the evidence for precise volume thresholds is controversial (11). One study of volumes and postcolonoscopy colorectal cancer (PCCRC) diagnosed within six to 36 months of colonoscopy did not find a significant relationship (12). Another study found that endoscopists in the lowest volume quintile (median 63 procedures annually) had three-fold higher odds of bleeding or perforation within 30 days of outpatient colonoscopy (OR, 2.96; 95%CI, 1.57%-5.61%) than the highest volume quintile (median, 417 procedures annually) (13). The consensus of the guideline development group was that the newer evidence was not significant or consistent enough to warrant a change from the recommendation of 200 colonoscopies per year stated in the previous version of this guideline (1). # Patient assessment All patients should receive a pre-procedure assessment, and any questions that the patient may have should be answered at that time. It is advisable to conduct the preassessment several days before the procedure if it is the patient's first encounter with the endoscopist, in order to allow sufficient time for safety concerns to be addressed or medication such as warfarin to be withdrawn (2), and to ensure that the patient has sufficient understanding of the bowel preparation process. If a preprocedure assessment with the endoscopist is not available, patient education regarding the issues listed below must be provided in written form and the associated care provider or endoscopy unit staff must be available to answer patient questions. In addition, the referring physician must provide data on medications, allergies and medical conditions listed below to the endoscopist. Pre-procedure patient history and assessment should include: - Instructions for anti-platelet agents/blood thinners, to be individualized to patient risk level. Instructions for glucose management in diabetics. Pre-procedure assessment should also include gathering of information regarding: - Indication for colonoscopy. A list of current medications and drug allergies. American Society of Anesthesiologists classification of patient status and other information that may influence type and level of sedation. Cardiac and respiratory disorders, including ischemic heart disease, hypertension, sleep apnea, and chronic obstructive pulmonary disease. Cardio-respiratory function should be reviewed on the day of the colonoscopy. Any other significant medical problems, including previous abdominal surgery. # Informed consent: - Should be obtained prior to the administration of sedation. Should be documented on the chart. All patients must receive follow-up care, including: Reports to the referring and family physician that include the following: type of procedure, date of procedure, sedation received, anatomical extent of colonoscope insertion, colonoscopic findings, histopathology report regarding any tissue that was removed, and recommendations regarding the need for and timing of follow-up colonoscopy as required. Where possible, instructions for arranging follow-up colonoscopy should be provided. A follow-up appointment with the physician who performed the colonoscopy, if indicated. The recommendations for pre-procedure assessment are the consensus of the working group, based on the previous version of this guideline, and guidance documents published by the European Commission (2) and the Quality Assurance Task Group of the National Colorectal Cancer Roundtable in US (14). # Infection control # Administrative aspects: - Establishment of a comprehensive Quality Assurance and Safety Program and procedures for monitoring adherence to the program, including standard operating procedures for preparing endoscopes and quality assurance procedures for reprocessing endoscopes and their accessories. Training and retraining of the staff involved with endoscope care and maintenance a clear chain of accountability for endoscope processing procedures. Technical aspects ( 15): Adherence to the endoscope manufacturer's operating manual and instructions for use. The Expert Panel endorses the standards detailed by the College of Physicians and Surgeons of Ontario (CPSO) concerning infection control (16). These standards are summarized below: Gastrointestinal endoscopes come into contact with mucous membranes and are considered semi-critical items. The minimum standard of practice for reprocessing is high-level disinfection. Accessories (e.g., reusable biopsy forceps) that penetrate mucosal barriers are classified as critical items and must be sterilized between each patient use. It is essential that endoscopes are cleaned to remove organic material before disinfection or sterilization. Accessories labeled as either single use or disposable should not be reprocessed. Endoscopes have been implicated in the transmission of disease when appropriate cleaning or disinfection procedures were not employed, therefore proper cleaning techniques should be used. In contrast to the CPSO standards, the Expert Panel recommends that automated endoscope reprocessing (AER), disinfection, and sterilization processes, and not manual processes, to be used to protect patients, personnel and equipment. Universal precautions must be observed in each facility in order to prevent contact with blood or other potentially infectious materials. All blood or other potentially infectious material should be considered infectious, regardless of the perceived status of the source individual. All personnel performing or assisting with endoscopic procedures should follow universal precautions and wear appropriate equipment to protect themselves from fluid and body substances. Eye protection should be worn to prevent contact with splashes during the cleaning procedure and disinfection/sterilization process. Moisture-or water-resistant gowns should be worn to prevent contamination of personnel due to splashes of blood or other body fluids or injury due to chemical disinfectant or sterilant contact. Gowns should be changed between patient procedures. Further guidance from the CPSO, published in 2010, is endorsed (17): In endoscopy/colonoscopy units, functionally separate areas are required for reprocessing, scope cabinet and dirty areas. # Key Evidence The recommendations for the administrative and technical aspects of infection control are the consensus of the working group, based on recommendations from the United States Food and Drug Administration (15) and the previous PEBC guideline (1). The remainder of the recommendations, except for the recommendation for AER, are based on guidance provided by the CPSO (16,17). The recommendation for automatic endoscope reprocessing was the consensus of the guideline development group that developed the previous version of this guideline. Since that time, national consensus standards have been released by the American Society for Gastrointestinal Endoscopy (ASGE) that state: " can enhance efficiency and reliability of high-level disinfection by replacing some manual reprocessing steps…Use of an AER may also reduce exposure of personnel to chemical germicides" (18). Likewise, European Society of Gastrointestinal Endoscopy -European Society of Gastroenterology standards call for the use of automatic "washer-disinfectors" for a number of reasons, including reliable, standardized and validated reprocessing cycles, reduction in the contact of staff and the environment with chemicals, and less risk of damage to scopes (19). # Use of sedation There is evidence that adequate sedation contributes to better patient outcomes in terms of greater patient cooperation, less patient memory of discomfort, reduction in reported pain, and increase in patient tolerance of the procedure. All patients should be offered sedation unless the endoscopist judges this to be contraindicated. Patients need to be aware that they have the right to refuse sedation if they so desire. # Key Evidence The Expert Panel endorses the sedation recommendations contained in the previous version of this guideline (1). # Monitoring during and after the administration of conscious sedation # When conscious or deep sedation is used: - Patients undergoing procedures with conscious or deep sedation must have continuous monitoring before, during and after sedative administration. Monitoring of all patients, including blood pressure, pulse, respiration, level of consciousness, and degree of discomfort at the initiation, during and at the completion of the procedure is recommended. Depending upon patient response, assessment may need to be more frequent. These data should be recorded at the endoscopy unit level, using a system chosen by the unit. Modern electronic monitoring equipment may facilitate assessment but cannot replace RNs or RPNs with appropriate certification or special training in sedation and endoscopy. Continuous electrocardiogram monitoring is reasonable in high-risk patients. This subgroup of high-risk patients would include those who have a history of cardiac or pulmonary disease, the elderly, and those patients for whom a prolonged procedure is expected. - The endoscopy unit should have a formal process to document sedation and patient comfort using a system of the unit's choice. The unit should audit its individual physicians' use of sedation. # Key Evidence The Expert Panel endorses the sedation recommendations contained in the previous version of this guideline (1). # Monitoring during recovery - A list of criteria such as the Aldrete score (respiration, oxygen saturation, consciousness, circulation and activity levels) ( 20) should be used to determine readiness for discharge (21). Readiness for discharge should be documented in the chart. Prior to discharge, pre-procedure teaching regarding driving, including the time period for not driving agreed to during the informed consent process, equipment operation, and making decisions requiring judgment should be reinforced. The teaching provided should be in written form and given to the patient prior to discharge. As the amnesia period that follows the administration of sedation is variable, written instructions should be given to the patient, including the procedures to follow if an emergency arises. # Key Evidence Recommendations regarding monitoring during resuscitation are the consensus of the working group, based on the previous version of this guideline (1). # Resuscitation capacity - A general plan for resuscitation, including the identification of properly trained personnel should be in place with: At least one physician certified and current in Advanced Cardiac Life Support on-site and available within five minutes. At least one additional person currently certified in Basic Cardiac Life Support in the endoscopy unit or in the room during the procedure (16). Resuscitation equipment should be available including defibrillator, endotracheal tubes, airways, laryngoscope, oxygen sources with positive-pressure capabilities, emergency drugs and oxygen tanks. # Key Evidence Recommendations regarding resuscitation capacity are the consensus of the working group, based on the previous version of this guideline (1). # Endoscope quality - All colonoscopies should be performed using a video colonoscope that can be maintained within manufacturers' specifications. - The equipment should have the capacity to create photographic records, either paper or digital. # Key Evidence This recommendation is the consensus of the working group. # III. COLONOSCOPY QUALITY INDICATORS AND AUDITABLE OUTCOMES Recommendations where there is sufficient evidence to endorse a specific target in this section are called quality indicators. These include: - CIR; Bleeding rate after polypectomy; Perforation rate. Some indicators had insufficient evidence to recommend a specific target; however, the working group agreed that they should be monitored as important components of a quality assurance program. These are labelled auditable outcomes and include: ADR; PR; Bowel preparation; PCCRC; Interval between colonoscopies. These labels are consistent with those used in other guidance documents (2,3). # Cecal intubation rate (CIR) Cecal intubation is defined as passage of the scope beyond the ileocecal valve into the cecal pole or terminal ileum (3). Lower CIR or completion rate has been significantly associated with greater risk of a post-colonoscopy colorectal cancer in a study using a large administrative database in Ontario (12). CIR targets can be unadjusted or reported after adjustment for factors such as indication, poor bowel preparation, strictures, previous colonic surgery (i.e., right hemicolectomy) or severe colitis. Adjusted targets are set higher than unadjusted rates. # Quality Indicator A cecal intubation rate of 95% is desirable in patients with adequate bowel preparation and no obstructive lesions. # Key Evidence - The above 95% adjusted rate is considered consistent with the 90% unadjusted rate recommended in the UK in a FOBT-based screening program (3). An 85%-90% unadjusted rate for all colonoscopies is recommended by CAG (22) as a reasonable expectation for "competent colonoscopists." Evidence that this expectation may be reasonable in the Canadian context comes from a point-of-care audit, which found that 94.9% of patients had a complete colonoscopy based on self-reported data from 5% of practicing Canadian endoscopists (23). Qualifying statement Written documentation of colonoscopy completion is required, along with photographic evidence. Where data on bowel preparation and colonoscopy findings are not available, use of an unadjusted rate of 90% is reasonable to audit performance. # Adenoma detection rate (ADR) Although CIR is the most commonly used quality indicator for colonoscopy, ADR, defined as the proportion of patients that have at least one adenoma identified and removed during colonoscopy, is a more specific and direct indicator of the quality of colonoscopy ( 24), because adenomas are known cancer precursors. ADR has also been associated with important clinical outcomes such as interval cancers. Expected ADR is influenced by the underlying characteristics of the population, including age, sex and a family history of a firstdegree relative with colorectal cancer before age 60. ADR can also vary depending on quality of bowel preparation, and the experience level of the endoscopist. Recently, sessile serrated polyps, which are distinct from adenomas, have been recognized as important cancer precursors (25). To date, there is no consensus that they should be measured as a part of the ADR. # Auditable outcome An ADR target level is not specified for this indicator; however, it should be tracked and monitored for the following patient subgroups as a key component of the quality assurance program: - Patients undergoing primary screening with colonoscopy; Patients who have a positive FOBT or FIT; Patients with a family history of CRC. Kaminski (2010) found ADR to be a reliable independent predictor of the risk of interval colorectal cancer (26). ADRs found in the literature are highly variable, with rates of any adenoma or cancer ranging from 14.9-37.5 (2,5). The wide variation reported likely reflects important differences in the populations studied. As such, these studies are not readily generalizable to the Ontario context. Therefore, the working group determined that there was insufficient evidence to make a specific target recommendation at this time for this indicator. As auditing of this indicator in the Ontario population continues and reporting improves, it is advised that future study be undertaken to determine an appropriate target. # Key Evidence # Qualifying statement - Endoscopists should monitor their individual ADR. # Polypectomy rate Polypectomy rate (PR) is defined as the proportion of patients who have at least one polyp identified and removed during colonoscopy. The previous version of this guideline did not assess PR as a quality assurance indicator. Since that time, research has been published on the use of PR as a proxy for adenoma detection rate. This indicator has the advantage that information on the presence or absence of polyps is available at the time of colonoscopy, unlike adenoma detection, which requires pathologic confirmation, and that it is captured in health administrative data. # Auditable outcome A PR target level is not specified; however, the rate should be tracked and monitored for the following patient subgroups as a key component of the quality assurance program: - Patients undergoing primary screening with colonoscopy; Patients who have a positive FOBT or FIT; Patients with a family history of CRC. # Key Evidence As this indicator was not used in the previous PEBC guideline, the working group assessed evidence to determine its relationship to previously established quality indicators such as ADR and PCCRC: - A study found a correlation between ADR and PR of r=0.88 (95%CI, 0.78%-0.94%) in an average-risk asymptomatic population with FOBT positive test results (27). Endoscopists' PRs yielded similar assessments of quality as their ADRs (r=.91, p<.0001 in men and r=.91, p<.0001 in women) in an average-risk screening setting (28). Endoscopists who achieved a PR of 40% in men and 30% in women almost always achieved an ADR of 25% and 15%, respectively, and also found more advanced lesions. Baxter et al (29) found that the median PR for endoscopists over a 2-year period was 17.7% (range, 0.0%-72.5%). Patients undergoing colonoscopy performed by an endoscopist with a PR ≥25% were less likely to develop a proximal PCCRC (diagnosed 7 to 36 months after the procedure) than if colonoscopy was performed by an endoscopist with a 10% PR (OR, 0.61; 95%CI, 0.42%-0.89%). PR was not associated with the diagnosis of a distal PCCRC. Based on these studies, the working group concluded that PDR is a valid proxy for ADR and may be a useful quality assurance indicator where ADR is not readily available. However, as rates in the literature are highly variable, it is not possible to specify a target for this indicator at this time. As auditing of this indicator in the Ontario population continues and reporting improves, it may be possible to determine an appropriate target in the future. # Bowel preparation Proper bowel preparation is important because it is associated with higher colonoscopy completion rates and ADRs (1). Split dosing (i.e., dosing at least half of the preparation on the day of the colonoscopy) has been established as superior to dosing all the preparation the day before the test (2), because it enhances the effectiveness of commercial preparations (30). # Auditable outcome Endoscopists should strive for adequate bowel preparation, and quality of bowel preparation should be recorded and monitored using a standardized scale of the endoscopy unit's choice. Users of the scale should be trained on the use of the scale to ensure it is consistently applied. # Key Evidence Several guidelines recommend that the percentage of colonoscopies where the bowel preparation was adequate to detect polyps larger than 5 mm should be measured, and inadequate preparation should occur in no more than 10% of colonoscopies (14). As auditing continues, it may be possible to determine an appropriate target for this indicator in the Ontario population in the future. # Qualifying Statements - In order to improve the effectiveness of bowel preparation, where possible, split dosing of the bowel preparation is preferred. A standardized tool such as the Ottawa Bowel Preparation Scale (OBPS) (31) or the Boston Bowel Preparation Scale (32) may be used to assess bowel preparation quality (33). An OBPS score of less than 5 can be used as a cut-off (23). # Withdrawal time Withdrawal time has been proposed as a proxy quality assurance measure to ensure that endoscopists are taking adequate time to withdraw the endoscope and examine the colon for adenomas. It is not necessary to achieve a specific withdrawal time target or to audit this indicator for quality assurance purposes. # Key evidence and rationale The previous PEBC guideline found insufficient evidence to set a target for withdrawal time, although it was listed as a performance measure. The consensus of the current guideline development group is that withdrawal time as an indicator does not necessarily reflect the true characteristics of high-quality endoscopy (34), and that longer procedure time does not necessarily mean higher quality; the endoscopist must be able to recognize important pathologic features and have the technical skills to ensure appropriate management (35); therefore, the working group has chosen to focus on other indicators of endoscopic skill. This opinion is supported by a study that did not find a relationship between withdrawal time and adenoma detection rate (36). Capturing withdrawal time is less important in a setting where other quality indicators that we have recommended for monitoring, including ADR, CIR and complications, can be monitored (37). It is also possible that a focus on withdrawal time would have a negative impact on productivity and efficiency for negligible gain (38). # Post-colonoscopy colorectal cancer (PCCRC) This indicator captures the occurrence of new or missed CRC diagnosed after colonoscopy. It is often defined as the proportion of persons with CRC who underwent a colonoscopy within six to 36 months prior to the diagnosis of CRC (those with a colonoscopy within 6 months of diagnosis are considered to be detected cancers) (12). The reason for a PCCRC is often unknown, and possible reasons include missed lesions, incomplete removal of adenomas, and new rapidly growing lesions (35). The associated time period in which the PCCRC is diagnosed following the colonoscopy can be specified (e.g., 1 year, 3 years, 5 years) (39). Among those with CRC who had colonoscopy, the rates of PCCRC ranged from approximately 5% (39) to 9% (12). PCCRC can also be defined as the rate of CRC in a cohort of individuals followed prospectively from the time of colonoscopy until CRC diagnosis. A Canadian study found that 14 years after negative complete colonoscopy, the overall incidence of CRC was 1.3% in an Ontario population (40). # Auditable outcome A target level is not specified for this indicator; however, it should be tracked and monitored as a key component of the quality assurance program. # Key Evidence It is the consensus of the working group that this indicator be added to the list of important quality indicators and monitored at the province-wide level. # Qualifying statement: - Incidence of PCCRC should be tracked at the facility or at system-wide level, because estimates at the endoscopist level are unstable due to the low incidence of PCCRC. # Bleeding rate after polypectomy Bleeding is the most common complication of polypectomy and can occur during or after the procedure (3). # Quality indicator Overall rates of clinically significant (leading to hospital admission) post-polypectomy bleeding should be no more than 1 per 100 colonoscopies. # Key Evidence In the opinion of the working group, bleeding in the absence of polypectomy is not considered a clinically significant event, thus only studies that included patients who had undergone polypectomy during colonoscopy were included in the evidence base for this indicator. Three of 12 studies in the USPSTF meta-analysis met this criterion (41), with rates ranging from 0.40% (42) to 0.48% (43). Our systematic review found bleeding after polypectomy rates of 0.50% in the 30 days after the procedure in a screening population (44), and 0.94% while in the endoscopy unit for a higher risk population (45). # Perforation rate Perforation is an uncommon adverse events that that can occur during or shortly after colonoscopy (5). Rates in patients being screened are expected to be lower because these patients are generally healthy and tend not to have colonic conditions that are associated with perforation. # Quality indicator Overall colonoscopy perforation rates should be less than 1 per 1000. # Key Evidence - Other guidelines have suggested an overall quality threshold of <1 per 1000 for perforations caused by colonoscopy (2,22,46). A systematic review was conducted by the US Preventive Services Task Force for their clinical practice guideline on screening for colorectal cancer. In a meta-analysis of 13 studies, it was noted that perforations occurred in asymptomatic populations in 0.56 per 1000 procedures. The majority of perforations were in colonoscopies with polypectomies (although the percentage with polypectomy was only reported in three studies) (41). Eight studies located in our review, which included diagnostic and therapeutic colonoscopies, also found that rates were generally lower than 1 per 1000. For example, using administrative data from Canadian provinces, Rabeneck et al found an outpatient perforation rate in usual clinical practice within 30 days of colonoscopy of 0.85 per 1000 (13). Qualifying statement Colonic conditions that are known to affect the risk of perforation include pseudoobstruction, ischemia, severe colitis, radiation-induced changes, stricture formation, bulky colorectal cancers, more severe forms of diverticular disease, and chronic corticosteroid therapy (5). As perforation is a rare event, perforation rates should be tracked at the facility and/or system-wide level. Measurements at the individual endoscopist level are likely to be unstable. # Interval between colonoscopies Although this indicator was not included in the previous PEBC guideline, it has been adopted as an audible outcome for this version of the guidance document. This indicator addresses the importance of adhering to appropriate evidence-based intervals between colonoscopies, in order to balance the potential for harm from the rare adverse events associated with colonoscopy, and the benefits of CRC prevention and early detection. # Auditable outcome The rate of adherence to locally recommended screening intervals should be monitored at the individual endoscopist level. # Key evidence There is evidence that many physicians perform examinations at shorter intervals than are recommended, which consumes colonoscopy resources, increases health care costs, and exposes patients to unnecessary risk (47). As well, recommended intervals for surveillance for individuals with a family history are often not adhered to, resulting in longer intervals or no follow-up (48). The addition of this indicator and the recommendation to monitor adherence to appropriate intervals between colonoscopies are the opinion of the guideline development group, in keeping with other recent colonoscopy quality assurance guidelines (2,14). # Qualifying statement: - The PEBC is currently developing a separate guidance document to be released in 2014 that will provide recommendations on appropriate colonoscopy intervals for individuals at various risk levels. # RELATED GUIDELINES Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

Questions JUDGEMENTS The GDG considered this topic a low priority for health economic analysis. The Working Group members agreed that the feasibility of PCI for this population has been well established. # Appendix 1: Affiliations and Conflict of Interest Declarations In accordance with the PEBC Conflict of Interest Policy, the Members of the Prophylactic cranial irradiation for SCLC GDG Working Group, Expert Panel, and Report Approval Panel were asked to disclose potential conflicts of interest.

For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca # Bone Health and Bone-Targeted Therapies for Prostate Cancer Recommendations This is a quick reference guide and provides the guideline recommendations only. For key evidence associated with each recommendation, the systematic review, and the guideline development process, see the Full Report. # GUIDELINE OBJECTIVE To evaluate the effectiveness of therapies targeting bone across all stages of prostate cancer. # TARGET POPULATION Men with prostate cancer. # INTENDED USERS Healthcare professionals, health care administrators, medical or radiation oncologists who treat genitourinary cancer, urologists, radiologists, nuclear medicine physicians, geriatricians, primary care physicians, osteoporosis experts, patients, and media. # RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE # QUESTION 1 Can therapeutic interventions reduce osteoporosis-related outcomes in men with prostate cancer receiving androgen deprivation therapy (ADT)? - For men with prostate cancer at high risk of fracture (with or without bone metastases) receiving ADT, denosumab at the osteoporosis-indicated dosage should be considered to reduce the risk of fracture. In situations or jurisdictions where denosumab is contraindicated or not available, a bisphosphonate is a reasonable option. # Qualifying statements: - Fracture risk can be estimated based on risk prediction tools such as the World Health Organization Fracture Risk Assessment Tool (WHO FRAX) or the Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool. - Baseline bone mineral density (BMD) testing with conventional dual X-ray absorptiometry is encouraged for men prior to starting ADT to help determine the risk of fracture and identify those individuals most likely to benefit from denosumab or bisphosphonates. If a BMD test has been performed in the past one to two years, a repeat BMD test is not likely to be informative prior to starting ADT unless the patient was initiated on denosumab or bisphosphonates. - The optimum duration of therapy is unknown. Current studies provide results up to 36 months of therapy. - The dosages used in the studies were: - Denosumab, 60 mg subcutaneous injection every six months (See Although both drugs were associated with increased BMD and toremifene reduced the risk of fracture, SERMs are associated with increased risk of venous thromboembolic events, raising safety concerns in this population. - Three small trials comparing exercise programs with usual care and one small trial comparing group exercise with personal training showed no difference in BMD between groups. One trial showed improvements in quality of life measures with exercise. A more comprehensive review of exercise for people with cancer is available (see Guideline 19-5: Exercise for People with Cancer). - In patients with metastatic disease, fracture is part of the skeletal-related events (SRE) composite outcome (See question 3). - Men with castration-sensitive prostate cancer with bone metastasis may derive benefit from starting or continuing denosumab at the osteoporosis-indicated dosage or a bisphosphonate for fracture prevention. However, few trials that were reviewed for this question included such men and analyses, stratified by the presence or absence of bone metastasis, were not performed. Therefore, the evidence of benefit is less compelling in this scenario. # QUESTION 2 Can therapeutic interventions prevent bone metastases in men with prostate cancer? 2a. In men with high-risk localized prostate cancer, bisphosphonates are not recommended to reduce the risk of first bone metastasis. 2b. In men with nonmetastatic castration-resistant prostate cancer (CRPC), denosumab at the bone metastasis-indicated dosage is not recommended to reduce the risk of first bone metastasis. - Denosumab has not been approved in Canada or the United States for this indication (2b). - Denosumab, 60 mg subcutaneously every six months, can still be used to prevent osteoporosis-related outcomes (see Recommendation 1). # QUESTION 3 Can bone-targeted therapies reduce the incidence of SREs, reduce pain, or improve quality of life in men with prostate cancer metastatic to bone? 3a. In men with metastatic CRPC (mCRPC), either ZA (minimally symptomatic or asymptomatic disease) or denosumab (disease independent of symptoms) (both at bone metastasis-indicated dosages) is recommended for preventing or delaying SREs. Insufficient evidence exists to make a recommendation with respect to men with castration-sensitive prostate cancer and bone metastasis. 3b. In men with symptomatic mCRPC and bone pain, radium (Ra)-223 should be considered for reducing symptomatic skeletal events and improving health-related quality of life. 3c. In men with mCRPC and bone pain, radiopharmaceuticals or IV bisphosphonates may be considered for pain palliation. # Qualifying statements for Question 3 recommendations: - See Table 1-1 for dosages. Patients receiving either denosumab or ZA should be taking 1000 mg of elemental calcium (from dietary and/or supplemental sources) and ≥400 IU of vitamin D daily. The dose of ZA should be reduced in cases of renal insufficiency (creatinine clearance 132.5 µmol/L). ZA is not recommended below a CrCl of 30 mL/min (or SCr >265 µmol/L). In patients over the age of 65, CrCl (whether estimated or directly measured) should be used rather than SCr. Denosumab and ZA should not be given in combination. - There is uncertainty regarding the optimum duration of therapy; with respect to ZA, less-intensive therapy (i.e., every 3 months) may be as effective as monthly treatment (CALGB 70604 Alliance study. - SRE definitions and data reporting pain are not identical across studies. - Recommendation 3b applies to men with predominantly bony metastases and no evidence of visceral metastases or large nodal metastases. - Radiopharmaceuticals can permanently reduce bone marrow reserves, and this should be considered if the patient remains a candidate for palliative cytotoxic chemotherapy. The recommended dose for Ra-223 is one IV injection of 55 kBq/kg of body weight every four weeks for a total of six injections (based on the primary standardization revision for Ra-223 in 2015 by the National Institute of Standards and Technology. The optimal sequencing of Ra-223, denosumab, and bisphosphonates is unclear, and recommendations to patients should be done in consultation with a clinician with expertise in CRPC treatment. - Systemic therapies for the treatment of mCRPC such as abiraterone/prednisone, enzalutamide, docetaxel, and cabazitaxel have been shown to reduce SREs, improve bone pain and health-related quality of life, and/or improve overall survival in mCRPC. Mitoxantrone has also been shown to improve pain and health-related quality of life (see Guideline 3-15: Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer). The optimal sequencing or combination of these therapies with bone targeted agents is unclear, and recommendations to patients should be done in consultation with a clinician with expertise in CRPC treatment. - Radiotherapy is one of the main therapeutic approaches to palliate pain in men with bone metastasis. # QUESTION 4 Can bone-targeted therapies improve overall survival in men with established prostate cancer and bone metastases? - In men with symptomatic mCRPC, Ra-223 is recommended to extend overall survival. # Qualifying statements: - This recommendation applies to men with predominantly bony metastases and no evidence of visceral metastases or large nodal metastases. - Ra-223 appears to be equally effective whether or not patients have received prior docetaxel or are eligible to receive docetaxel. - Other options are available aside from bone-targeted therapies or radiopharmaceuticals for improving outcomes (see Guideline 3-15: Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer). The optimal sequencing of therapies is unknown. - There is insufficient evidence to support an improvement in overall survival with bisphosphonates or denosumab in this population. - Systemic therapies for the treatment of mCRPC such as abiraterone/prednisone, enzalutamide, docetaxel, and cabazitaxel have been shown to reduce SREs, improve bone pain and health-related quality of life, and/or improve overall survival in mCRPC (see Guideline 3-15: Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer). The optimal sequencing or combination of these therapies with bone-targeted agents is unclear, and recommendations to patients should be done in consultation with a clinician with expertise in CRPC treatment.

# RECOMMENDATIONS (The recommendations were slightly modified with respect to risk category 5 during the 2017 ENDORSEMENT) MRI in addition to mammography is recommended for women in target population risk categories 1, 2, 3, and 5 above. The evidence is insufficient to recommend MRI screening for patients in risk category 4. - Multiple studies, four in abstract form, were identified that evaluated MRI in comparison to mammography in women at high risk for breast cancer. These studies all found superior sensitivity for the detection of breast cancer with MRI compared to mammography. MRI was also found by most studies to have inferior specificity to mammography, with higher recall and biopsy rates associated with MRI. # Expert Opinion and Qualifying Statements While there is insufficient evidence at this time to make a definitive recommendation regarding the appropriate screening frequency, it is the opinion of the Working Group that women should be screened annually, as this was the frequency typical of the identified studies on which the recommendation for screening is based. While there is insufficient evidence at this time to make a definitive recommendation regarding the ages of patients who should be screened, it is the opinion of the Working Group that women should be screened annually from 30 to 69 years of age. Age 30 is an appropriate age to begin screening as women at that age with BRCA mutations are at much greater risk of breast cancer than women aged 50 and older in the general population. Age 69 is an appropriate age to end screening because: the relative risk of cancer decreases with age in the population at hereditary risk; mammographic sensitivity increases with age; very few subjects were included in the studies greater than age 69; and the evidence for mortality reduction from screening in the general population is lacking for women older than age 70. # Expert opinion and qualifying statements modified in the 2017 Endorsement: It is the opinion of the Working Group that the benefits of MRI in terms of increased sensitivity outweigh the potential harms of higher recall rates and biopsy rates for all women in risk category 5 who received ≥20 Gy radiation before the age of 30. 1.2017] . Accessed 20 November 2017). This (Ontario) Working Group, however, did not find justification for screening from age 25 in this group (or any of the other high risk groups). In particular, a review of one prospective and 3 retrospective studies published since 2011 that looked at the results of adding MRI to mammography for screening risk category 5 found only 3 cases of breast cancer detected before age 30 out of a total of 51 cases and all 3 of these were detected by both MRI and mammography (See Section 4 for additional information). With respect to risk category 4, there are preliminary data that a subgroup of patients in risk category 4 might benefit from the addition of MRI to mammography (e.g., women who in addition to a high risk benign biopsy or previous breast cancer, also have breast density ≥50% and a family history of breast cancer though insufficient to put them in category 3 Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

December 2018 placed Evidence-Based Series (EBS) 26-3 IN REVIEW. This means that it is undergoing a review for currency and relevance. It is still appropriate for this document to be available while this updating process unfolds. The PEBC has a formal and standardized process to ensure the currency of each document (PEBC Assessment & Review Protocol) EBS 26-3 is comprised of 3 sections.# Section 1: Guideline Recommendations Section 2: Evidentiary Base Section 3: Development Methods, Recommendations Development and External Review Process For information about this document, please contact Yee Ung, the lead author, through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca Table 1 summarizes the recommended evaluations and intervals for the routine surveillance of NSCLC and SCLC survivors. These recommendations are based on the expert opinion of the authors, interpretation of the available evidence, and feedback obtained from health care professionals across Ontario through an extensive review process (described in Section 3 of this document). There is currently no data demonstrating improvements in survival from routine surveillance. There are however clinical options for managing local or locoregional recurrence. Therefore, routine surveillance schedules have been designed in order to detect local or locoregional recurrence and new primary lung cancers that are amenable to salvage therapy in asymptomatic patients during follow-up care. Survivors who develop symptoms suggestive of recurrence, should be evaluated according to those symptoms. # RECOMMENDATION 1 Following curative-intent treatment for NSCLC, survivors should receive scheduled follow-up visits that include a medical history, physical examination and chest imaging. Clinical evaluations should be conducted every three months in years 1 and 2, every six months in year 3 and annually thereafter. # Summary of Key Evidence for Recommendation 1 One systematic review with meta-analysis found no survival benefit with a more intense follow-up schedule for NSCLC survivors (hazard ratio 0.83; 95% confidence interval 0.66-1.05; p=0.13) (1). However, asymptomatic recurrence detection was associated with a longer survival time (HR, 0.61; 95%CI, 0.50-0.74; p<0.01) (1). Other research has determined that in both NSCLC and SCLC, the majority of recurrences are diagnosed in the first two years (2). A systematic review that evaluated the role of computed tomography (CT) follow-up one year after lobectomy did not find a clear survival benefit for CT scans (3). However, a more recent study points to a role for minimal-dose CT (MnDCT) scans, which showed higher sensitivity (94.2% vs. 21.2%; p<0.0001) and negative predictive value (99.7% vs. 96.2%; p=0.007) than chest x-ray for detecting new primary tumours and recurrent lung cancer at an early stage (4). # Justification for Recommendation 1 There is very little high level evidence to inform this recommendation. NSCLC survivors should be followed after curative-intent treatment in order to detect local or locoregional recurrence and new primary lung cancers, which are amenable to resection or radical radiation therapy for salvage. For this reason, the Working Group valued overall survival rate over recurrence detection rate. Visits should include medical history with attention to new symptoms in the aerodigestive tract, physical examination and chest imaging. Due to the lack of evidence to inform which frequency is most appropriate, a consensus approach was used to make a recommendation on the appropriate timing of followup evaluations in the expert opinion of the Working Group. The consensus process incorporated the evidence that most recurrences are detected in the first two years following curative treatment (2), the indication that asymptomatic recurrence detection is associated with longer survival (1) and the clinical experience of the Working Group members. Additionally, even though data for surveillance beyond five years is limited, the Working Group feels confident in recommending ongoing annual surveillance after year five as this population of patients remains at a heightened risk of developing new lung cancers. Data from the National Lung Screening Trial (5,6) for screening high risk populations for lung cancer recommended low dose CT scans to reduce mortality rates from lung cancer. Due to the limited evidence, there is no clear indication of the most appropriate chest imaging modality for surveillance. However, based on the limited evidence and expert opinion, Qualifying Statements with imaging modality suggestions have been included for NSCLC survivors. Although there is no clear evidence from studies focusing on recurrence rate detection, the clinical standard among Ontario health care professionals is CT scan, with the appropriate dose and use of contrast IV remaining controversial. Due to radiation dose concerns when performing CT scans for surveillance, lower dose CT scan protocols are of great interest. The best evidence for the value of low-dose CT (LDCT) surveillance comes from the National Lung Screening Trial (5,6), which indicated that LDCT was better than chest radiography in detecting early-stage lung cancers. The Working Group concluded that the cohort study that demonstrated the superiority of MnDCT over chest x-ray for follow-up of NSCLC survivors (4) paired with the success of LDCT in screening (5,6) provide rationale to suggest either LDCT or MnDCT rather than chest x-ray in follow-up care of NSCLC survivors. The suggestion to include chest CT as a reasonable option for appropriate surveillance imaging of NSCLC survivors is in agreement with recommendations published by the American Association for Thoracic Surgery (AATS) (7), the American College of Chest Physicians (ACCP) (8), the European Society for Medical Oncology (ESMO) (9) and the National Comprehensive Cancer Network (NCCN) (10). # Qualifying Statements for Recommendation 1 (Table 1) Selection of an appropriate imaging modality should reflect the competing risk of locoregional recurrence, which is potentially curative versus distant recurrence, which is not curative. A cohort study (4) and the National Lung Screening Trial (5,6) indicated that MnDCT and LDCT detect pulmonary lesions better than chest x-ray, yet no demonstrated survival benefit has been established in patients treated by surgical resection with curative intent. Thus, for routine surveillance, LDCT or MnDCT without IV contrast may be a reasonable option instead of chest x-ray. The MnDCT cohort study conducted chest CTs at three months posttreatment, followed by six months post-treatment, then at six month intervals until the end of year 2, followed by annually until year 5. As this is the best available schedule at this time, the intervals are considered reasonable, with the addition of annual surveillance exceeding year 5, as outlined in the Justification section. Even though surveillance is recommended annually until end of life, health care professionals should use their own discretion in determining the applicability of annual surveillance in patients who are not well enough to undergo treatment if a new cancer is detected. When recurrent disease or new disease is suspected, either from constitutional symptoms or chest imaging findings, diagnostic chest CT plus upper abdomen CT scan is suggested to identify local recurrence or a new lung primary. # RECOMMENDATION 2 Following curative-intent treatment for SCLC, survivors should receive scheduled follow-up visits that include a medical history, physical examination and chest imaging. Clinical evaluations should be conducted every three months in years 1 and 2, every six months in year 3 and annually thereafter. # Summary of Key Evidence for Recommendation 2 One systematic review with meta-analysis found no survival benefit with a more intense follow-up schedule for SCLC survivors (1). Other research has determined that in both NSCLC and SCLC, the majority of recurrences are diagnosed in the first two years (2). # Justification for Recommendation 2 There was very little high level evidence to inform this recommendation. SCLC survivors should be followed after curative treatment in order to detect new primary lung cancers and local recurrences that may be amenable to further curative treatment. For this reason, follow-up schedules that result in a high detection rate for recurrence are only of value if this translates into an increase in overall survival. Thus, overall survival rate is valued over recurrence detection rate by the Working Group. Visits should include medical history with attention to new symptoms in the aerodigestive tract, physical examination and chest imaging. A consensus approach was used to determine the appropriate timing of follow-up evaluations in the expert opinion of the Working Group. The consensus process incorporated both the evidence that most recurrences are detected in the first two years following curative treatment (2) and that more intense follow-up schedules do not result in a longer overall survival time (1), as well as incorporating the clinical experience of the Working Group members. Due to a lack of evidence, there is no clear indication in the literature on the appropriate surveillance imaging modality for SCLC survivors. The clinical standard among Ontarian oncologists is to perform a CT scan, but there is no evidence to support this choice in a lung cancer survivor population. Based on extrapolation from screening data and expert opinion, Qualifying Statements with imaging modality suggestions have been included for SCLC survivors. Data from the National Lung Screening Trial (5,6) indicated that LDCT was better than radiography in detecting early-stage lung cancers. Based on the superiority of CT to chest x-ray for screening in a high-risk population, in the expert opinion of the Working Group, surveillance of SCLC survivors with CT scans for detection of recurrence or progression may be a reasonable option. Since this suggestion is based on expert opinion and interpretation of data from a screening population, and not the target population of the guideline, a specific radiation dose cannot be included. The suggestion to include chest CT as a reasonable option for appropriate surveillance imaging of SCLC survivors is in agreement with the ESMO guideline for SCLC patients, which states that survivors should be followed with CT scans (11). # Qualifying Statements for Recommendation 2 (Table 1) Selection of an appropriate imaging modality should reflect the competing risk of locoregional recurrence, which is potentially curative versus distant recurrence, which is not curative. Based on the clinical experience of the Working Group and results from the National Lung Screening Trial (5,6), for routine surveillance, diagnostic CT without IV contrast is preferable to chest x-ray for detection of pulmonary lesions, though no survival benefit has been established. Also based on the clinical experience of the Working Group, diagnostic CT with contrast is suggested for detection of recurrence in mediastinal lymph nodes. In the expert opinion of the Working Group, CT imaging may be conducted three months posttreatment, followed by six months post-treatment, then at six month intervals until the end of year 2, followed by annually thereafter. Beyond year 2, LDCT or MnDCT could be considered rather than a diagnostic CT. Even though surveillance is recommended annually until end of life, health care professionals should use their own discretion in determining the applicability of annual surveillance in patients who are not well enough to undergo treatment if a new cancer is detected. When recurrent disease or new disease is suspected, either from constitutional symptoms or chest imaging findings, diagnostic chest CT plus upper abdomen CT scan is suggested to identify local recurrence or a new lung primary. (5,6). III Based on a MnDCT vs. chest x-ray cohort study (4). Abbreviations: LDCT, low-dose computed tomography; MnDCT, minimal-dose computed tomography; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer. # RECOMMENDATION 3 For both NSCLC and SCLC survivors, no recommendation can be made in relation to positron emission tomography (PET)/CT. # Summary of Key Evidence for Recommendation 3 The only identified studies that assessed PET/CT surveillance of lung cancer survivors were in NSCLC survivor populations. Two PET/CT diagnostic studies indicated a benefit for PET/CT over CT alone for recurrence detection (12,13), while another demonstrated a benefit for PET/CT over non-contrast CT for detection of extrathoracic and mediastinal metastases (14). One study, looking at the ability to detect local recurrence, found that almost 26% of the recurrences diagnosed by PET/CT were recurrences within the ipsilateral lung (12). In another diagnostic study, PET/CT scanning led to the detection of lung cancer recurrence that was amenable to salvage therapy in a small proportion (3% of total) of the patients enrolled (13). # Justification for Recommendation 3 The Working Group was unable to provide a recommendation for PET/CT surveillance of NSCLC and SCLC survivors based on the identified evidence. Diagnostic studies have shown better sensitivity, specificity and accuracy of PET/CT compared with CT alone and point to a role for PET/CT in diagnosing local and locoregional recurrences, which may be amenable to salvage therapy (12,13). However, due to the low percentage of local recurrence detected by PET/CT in these studies and the higher doses of radiation patients would receive with PET/CT compared with CT alone, the Working Group feels that the evidence does not point to a clinically important difference in patient outcomes with PET/CT and the data are not strong enough upon which to base a recommendation. # RECOMMENDATION 4 In the expert opinion of the authors, any new and persistent or worsening symptom warrants the consideration of a recurrence, especially: # Summary of Key Evidence for Recommendation 4 Only one prospective cohort study was identified to inform this recommendation. This PET/CT diagnostic study recorded the symptoms experienced by patients who had developed progressive disease and found that these patients experienced more pain and neurological issues than did those without progressive disease (13). # Justification for Recommendation 4 The included study enrolled a modest sample size of 100 patients, with only 24 patients developing progressive disease (13). Due to the lack of evidence and small sample size of the included study, the Working Group decided to use expert opinion in a consensus process to list the potential symptoms of recurrence. # RECOMMENDATION 5 Health-related quality of life (QoL) is very important for long-term survivors suffering from late side effects of their curative-intent therapy (including surgery, chemotherapy and radiation therapy). The following is a summary of issues reported by survivors. Health care professionals need to aid lung cancer survivors in handling these symptoms to improve QoL. # Summary of Key Evidence for Recommendation 5 When overall QoL profiles of lung cancer survivors were analyzed, it was found that survivors of both NSCLC and SCLC experienced a reduction in the physical domains of the QoL questionnaires for up to one year post surgery (15,16). There was an increase in the QoL mental domain level above that experienced pre-surgery by two years, but this level was still lower than an age-matched reference population (16). When only NSCLC survivors were followed after lobectomy, 66% of survivors experienced improved or stable QoL scores, while 71% of survivors experienced improved or stable scores following pneumonectomy or bilobectomy (17). A systematic review that assessed the specific treatment-related long-term effects found that survivors of lung cancer report physical ability restrictions, depression, decreases in general health and vitality, and increased body pain (2). Prospective cohort studies evaluating non-recurrence related issues found that lung cancer survivors experienced longterm dyspnea (18)(19)(20), cough (18,20), fatigue (18,20), impaired breathing (21), increased pain (20,21), decline in appetite (20,21) and reduced sleep efficiency (19). Studies that focused solely on survivors of NSCLC found that a majority of these survivors experienced some degree of pneumonitis ( 22) and a sustained decrease in multiple QoL domains (23). # Justification for Recommendation 5 The literature search on this question was designed to assess both the QoL and treatment-related symptom burden of lung cancer survivors, which quite often go hand-inhand. The studies that informed the research question ranged from systematic reviews and randomized controlled trials (RCTs) to non-randomized prospective cohort studies. All the included studies used prospective data collection and analyzed the study population through comparisons either between groups or within the study group, across time. Unfortunately, since all non-randomized studies carry an unclear risk of bias and most of the studies relied on the use of self-reported QoL tools, which inherently introduce recall bias, it was believed that the studies informing this evidence were of low quality. The Working Group does recognize that this is the best data available as QoL and late treatment effect data are generally not included in treatment trials a priori. However, due to the low quality of studies discovered, the Working Group decided to use both the literature and their clinical experience to summarize the late side-effects and QoL issues reported by long-term survivors of lung cancer. # RECOMMENDATION 6 For lung cancer survivors who have completed curative-intent therapy, surveillance is required and may be provided by specialists, family physicians or hospital-based nurses. # Summary of Key Evidence for Recommendation 6 The literature was searched for studies that compared follow-up care provided by a specialist with care provided by family physicians or nurses. The search returned no studies focusing on lung cancer survivors that compared family physician follow-up with specialist-led care. However, one RCT which compared hospital-based nurse-led follow-up care with specialist-led follow-up care following treatment for SCLC or NSCLC was identified (24). The study found that both QoL and recurrence outcomes were not different between the two groups, indicating that nurse-led follow-up did not negatively impact QoL or recurrence detection. # Justification for Recommendation 6 Unfortunately, the identified RCT is more than 10 years old, and when it was conducted, no effective salvage therapy and no effective second-line chemotherapy were available, which may account for the lack of difference in overall survival being detected. Also, nurses within the study were supervised by specialists and the study allowed for additional visits to the family physician, which may have confounded some of the direct comparisons. Finally, the study included a more advanced disease population than was our target population. The Working Group considered the study limitations and even though this patient population would be managed differently today due to new treatment options, thr group accepts this study as it is the best available evidence. Additionally, for this research question, QoL and satisfaction with care are highly valued. Thus, the Working Group believes that a weak recommendation for care provided by non-specialists is warranted. # Qualifying Statements for Recommendation 6 Although the identified literature only evaluated hospital-based nurse-led care models, expert opinion supports family physician-led care models. Additionally, family physicians should be included in all survivorship care models. There is no evidence to support timing for when lung cancer survivors can be transitioned into non-specialist care, thus no recommendation can be made for when transition is appropriate. # RECOMMENDATION 7 Smoking cessation counselling is recommended for patients who have completed curativeintent therapy for NSCLC and SCLC. Although verbal cessation advice from a health care professional is of benefit, interventions that involve behavioural and pharmacotherapy support in addition to verbal advice is recommended. # Summary of Key Evidence for Recommendation 7 Systematic reviews that assessed the efficiency of smoking cessation counselling concluded that any intervention is better than no cessation advice from a health care professional (25), and that an intensive intervention that adds further follow-up visits is more effective than brief intervention (25). When pharmacotherapy and behavioural support are added to advice from a health care professional alone, the benefit of the counselling is increased (26). The three systematic reviews and one cohort study that evaluated the benefits of smoking cessation after diagnosis of lung cancer or prior to surgery all concluded that smoking cessation improved clinical outcomes (27)(28)(29)(30). Cohort studies that looked at the association between smoking cessation and QoL found that never-smokers reported the best QoL after curative treatment (31,32). However, patients who quit smoking within one year prior to diagnosis or during follow-up reported better overall QoL and symptom scales, compared with survivors who continued to smoke (31)(32)(33). # Justification for Recommendation 7 Even though none of the identified studies directly evaluated the value of smoking cessation counselling directly, the Working Group members agreed that taken together, the evidence for the benefit of smoking cessation counselling, the evidence for the benefits of cessation in lung cancer survivors and the evidence for the QoL benefits of cessation can be combined to adequately inform this recommendation. # HOW THIS GUIDELINE CONTRIBUTES TO THE CARE OF PATIENTS Studies showing the benefits of surveillance after treatment for lung cancer are fairly new. For this reason, many physicians have not favoured intensive follow-up or advanced imaging because it was thought to be of little value. In the current era, improved treatment options exist, producing a larger population of lung cancer survivors and thus making followup more important. However, there is currently great variability in the follow-up care being provided to lung cancer survivors in Ontario due to a lack of high-quality evidence to support one surveillance schedule. Additionally, there is a lack of high-quality evidence to inform which clinical evaluations should be performed at follow-up visits. The current evidencebased guidance document provides recommendations on appropriate follow-up schedules and evaluations for survivors of NSCLC and SCLC. This guidance document also outlines specific symptoms that may indicate recurrence or progression of lung cancer and that should be further investigated by an appropriate health care professional. Lung cancer survivors have specific post-treatment health-related QOL issues. Physicians and other health care professionals can assist patients with these issues. Finally, health care professionals can positively impact the rate of smoking cessation in lung cancer survivors by ensuring that smoking cessation counselling occurs. # FUTURE RESEARCH High-quality literature for this topic was very limited. As such, many of the recommendations are based on clinical standards and expert opinion. Research into better salvage therapies, as well as detection of recurrent disease and second primary cancers at an earlier stage is greatly needed. Additionally, very little evidence was identified that assessed symptoms of lung cancer recurrence or development of second primary tumours. Research into these areas will allow for better guidance for health care professionals. Additionally, studies that investigate other issues experienced by cancer survivors, such as fear of recurrence, sexual health, return to work and psychosocial coping, have not been addressed in solely lung cancer survivor groups, presenting an area in need of future work. Finally, although survivorship follow-up care plans facilitate continuity of care and may minimise adverse outcomes as survivors transition into non-specialist follow-up care, care plans have not been extensively evaluated in lung cancer survivor populations, presenting another area in need of future research. # RELATED GUIDELINES - PEBC EBS No. The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol, available on the CCO website at: .

# GUIDELINE OBJECTIVES This guideline aims: -To describe the role of active surveillance (AS) as a management strategy for patients with localized prostate cancer. -To identify patients with prostate cancer that would most benefit from AS. -To develop an evidence-based protocol for AS in localized prostate cancer and to identify the factors affecting the offer of, acceptance of, and adherence to AS. -To understand the role of 5-alpha reductase inhibitors (5ARI) (e.g., finasteride and dutasteride) in patients with localized prostate cancer undergoing AS. -To identify which physician is responsible for managing the AS protocol and if any other human resources required to offer AS (e.g., genitourinary pathologist, psychosocial specialist, etc.) would need specific training. # TARGET POPULATION Men with clinically localized prostate cancer (stage T1 and T2, Gleason score ≤7). # INTENDED USERS Clinicians and specialists providing care to patients with prostate cancer (i.e. urologists and radiation oncologists). Prostate cancer is often a slowly progressive or nonprogressive indolent disease diagnosed at an early stage with localized tumours that are unlikely to cause morbidity or death (1). Standard active treatments for prostate cancer include radiotherapy (RT) or radical prostatectomy (RP). However, harms from overdiagnosis and overtreatment are a significant concern and the risks of active treatment may outweigh the benefits in many patients, particularly those with low-grade disease. To address these concerns, AS is increasingly being considered as a management strategy to avoid or delay the potential harm caused by unnecessary radical treatment (2) in those patients with prostate cancers that are unlikely to progress. There are no published randomized controlled trials (RCTs) comparing AS to active interventions. Some of the evidence used in this guideline comes from trials comparing active intervention (such as RP) to watchful waiting (WW) or observation. AS differs from WW or observation in both intent and in the utilization of serial biopsy strategies. The intent of WW or observation is to avoid active intervention in patients with limited long-term survival expectancy by providing delayed noncurative therapy for patients who experience metastatic progression. Patients with Gleason ≤6 prostate cancer rarely experience metastatic progression on WW or observation and therefore the members of the Working Group and Expert Panel feel that the results from these trials give important natural history information and the results can be used to inform this guideline on AS. The intent of AS is curative, allowing the option of active treatment for those patients on AS who are reclassified to higher risk or who show disease progression. AS involves regular follow-up testing for prostate-specific antigen (PSA), digital rectal examination (DRE), repeat prostate biopsy, and use of prostate imaging, when indicated. The goal of this strategy is to monitor cancers at low risk of future progression to select patients with occult cancers of higher grade and risk who require timely therapy, while maintaining surveillance on patients who remain classified as having low-risk cancers (1). The majority of prostate cancers at low risk of future progression are the low-grade cancers which have the most favourable outcomes. The Gleason grading system is effective in predicting the biological behaviour and prognosis of these cancers. In combination with measurements of tumour extent, Gleason score is the most meaningful pathologic determinant of eligibility for AS protocols. Modifications to the Gleason scoring system in recent years have enabled the identification of more homogeneous, truly low-grade Gleason <6 prostate cancers (3). Pure Gleason 6 cancers defined according to these criteria showed lymph node metastases in only 0.48% of patients in a recent meta-analysis of 21960 RP specimens (4). In Ontario, the selection of patients and the protocols used for AS vary across the province, and the importance of establishing a standardized protocol for AS has led to the development of these evidence-based recommendations. The term "low-risk" prostate cancer as used in this guideline is defined as the risk status for patients who have Gleason score ≤6, PSA <10, and ≤ stage T2A. The Working Group and Expert Panel have defined our target populations for AS recommendations by Gleason score ≤6 and also Gleason score 3+4. # RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION # RECOMMENDATION 1 For patients with low-risk (Gleason score ≤6) localized prostate cancer, AS is the preferred disease management strategy. # Summary of Key Evidence for Recommendation 1 -Eight noncomparative studies of low-risk patients undergoing AS reported prostate cancer survival rates of 100% (5-12) and another two noncomparative studies reported high prostate cancer survival rates of 97% ( 13) and 98% respectively ( 14). -Studies comparing immediate RP with delayed RP in patients undergoing AS detected no significant differences in biochemical recurrence rate, positive surgical margins, extraprostatic extension (15)(16)(17), and risk of incurable cancer (18)(19). # RECOMMENDATION 3 The AS protocol should include the following tests: -PSA test every 3 to 6 months. -DRE every year. -12-to 14-core confirmatory transrectal ultrasound (TRUS) biopsy (including anterior directed cores) within 6 to 12 months, then serial biopsy a minimum of every 3 to 5 years thereafter. The AS protocol may include the following test: -Multiparametric MRI (mpMRI). This is indicated when a patient's clinical findings are discordant with the pathologic findings and it is useful in identifying occult cancers or changes indicative of tumour progression in patients at risk. (36,37). Multiparametric MRI also had a negative predictive value of 83% to 100% (38) in one study that used transperineal template mapping saturation biopsy as a reference standard, and which included patients with a PSA range of 0.9 to 29 (median 7). One study also showed mpMRI to be a predictor of high-risk disease in the AS context (37). # Summary of Key Evidence for # Justification for Recommendation 3 -This recommendation is consistent with the AS protocol presented in most of the studies reviewed for this guideline. Since most studies employed PSA testing, DRE, and biopsy, these can be considered the three most important components of an AS protocol. -Although many studies reviewed here followed a repeat biopsy frequency of 1 to 2 years in their AS protocol, the study with the most mature cohort of patients undergoing AS (13) and two other studies opted for a repeat biopsy frequency of 2 to 4 years (8,11) and found similarly high prostate-cancer survival rates of 97% to 100%. -Current evidence shows that PSA kinetics does not reliably predict disease stability or reclassification to higher risk state. -Although one correlational study detected that patients from multidisciplinary clinics were more likely to receive AS than patients under the care of individual practitioners (39), there is insufficient evidence to address the factors affecting the offer of, acceptance of, and adherence to AS. Qualifying Statements for Recommendation 3 -Decisions about frequency of biopsy need to take into consideration individual patient factors including age, risk of progression, comorbidities, etc. The repeat biopsy frequency recommendation of a minimum of once every 3 to 5 years is based on the series reported by Klotz et al (40), which included 450 patients on AS with a median follow-up of 6.8 years (range, 1 to 13 years). Overall survival rate was 78.6%. The 10year prostate cancer actuarial survival rate was 97.2%. Compared with shorter repeat biopsy intervals, this recommended frequency potentially reduces the risk of complications that are associated with TRUS biopsy, including urosepsis (41,42), without negatively affecting outcomes. A shorter interval between biopsies may be reasonable in selected patients and should be at the discretion of the ordering physician in consultation with the patient. Serial biopsy should not continue past the age of 80. -The role of magnetic resonance imaging (MRI) in AS is evolving. Prospective multicentre trials reporting utility of MRI on entrance into AS or in reclassification of disease risk are lacking. Single-centre publications looking at all men undergoing biopsy have found that mpMRI can reclassify patients when combined with systematic biopsy by identifying tumour targets missed with systematic biopsy (38). Multiparametric MRI is useful in identifying anterior and higher volume tumours, and it is good in identifying findings that predict disease reclassification (36,37).Whether this should be done on all patients or only on those in whom there is discordance between clinical findings such as PSA and DRE is an open question. However, being cognizant of both the high cost of mpMRI and its promise, it is recommended that when a patient's clinical findings are discordant with the pathologic findings, a mpMRI is indicated. When indicated, it may be considered at entry or during follow-up. -Discordant findings between a patient's clinical course and pathologic findings can include rapidly rising PSA, PSA density over 0.2, higher PSA than expected for prostate size, DRE abnormality, and very low PSA free/total ratio. Presence of these findings requires further investigation with mpMRI or earlier repeat biopsy. # RECOMMENDATION 4 Daily 5-alpha reductase inhibitors may have a role in men on AS. # Summary of Key Evidence for Recommendation 4 -An RCT found that in men with very low-risk prostate cancer undergoing AS and followed for 3 years, daily dutasteride delayed disease reclassification (hazard ratio 0.62; confidence interval 0.43 to 0.89) and improved quality of life at 18 months (28). # Justification for Recommendation 4 -Evidence from a high-quality RCT detected a benefit for dutasteride administered to patients undergoing AS (28). Qualifying Statements for Recommendation 4 -It should be noted that the RCT had short follow-up of 3 years and detected no difference between groups in survival rate outcomes (28). -Dutasteride is the only 5ARI that has been tested in an RCT. However, it is the opinion of the Expert Panel that the evidence likely demonstrates a drug class effect and that finasteride may also have a role in men on AS. -While the U.S. Food and Drug Administration (FDA) has issued a warning about a possible low but increased risk for high-grade prostate cancer with the use of 5ARIs based on two RCTs that did not meet inclusion criteria for this guideline (43), it is the opinion of the Expert Panel members that the benefits of 5ARIs outweigh the risks and they can be prescribed to a patient undergoing AS as long as the patient is adequately informed about the risk and benefits of treatment. This is consistent with the Canadian Consensus Conference statement (44). # RECOMMENDATION 5 For patients undergoing AS who are reclassified to a higher risk category, defined by repeat biopsy showing Gleason score >7 and/or significant increases in the volume of Gleason 6 tumour, consideration should be given to active therapy (e.g., RP or RT). # Summary of Key Evidence for Recommendation 5 -Based on RCTs of treatment versus observation, the patients who benefitted most from therapy had Gleason 7 and higher prostate cancer volume (20,46). # Justification for Recommendation 5 -Gleason score is a widely used disease classification measure and biopsy is the gold standard for measuring the status of disease. Thus Gleason 7 (4+3 pattern or 3+4 with Gleason pattern 4 pathology accounting for >10% total tumour) is the recommended indicator for disease reclassification to higher risk in prostate cancer. -The most commonly reported active treatments received by patients on AS who were reclassified to higher risk were RP and RT (5)(6)(7)(9)(10)(11)(12)(13)21,45). -Although clear biopsy criteria for defining progression of high volume Gleason 6 disease have not been established, it is the consensus of the Expert Panel members that increasing volume of Gleason 6 tumour is an indicator of disease progression and of the need to consider active treatment. It is the consensus of the members of the Expert Panel that patients on AS with Gleason 7 disease on repeat biopsy can be considered for continued AS provided that Gleason pattern 4 accounts for ≤10% of total tumour. -Prospective intradepartmental consultation should be encouraged as an important quality assurance activity for Gleason score interpretation (27). Qualifying Statements for Recommendation 5 -An RCT comparing RP to WW found that RP reduced the risk of distant metastases and reduced prostate cancer mortality rates (46). -In six studies, 17% to 31% of patients undergoing AS were reclassified to a higher risk group over time (8)(9)(10)(11)(12)(13)(14)(15)45). -In 11 studies, 14% to 42% of patients undergoing AS received active treatment because of disease reclassification to higher risk, anxiety, patient choice, or another reason (5)(6)(7)(8)(9)(10)(11)(12)(13)19,45). -Since evidence to predict disease reclassification in prostate cancer was conflicting for PSA level and lacking for DRE and prostate cancer antigen3 (PCA3) level these were not included in the recommendation. This recommendation is based on a consensus of opinion of the Expert Panel members. - # FURTHER QUALIFYING STATEMENTS Currently, there is insufficient evidence to make recommendations with regard to the personnel who should be responsible for the management of AS protocols. However, patients should have access to a multidisciplinary consultative approach when a change to active treatment is considered. # FUTURE RESEARCH Although a National Cancer Institute trial has previously shown that RCTs comparing AS with immediate active treatments for prostate cancer are difficult to conduct because of insufficient patient accrual (ClinicalTrials.gov registration number: NCT00499174), RCTs would still provide the best evidence on which to base clinical recommendations. Should RCTs become available in the future, these Guideline Recommendations may change. Every few years, the PEBC conducts a review and assessment of its guidelines to update the evidence and any new relevant studies identified will be taken into consideration to evaluate whether these Guideline Recommendations are still valid.

For information about this document, please contact Dr. Eric Winquist, the lead author, through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: ccopgi@mcmaster.ca # PUBLICATIONS RELATED TO THIS REPORT The evidence review has been published as a Supplement Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Questions 1. What treatment provides the optimum disease control and survival in older patients (at least 60 years of age) with newly diagnosed, advanced-stage, aggressive histology lymphoma? 2. What are the toxicities associated with these treatments? 3. What are the roles of granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor in combination with chemotherapy in these patients?These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 4 and no significant comorbid illnesses. Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity. Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy.  While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected.  The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever. These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy, or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma.  The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia. Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues, and the goals of the treatment program. These factors may alter recommendations for individual patients and require discussion between health care providers, patients, and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients.# - In a randomized trial comparing CHOP with a regimen considered to be less toxic (etoposide, mitoxantrone and prednimustine, progression-free and overall survival were superior in the group receiving CHOP. In a randomized trial comparing a CHOP-like regimen, in which pirarubicin is substituted for doxorubicin and teniposide is substituted for vincristine (CTVP), with a regimen considered to be less toxic (cyclophosphamide, teniposide and prednisone, progression-free and overall survival were superior in the group receiving CTVP. In a randomized trial comparing CHOP with a fractionated schedule of weekly CHOP, overall survival was superior in the group receiving standard CHOP. In two randomized trials comparing CHOP with a regimen in which mitoxantrone was substituted for doxorubicin (CNOP), progression-free and overall survival were superior in the groups receiving CHOP. In a third randomized trial in which a weekly doxorubicin-containing regimen was compared with a regimen in which mitoxantrone was substituted for doxorubicin, response rate and overall survival were superior in the group receiving the mitoxantrone-containing regimen. The investigators of this study are currently conducting a randomized trial in which the weekly mitoxantrone-containing regimen is compared with CHOP. In a randomized trial comparing CHOP to a combined regimen of rituximab and CHOP, event-free and overall survival were superior in the group receiving CHOP plus rituximab. In three randomized trials evaluating the primary use of granulocyte-colony stimulating factor, no differences between the randomized groups were detected in disease control or overall survival. Less severe granulocytopenia and fewer infections and days of antibiotic use were observed in patients receiving granulocyte-colony stimulating factor. # Related Guidelines # PREAMBLE: About our Practice Guideline Reports The Practice Guidelines Initiative (PGI) is a project supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care, as part of the Program in Evidence-based Care (PEBC). The purpose of the Program is to improve outcomes for cancer patients, to assist practitioners to apply the best available research evidence to clinical decisions, and to promote responsible use of health care resources. The core activity of the Program is the development of practice guidelines by multidisciplinary Disease Site Groups of the PGI using the methodology of the Practice Guidelines Development Cycle. 1 The resulting practice guideline reports are convenient and up-to-date sources of the best available evidence on clinical topics, developed through systematic reviews, evidence synthesis and input from a broad community of practitioners. They are intended to promote evidence-based practice. This practice guideline report has been formally approved by the Practice Guidelines Coordinating Committee (PGCC), whose membership includes oncologists, other health providers, patient representatives, and Cancer Care Ontario executives. Formal approval of a practice guideline by the Coordinating Committee does not necessarily mean that the practice guideline has been adopted as a practice policy of CCO. The decision to adopt a practice guideline as a practice policy rests with each regional cancer network that is expected to consult with relevant stakeholders, including CCO. # Glossary of Chemotherapy Regimens # II. CHOICE OF TOPIC AND RATIONALE The numbers of elderly persons are increasing and are soon expected to make up 20% of the population in North America (24). One-half of patients with aggressive histology lymphoma are older than 65 years (25). Age is known to be a powerful prognostic factor for overall survival for patients with aggressive histology lymphoma (26). Until recently, patients older than 65 have been underrepresented in clinical trials, and most conclusions about the best chemotherapy for these patients have not been based on direct evidence. Outcomes of older patients with lymphoma may differ from those of younger patients due to alterations in disease biology and poorer tolerance of standard chemotherapeutic regimens. Biological age plays a more important role than chronological age, and compromises in response and survival may occur if suboptimal chemotherapy is given to patients with chemosensitive lymphoma (27)(28)(29)(30). The members of the Hematology Cancer Disease Site Group (Hematology DSG) suspected that the selection of chemotherapy for this group of patients varied across Ontario. The availability of recent evidence, the perceived variability in practice patterns, and the potential for this variation to influence the outcomes of older patients led to the development of this topic as a practice guideline. The few published guidelines for patients with lymphoma (31)(32)(33) have either not specifically focused on the treatment of older patients (32) or have not used systematic review methodology in their data collection (31;33). Two published guidelines (34)(35)(36) and one expert panel review (37) for the use of colony stimulating factors in patients with malignancy have made recommendations in patients receiving myelosuppressive chemotherapy but do not address the older population specifically. The Hematology DSG felt it appropriate to appraise studies on the use of colony stimulating factors in older patients to see whether suggestions should differ from those already published. This guideline will, therefore, address both the optimum choice of primary therapy and the role of granulocyte-(or granulocytemacrophage) colony stimulating factor when treating older patients with aggressive histology lymphoma. The role of radiation therapy may also be an important part of the overall treatment plan for these patients but will not be addressed in this document. A previous version of this guideline report was circulated for practitioner feedback in August 2000. Based on the practitioner feedback and the availability of new data, the document was revised and recirculated for practitioner feedback. Portions of this guideline have been published as a systematic review of full paper publications of chemotherapy trials for older patients with aggressive histology lymphoma (38). # III. METHODS Guideline Development This practice guideline report was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-based Care (PEBC), using methods of the Practice Guidelines Development Cycle (39). Evidence was selected and reviewed by four members of the PGI's Hematology DSG and methodologists. Members of the Hematology DSG disclosed potential conflict of interest information. The practice guideline report is a convenient and up-to-date source of the best available evidence on chemotherapy and growth factors in older patients with newly diagnosed aggressive histology lymphoma, developed through systematic reviews, evidence synthesis, and input from practitioners in Ontario. The body of evidence in this report is primarily comprised of mature randomized controlled trial data; therefore, recommendations by the DSG are offered The report is intended to promote evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC). The PGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Literature Search Strategy Searches were performed without language restriction in the following databases (40)). The following terms were used for MEDLINE and CANCERLIT: "lymphoma, non-Hodgkin" (MESH, text word), "lymphoma" (text word) combined with "aged" (text word) or "older" (text word) combined with "chemo:" (text word). These terms were then combined with search terms for the following study designs: practice guidelines, systematic reviews, meta-analyses, and randomized controlled trials. The detailed search strategy has been described in Appendix I. Bibliographies of major textbooks, review articles, and primary studies were hand searched. Conference proceedings of the American Society of Hematology (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001), American Society of Clinical Oncology (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001), International (Lugano) Conference on Malignant Lymphoma (1996,1999), and the European Cancer Conference (ECCO 1995(ECCO 1997(ECCO 1998(ECCO 2001 were searched. A manual review of the table of contents was performed for the following journals from 1993 to 1998: American Journal of Hematology, Annals of Oncology, Blood, British Journal of Hematology, Cancer, European Journal of Cancer, European Journal of Hematology, Journal of Clinical Oncology, and the New England Journal of Medicine. The Physician's Data Query (PDQ, National Cancer Institute, USA) clinical trials database on the Internet (/) was searched for trials in progress using the terms "non-Hodgkin's lymphoma, adult" and "chemotherapy". A separate search for studies assessing risk factors predictive of fever and neutropenia in elderly lymphoma patients was undertaken to assist the Hematology DSG in evaluating the role of primary prophylaxis with growth factors. The following terms were searched in MEDLINE (1966through September 2001 and CANCERLIT (1984through September 2001: "lymphoma, non-Hodgkin" (MESH, textword), "lymphoma" (textword) combined with "neutropenia" (textword) and "risk factor" (textword). Abstract publications were not included. Specific parameters to assess the quality of these studies were not applied. # Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized controlled trials (RCTs) involving newly diagnosed patients with aggressive histology lymphoma who were 60 years of age and older. The age threshold of 60 years was chosen in order to remain consistent with the findings of the International Prognostic Index (IPI) (26). - To assess the role of chemotherapy, RCTs must compare at least two chemotherapy regimens. 2. To assess the role of colony stimulating factors, RCTs comparing the use of G-CSF or GM-CSF with a control group were sought. In the initial phase of this guideline, non-randomized studies utilizing colony stimulating factors that included at least ten patients (chosen arbitrarily) were also eligible. These trials were subsequently made ineligible in February 2001 when data from three randomized trials became available. 3. Randomized studies assessing the use of monoclonal antibodies (e.g., rituximab) were eligible. 4. Subgroup analyses based on age or histology were eligible. The outcome measures of interest included at least one of the following: overall survival (OS), disease-free (DFS) or failure-free survival (FFS), time-to-treatment failure (TTF), relapse-free survival (RFS), response rate, toxicity, or quality of life measures. # Exclusion Criteria Studies were excluded if: 1. Patients included had indolent lymphoma, refractory or relapsed lymphoma, human immunodeficiency virus (HIV) related lymphoma, Hodgkin's disease, multiple myeloma, or other hematological malignancies; 2. Transplantation, maintenance chemotherapy, or interferon were used as interventions; or 3. Radiation therapy was used unevenly in experimental and control groups. Studies assessing the role of chemotherapy were excluded if they incorporated growth factors as part of the primary therapy in all randomized groups. Also, letters and editorials were not considered. # Risk Factors for Fever and Neutropenia Responses obtained in the first external review by Ontario practitioners of the initial draft version of the evidence-based recommendations supported a need to review and clarify recommendations regarding the use of hematopoietic growth factors for primary prophylaxis to prevent fever with neutropenia. Subsequently, new data assessing the use of growth factors became available. To better evaluate the potential role of primary prophylaxis, the DSG determined that a separate analysis limited to elderly lymphoma patients assessing risk factors that predict for fever with neutropenia and treatment-related mortality would be helpful. # Article Selection Citations were blinded for authors, journal name, institution, and results by one author. An assessment was made by two independent observers who scored each blinded citation as: "yes" (inclusion criteria were met, no exclusion criteria were met); "no" (one or more exclusion criteria were met); or "maybe" (unclear from citation if article meets any criteria). The full-length article was retrieved if the citation scored "yes" or "maybe" by at least one observer. Inclusion and exclusion criteria were applied again to the full article if necessary. Interobserver kappa coefficients (quadratic weighted) were calculated using PCAgree © (42) for the MEDLINE, CANCERLIT, and EMBASE databases, and an intraobserver coefficient was calculated from a random sample (random numbers table) of twenty MEDLINE citations for the citations assessing the role of chemotherapy. Acceptable kappa coefficients were 0.60 or greater (43). The citation lists for subsequent search updates were reviewed by one author using the same inclusion/exclusion criteria outlined previously. # Study Quality Assessment Methodological assessment was performed using the published validated quality assessment tool of Jadad et al. for randomized controlled trials (44), but the score was not used to explicitly weight study results or to exclude studies from the analysis. This scale assigns one point if the study is randomized, one point if it is double-blinded, and another point if there is a complete description of withdrawals. An additional point each may be awarded if the randomization and the blinding were done appropriately. Studies may therefore score from zero to five points. It has been shown that studies scoring 2 points or less on this scale are more likely to produce treatment effects that are on average 35% larger than those produced by trials scoring 3 points or more (45). Randomized trials were also assessed based on whether the study population was explicitly defined, how baseline characteristics of the randomized groups compared, whether primary and secondary outcome measures and minimum important differences were stated, how the target sample size was projected (46), whether an intentionto-treat analysis was performed (47), whether randomization was concealed, whether co-interventions and endpoints were explicitly stated, and whether appropriate statistics were used. Fully published articles are generally required in order to be most confident that the methodological assessment has identified the strengths and weaknesses of the trials. Most abstracts provide information of a more preliminary nature that may result in a lesser degree of confidence in making treatment recommendations. Subset analyses, while providing information of a hypothesisgenerating nature, may be potentially misleading (48) and thus provide limited information for devising treatment recommendations. Therefore, conclusions about the use of chemotherapy and growth factors are most influenced by the full paper publications of primary studies. # Synthesizing the Evidence Pooling trial results for both the chemotherapy and colony stimulating factor trials was considered but was not feasible. The nature of the chemotherapy regimens tested was very heterogeneous, making meaningful results from pooling impossible. Pooling of outcomes for studies assessing G-CSF was also considered but was not feasible because of the differences in outcome measurement assessed and the timing of assessment. Where p values were missing in individual studies, the appropriate statistical test was done using the Statistical Package for the Social Sciences (version 8.0, SPSS Inc., Chicago, IL) (49). # IV. RESULTS # Literature Search Results Two hundred and eighty-nine publications were initially identified from MEDLINE, 106 publications from CANCERLIT, 376 from EMBASE and 52 from Current Contents for the chemotherapy question, up to 1999. No additional appropriate publications were found by searching the thesis database, Best Evidence, or the Cochrane Library. Six abstracts were found by hand searching. After removing duplicate citations and those dealing exclusively with Hodgkin's disease, myeloma, leukemia, or younger patients, a total of 385 blinded citations were assessed by two independent reviewers. This search was updated in 2001 and 2002. Including the updated searches, 23 publications (13 full papers, 10 abstracts) met the eligibility criteria for chemotherapy trials and were included. Two systematic reviews were also found (38;50), one of which represents a portion of this document published as a systematic review (38). From the initial search for studies assessing the role of growth factors, 246 citations were found in EMBASE, 421 in MEDLINE, 130 citations in CANCERLIT, and 25 in Current Contents. No additional relevant publications were found by searching the thesis database, Best Evidence, or the Cochrane Library. Three abstracts were found by hand searching. Two independent reviewers assessed a total of 293 blinded citations. This search was also updated in 2001 and 2002. In the updated searches, five articles were reviewed for this section: two practice guidelines, one full-length paper, and two abstracts. Table 1 summarizes the reasons that publications were excluded based on the original searches. The search for risk factors for febrile neutropenia and treatment-related mortality resulted in 955 citations that were reviewed by one author. # Agreement Statistics The interobserver weighted kappa was 0.74 for the chemotherapy citations. The intraobserver weighted kappas for the random sample of 20 MEDLINE chemotherapy citations were 0.60 (reviewer 1) and 0.80 (reviewer 2). The interobserver weighted kappa was 0.82 for the colony stimulating factor citations. These represent adequate agreement coefficients (43). # Quality Assessment Scores Of the 23 studies assessing the role of chemotherapy (Table 2), three scored 3 on the Jadad quality scale (11;22;51), ten scored 2 (4;5;7;12;16;18;52-55) and ten scored 1 (1;2;6;10;15;20;21;56-58). The studies assessing the use of colony stimulating factors scored 2 points (23) and 1 point (57;59). One study assessing the role of rituximab scored 2 points (9). A total of 23 publications (1-7;10-12;15;16;18;20-22;51-55;57;58) and two systematic reviews (38;50) were identified that addressed the chemotherapy guideline question. One systematic review (50) contained a section on elderly patients with lymphoma; however, it was not explicit about the individual studies included, and the majority of studies present in this practice guideline report were not identified or discussed. The other systematic review was the published chemotherapy review portion of this practice guideline report (38), which only included full paper publications of randomized trials and not abstract reports. The studies testing various chemotherapy regimens fell into one of three general categories: (a) those comparing regimens that differed only in the type of anthracycline used; (b) those comparing different chemotherapy schedules; and (c) those comparing chemotherapy regimens that differed by other parameters (Table 2). (a) Comparison of regimens that differ only in the anthracycline This category consists of eight studies: five full papers (4;5;11;16;52) and three abstracts (2;21;57). None of the studies were blinded, only one described the randomization method (11), and none made any comments with respect to concealment. The full papers had complete descriptions of subject withdrawals, but the abstracts did not. The studies are summarized in Tables 3 and 4. Mainwaring et al. ( 16) randomized 473 patients 60 years of age and older to a doxorubicin-(35 mg/m 2 or a mitoxantrone-containing (7 mg/m 2 weekly combination regimen (PAdriCEBO v. PMitCEBO). Up to 40 percent of patients had stage I or II disease, and 66 percent had a World Health Organization (WHO) performance status of less than 2. The overall response rate was superior in patients receiving the mitoxantrone-containing regimen (Table 4). Although no difference in RFS was detected, four-year OS was superior in patients randomized to the mitoxantrone-containing regimen (Table 4). A multivariate analysis of prognostic factors in this trial identified the chemotherapy regimen, age greater than 70, advanced stage, and poor performance status as significant factors for survival. Björkholm et al. (57) reported on 455 patients aged 60 years of age and older randomized to CHOP or CNOP as part of a factorial design also involving G-CSF. Patients receiving CHOP had improved OS compared with those receiving CNOP (Table 4), but groups did not differ for complete response (CR) (Table 4). Aoki et al. ( 52) randomized 37 patients to low doses of CHOP or to one of two pirarubicin-based regimens (THP-COP or THP-COPE). Seven patients (19%) were subsequently withdrawn due to ineligibility and protocol violations, and the analysis was based on the remaining 30 patients. The overall response rate was similar among patients receiving low dose CHOP, THP-COP, and THP-COPE (Table 4). There was no significant difference in two-year OS (Table 4; p value not stated). Avilés et al. ( 5) randomized 169 patients to receive either CEOP-Bleo (epirubicin-based) or CIOP-Bleo (idarubicin-based) with escalating doses of the anthracycline. The group receiving the epirubicin-containing regimen had a superior CR rate (Table 4) and three-year OS (Table 4). There is a potential concern regarding patients who were excluded from the analysis if they experienced more than a two-week delay in chemotherapy administration. In addition, the study recorded no treatmentrelated mortality. Sonneveld et al. (11) tested whether the substitution of doxorubicin in CHOP for mitoxantrone (CNOP) improved outcomes in 148 patients 60 years of age and older. Almost half of the patients were less than 70 years, and in contrast to other studies, some degree of cardiac dysfunction (left ventricular ejection fraction at least 40%) was permitted. Patients receiving CHOP had a higher CR rate (Table 4), a superior median OS (Table 4), and a superior three-year OS (Table 4). At three years, 17% of CHOP and 13% of CNOP patients were alive and disease-free (p=0.12). Patients receiving CHOP experienced significantly more alopecia (p<0.001), nausea (p=0.02), and vomiting (p=0.02). The remaining studies (2;4;21) are summarized in Tables 3 and 4. Conclusions from these studies are limited due to lack of details reported in the papers. # Interpretive summary for this category This category contains studies with varied results. All studies included patients who were free of important comorbid illness. Two large studies (11;57) showed a survival benefit of doxorubicin compared with mitoxantrone when given in CHOP. When doxorubicin was compared with mitoxantrone in a non-CHOP-like, multi-agent chemotherapy regimen that was administered on a weekly basis, there was a survival benefit for patients receiving the mitoxantrone-based regimen (16). This study contained a higher proportion of patients with limited stage (I and II) disease. The remaining studies examining epirubicin, pirarubicin and idarubicin-based regimens were limited due to: concerns about the reporting of patient withdrawals and the lack of treatment-related mortality data (5); small numbers of patients; lack of an intention-to-treat analysis; use of less than standard doses of CHOP (52); lack of survival data (4); and reporting of subgroup analyses (2). # (b) Comparison of regimens with different schedules This category contains three studies: one full paper (53) and two abstracts (7;10). The studies were not blinded and did not mention the method of randomization or concealment. The studies are summarized in Tables 5 and 6. Pfreundschuh et al. (10) reported results of a four-arm randomized trial evaluating patients 61 to 75 years of age with aggressive histology lymphoma and comparing CHOP administered either every 21 days or 14 days and CHOP plus etoposide (CHOEP) also administered every 21 days or 14 days. Patients receiving either 14-day regimen (i.e., CHOP-14 or CHOEP-14) also received G-CSF. The trial was to be analyzed using a factorial design in order to assess the effect of compressing the treatment schedule and the addition of etoposide. Because of an interaction between the addition of etoposide and schedule compression, in which patients receiving CHOEP every 14 days experienced excessive toxicity, the trial was instead analyzed as a four-armed comparison using a Cox model. With respect to compressing the treatment schedule, a comparison of outcomes between the CHOP-21 and CHOP-14 groups detected that the CHOP-14 group had a superior 40-month TTF (Table 6) and OS (Table 6), with a trend for improved CR rate (Table 6). The randomized phase II study by Soubeyran et al. (7) published in abstract form, compared standard and fractionated schedules of CEVOP. No difference was detected in achievement of a CR. The group receiving the fractionated schedule of chemotherapy received therapy of reduced dose intensity, had a higher frequency of treatment interruptions due to toxicity, and reported lower quality of life scores. Specific data were not provided. A randomized phase II study by Meyer et al. ( 53) compared the conventional CHOP schedule with one-third doses administered weekly (chop) for the same intended dose-intensity. There were no differences in received dose intensities (primary outcome) when calculated by two different methods (53;60) or in the CR rate between CHOP and chop (Table 6). Although two-year progression-free survival (PFS) was similar between CHOP and chop (Table 6), the two-year OS was of borderline significance in favour of CHOP (Table 6). Apart from more leukopenia in patients randomized to CHOP, there were no statistically significant differences in important toxicities. # Interpretive summary for this category No benefits from fractionating the treatment schedule have been detected; the potential for outcomes to be inferior is suggested. In a preliminary abstract publication reporting results of compressing the schedule of CHOP from 21 days to 14 days, improvements in disease control and survival are indicated (10). However, the interpretation of this study is limited by the complex statistical analysis and requires a full report in article form for complete assessment. # (c) Comparison of other chemotherapy regimens This (3;6;12;15;18), and one study compared different doses of the same regimen, with dose determined by age stratification (20). These studies are highlighted in Tables 7 and 8. Of the seven trials comparing CHOP with another regimen, one (22) has been published in article form, three as subgroup analyses (51;55;58), and three in abstract form (1;10;54). A European Organization for the Research and Treatment of Cancer (EORTC) trial ( 22) randomized 120 patients 70 years of age and older to CHOP or VMP. Patients with a performance status of 2 or 3 were started at 75 percent of the standard chemotherapy dose. Patients who received CHOP had a higher overall response rate (Table 8), a borderline higher CR rate (Table 8), a longer median PFS (Table 8), a longer median OS (Table 8), and an improved four-year OS (Table 8). There was a trend toward more cardiovascular toxicity in patients receiving CHOP; they also experienced more alopecia and gastrointestinal and neurological toxicity. None of the other publications in this category have reported a survival advantage for patients receiving a treatment that was compared with CHOP. A Group d'Etude des Lymphomes de l'Adulte trial (GELA) (1) randomized 708 patients aged 61-69 years to ACVBP or CHOP. No differences were detected in CR rate or three-year OS. There was an improvement in three-year event-free (Table 8) and disease-free survival (Table 8) in patients randomized to ACVBP. These benefits appear to be offset by an increased treatment-related mortality in patients receiving ACVBP (13% v. 7%; p<0.01). A study published in abstract form compared CHOP with CHOP plus etoposide (10) in patients greater than 60 years old. No differences were detected in response rate, TTF, or OS, and the authors commented that the addition of etoposide was associated with significant toxicity. Four studies (51;54;55;58) compared CHOP with one or more "second or third generation" regimens. In each of these studies, no advantage favouring an experimental arm was detected in any outcome measure. Treatment with MACOP-B was associated with an inferior response rate in one study (51) and inferior OS in another (54). Five studies (6;12;15;18;56) compared regimens that did not include CHOP, and one study examined dose intensities of the same regimen in older patients of different ages (20); two reports are in article form (12;56). Bastion et al. (12) randomized 453 patients at least 70 years of age to CTVP or CVP. Treatment with CVTP was associated with a superior CR rate (Table 8), median TTF (Table 8), five-year TTF (Table 8), and five-year OS (Table 8) and a lower rate of progressive disease (Table 8). Patients receiving CTVP experienced more alopecia and mucositis and had more frequent and prolonged hospitalizations. The remaining studies (6;15;18;20;56) are summarized in Tables 7 and 8; all contain insufficient information to influence guideline development. # Interpretive summary for this category Except for one study (3), the studies in this category included patients who did not have any significant comorbid illnesses. In comparison with regimens presumed to be less toxic (e.g., VMP, CVP), anthracycline-containing regimens such as CHOP (22) or CTVP (12) were associated with improvements in OS in patients 70 years of age and older. Two studies (1;10) testing chemotherapy regimens that are more intensive than CHOP both detected an increase in toxicity with no survival benefit detected. Subset analyses comparing CHOP with "second and third generation" regimens (51;54;55;58) show that CHOP is at least as effective or less toxic than these other regimens. The remaining studies (6;15;18;20;56) in this category did not contribute additional information. # Monoclonal Antibodies One study by GELA (9) evaluated the combination of chemotherapy and monoclonal antibodies. This study scored 2 on the Jadad quality scale, contained adequate information about patient withdrawals, but was not blinded and did not provide the details of the randomization process or concealment. In this trial (9) 399 patients ages 60-80 years were randomized to receive CHOP with or without rituximab 375 mg/m 2 on day 1 of each treatment cycle. Patients randomized to CHOP plus rituximab experienced an improved CR rate (76% v. 63%; p=0.005) and 2-year event-free (57% v. 38%; p<0.001) and overall survival (70% v. 57%; p=0.007). No differences in standardly measured treatment-related toxicity were detected; nine percent of patients receiving rituximab experienced grade 3 or 4 infusion-related toxicities. # Interpretive summary for this category The administration of rituximab with CHOP improves the response rate and event-free and overall survival compared with CHOP alone and is well tolerated. # Colony Stimulating Factors Two practice guidelines (34;36) and three RCTs (23;57;59) were identified, which address the growth factors guideline question. One practice guideline (34) has been updated (35;61). # Practice guidelines Two practice guidelines (34-36;61) address the use of colony stimulating factors in patients receiving myelosuppressive chemotherapy. Based on the results of three randomized trials (62-64), the American Society of Clinical Oncology (ASCO) produced a guideline (34;35) suggesting that primary prophylaxis with colony stimulating factors may reduce the incidence of febrile neutropenia by 50 percent if the incidence of febrile neutropenia is greater than 40 percent in a control population (34). In conjunction with a decision analysis (65) that concludes that primary prophylaxis is cost-effective in this circumstance, the ASCO guideline recommends use of colony stimulating factors when the risk of febrile neutropenia is estimated to be greater than 40 percent. The decision analysis utilized data extracted from a randomized trial assessing primary prophylaxis in patients with small cell lung cancer (62) in which neutropenia was defined as a count of less than 1.0x10 9 /L and all patients with febrile neutropenia were treated with intravenous antibiotics in hospital; the perspective taken was that of the hospital-costs payer. The authors do not indicate whether the value of 40 percent applies to the risk to the patient over an entire treatment course or to an individual treatment cycle. The second guideline was published by the Cancer Care Ontario Systemic Treatment DSG (36) and suggests that G-CSF is a reasonable option if quality of life is expected to be improved by a reduction in the number or duration of febrile neutropenic episodes. # Randomized studies Three randomized studies have evaluated primary prophylaxis with G-CSF in older patients with aggressive histology lymphoma (23;57;59); these trials are detailed in Tables 9 and 10. Two trials scored 2 (23;59) and the third scored 1 (57) on the quality scale. A full paper publication (23) and one abstract (59) contain information on patient withdrawals but not about the method of randomization or concealment. The other abstract (57) lacks details about withdrawals, randomization and concealment. 10). The percentage of treatment cycles associated with a WHO grade II-IV infection was 14 (134/949) in patients receiving CHOP alone and 10 (95/926) in patients receiving CHOP plus G-CSF (J.K. Doorduijn, personal communication). While this difference reached statistical significance (p=0.011), the absolute risk reduction of 4 percent corresponds to a number needed to treat (NNT) of 25 cycles in order to prevent one WHO grade II-IV infection. No difference in the percentage of patients experiencing a WHO grade II-IV infection was detected (53% treated with CHOP v. 46% treated with CHOP plus G-CSF; p=0.20). Quality of life was evaluated in this study using the European Quality of Life Questionnaire (EuroQoL), EORTC Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30), and the Multidimensionele Vermoeidheids Index (MVI; a fatigue scale) questionnaires administered after the second, fourth and sixth cycle of treatment and at 3, 6, 10, and 18 months of follow-up (66). Out of the entire group, 162 patients were selected to participate in the quality of life analysis, and 132 agreed to do so, with a 90% questionnaire return rate. No differences in scores between randomized groups were detected. Using a factorial design, Björkholm et al. (57) randomized 455 patients at least 60 years of age to CHOP or CNOP with and without G-CSF. No differences in CR rate or five-year OS were detected between patients receiving or not receiving G-CSF. Patients receiving G-CSF experienced less WHO grade 4 neutropenia (Table 10) and fewer infections during granulocytopenia (Table 10). Using these data, the patient NNT to prevent one infection during granulocytopenia was six. Zinzani et al. (23) randomized 149 patients at least 60 years of age to VNCOP-B with or without G-CSF. No statistically significant differences were detected in CR rate (Table 10), partial response rate (Table 10), relapse-free survival (RFS) at 30 months (Table 10), or OS at 30 months (Table 10). Patients randomized to G-CSF experienced less neutropenia (less than 0.5 x 10 9 /L; Table 10) and fewer clinically relevant infections (Table 10). Using these data, the patient NNT to prevent one clinically relevant infection was six. One-third of the patients in the control group who experienced an infection required parenteral antibiotics or hospitalization compared with none in the G-CSF group. The report does not comment on the rate of febrile neutropenia in the control group. # Risk factors for toxicity The trials testing the role of growth factors failed to detect differences in disease control or survival but did show a reduction in the risk of infections. The Hematology DSG therefore concluded that the ability to make a recommendation regarding the role of primary prophylaxis with growth factors in older patients with aggressive histology lymphoma might be assisted by an evaluation of literature addressing factors that predict for an increased susceptibility to the toxic effects of therapy, including the risk of infection. An evaluation of these prognostic factors is complicated by the inclusion in some studies of an evaluation of factors that predict for other outcome measures, such as OS. Specific multivariable toxicity analyses from two randomized trials (11;12) were reviewed along with an additional six retrospective studies (67-72) dealing with risk factors for toxicity. Two randomized trials evaluated factors associated with an inferior OS (11;12). In the trial comparing CHOP with CNOP (11), the early toxic death rate was 10 percent for patients receiving CHOP; a multivariate analysis of prognostic factors detected that treatment with CNOP, high lactate dehydrogenase (LDH), bulky disease, and poor performance status (ECOG greater than 1) were associated with a higher risk of death. In the trial comparing CTVP with CVP (12), the group receiving CVTP had a toxic death rate of 15 percent and 13 percent experienced a major infection following the first cycle of therapy; a multivariate analysis detected that advanced stage, performance status, LDH, and albumin were predictive for shorter survival. Six studies (67-72) have retrospectively evaluated (70;71) factors that predict for treatment toxicity in patients with lymphoma. Only one of these reports was limited to older patients and included a multivariate analysis (67). Gomez et al. (67) evaluated 267 patients 60 years of age and older who received CHOP without growth factors; 53 percent of patients were older than 70 years, 52 percent had stage III or IV disease and 28 percent fell within the high-intermediate or high IPI risk groups. A toxic death was defined as a death occurring within six months of commencing treatment; 13 percent of patients suffered a toxic death with 83 percent of these secondary to infection. Sixty-five percent of the infection-related deaths were associated with neutropenia. A multivariate analysis detected that the only factor that independently predicted for a toxic death was an ECOG performance status of 2 or greater (relative risk 3.5; p=0.000001). Other factors assessed included age, histology, Ann Arbor stage, presence of extranodal disease or B symptoms, disease bulk, IPI risk category, LDH, and doxorubicin dose intensity. # Interpretive summary for this category Three randomized trials (23;57;59) assessing primary prophylaxis with G-CSF have failed to detect a difference between groups in OS or any measure of treatment efficacy, such as initial response rate or duration of disease control. All three trials, however, did show a reduction in the frequency of severe neutropenia and in the risk of infection. Two studies (23;57) detected that the patient NNT to avoid having one patient experience an infection was six; another study (59) detected that the number of cycles needed to treat to avoid an episode of infection was 25. One study (66) reported quality of life outcomes and failed to detect a difference between randomized groups. Baseline ECOG performance status is the most powerful factor predicting for treatment-related toxicity that results in a toxic death. ONGOING TRIALS The Hematology DSG is aware of the following ongoing trials: # VI. DISEASE SITE GROUP CONSENSUS PROCESS The Hematology DSG considered the management of older patients with aggressive histology lymphoma to be an important topic for guideline development because of its incidence, the availability of evidence, and a perception that practice patterns varied outside a range suggested by this evidence. The Hematology DSG concluded that treatment of these patients is complex, with the decision-making process requiring knowledge of available evidence and with application of this evidence to each patient after evaluating their specific circumstances, including their preferences. Based on the results of randomized trials that have tested many chemotherapy regimens founded on different principles, the Hematology DSG concluded that it is possible to provide specific treatment recommendations for older patients who have no significant comorbid health problems or specific preferences that would reduce the priority of providing therapy that offers the best opportunity of durable disease control. The first topic dealt with the optimum base chemotherapy regimen. The Hematology DSG concluded that CHOP should remain as standard therapy for these patients, just as it currently is for younger patients. The Hematology DSG concluded that age alone should not be the prime determinant for selecting the base chemotherapy regimen but that alternatives to CHOP should be reserved for patients of any age who have significant comorbid conditions or specific preferences. Physicians should be cautioned that many older patients might have significant comorbid illnesses or preferences that would make the use of CHOP inappropriate (75). The second topic considered dealt with the addition of rituximab to CHOP. The GELA trial testing this agent ( 9) included patients ages 60 to 80 years with stage II-IV diffuse large B-cell lymphoma, an ECOG performance status of less than 2 and no contraindications to doxorubicin. The Hematology DSG concluded that the reported data were sufficiently strong enough to justify a recommendation stating that these patients should receive rituximab in combination with CHOP. The Hematology DSG also discussed whether this recommendation should be generalized to other patients such as those older than 80 years, with limited stage disease, receiving chemotherapy other than CHOP or receiving subsequent-line chemotherapy. The Hematology DSG concluded that patients older than 80 years who otherwise satisfy criteria for treatment with CHOP do not represent a specific prognostic entity and should, therefore, receive similar treatment to patients aged 60 to 80 years of age. The Hematology DSG concluded that current data are insufficient to support a recommendation to add rituximab to chemotherapy for patients with limited-stage or relapsed disease or for patients receiving chemotherapy other than CHOP. The third topic considered dealt with the use of growth factors as part of primary therapy in combination with chemotherapy and rituximab. The Hematology DSG initially concluded that in the absence of trials detecting superior disease control, survival, or quality of life, current data were insufficient to support a recommendation to use growth factors as part of primary therapy. The Hematology DSG did conclude that secondary prophylaxis with G-CSF was appropriate and recommended for patients who have experienced a previous episode of neutropenic fever or a treatment delay resulting from prolonged neutropenia. This initial recommendation concerning primary therapy did not achieve unanimous approval from the Hematology DSG-some members regarded a reduction in the risk of infection as a sufficient outcome to justify using G-CSF as primary therapy for all patients. A minority of practitioners from across Ontario who reviewed the initial guideline (August 2000) also supported this position. With the availability of results from three randomized trials indicating that the absolute reduction in infections may be less than initially anticipated (55) and with a review of data that assists in predicting which patients are at greatest risk of life-threatening infections, the Hematology DSG reached consensus for a modified recommendation. The Hematology DSG now concludes that there are insufficient data to support a recommendation to routinely use growth factors as part of primary therapy but does support the primary use of growth factors for patients at high risk of developing life-threatening infections. These patients are best identified as those with a poor (ECOG greater than 1) performance status. The Hematology DSG also concluded that this recommendation should be expanded to include those patients who present with neutropenia or who have an active infection at the time that therapy is commenced. The recommendation for using growth factors as part of secondary prophylaxis was not altered. # VII. EXTERNAL REVIEW OF THE PRACTICE GUIDELINE REPORT Draft Recommendations Based on the evidence described above, the Hematology DSG drafted the following recommendations: # Target Population These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an ECOG performance status of less than 4 and no significant comorbid illnesses. # Draft Recommendations Key Recommendations Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity. Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy. While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected. The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever. These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma. The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia. Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues and the goals of the treatment program. These factors may alter recommendations for individual patients and require discussion between health care providers, patients and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients. # Related Guidelines Practice Guidelines Initiative's Practice Guideline Report #12-2: Use of Granulocyte Colony-Stimulating Factor (G-CSF) in Patients Receiving Myelosuppressive Chemotherapy for the Treatment of Cancer and Evidence Summary Report #6-8: Rituximab in Lymphoma. # Practitioner Feedback Based on the evidence and the draft recommendations presented above, feedback was sought from Ontario clinicians. Practitioner feedback was obtained through a mailed survey of 110 practitioners in Ontario (49 medical oncologists, 30 hematologists, 21 pharmacists and 10 resident hematologists). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. The practitioner feedback was mailed out on August 6, 2002 or October 28, 2002 for staff clinicians and October 10, 2002 for resident hematologists. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Hematology DSG reviewed the results of the survey. Sixty-four responses (three residents and 61 staff clinicians) were received out of the 110 surveys sent (58% response rate). Responses include returned completed surveys as well as phone, fax, and email responses. Of the practitioners who responded, 53 (three residents and 50 staff clinicians) indicated that the report was relevant to their clinical practice and completed the survey. Key results of the practitioner feedback survey are summarized in Table 11. # Summary of Written Comments Eighteen respondents (34%) provided written comments. The main points contained in the written comments were: - Three respondents felt that the conclusions about CHOP plus rituximab (CHOP-rituximab) were premature and required confirmation. One of these respondents felt that the use of CHOPrituximab should be permissive rather than prescriptive since there are resource utilization issues with CHOP-rituximab. - One respondent asked why rituximab use with CHOP was limited to those 60 years of age and older. - One respondent felt that the data from the German trial (CHOP-14/21±etoposide) (10) were compelling and that the results were unlikely to change upon publication. The respondent felt that either these results should be incorporated into the conclusions of the guideline or that the guideline's conclusions should be delayed until full paper publication of this study. - One respondent commented on the poor quality of the data used to better define the risk factors for toxicity. - One respondent requested more guidance on the management of those patients with comorbid illness. Modifications/Actions 1. The DSG felt that the survival advantage reported with CHOP-rituximab was statistically significant and clinically important, despite the short follow-up. Based on these results, the DSG felt that rituximab should be added to CHOP in this patient population. No changes were made to the recommendations. - The DSG has summarized this aspect in the DSG consensus section based on: the lower age limit in the randomized trial, the extension of the treatment principles of those aged 60 to 80 years to those above the age of 80, and the lack of evidence for benefit of CHOP-rituximab, thus far, in younger patients. No changes were made to the recommendations. - The DSG concluded that recommendations could be made regarding the use of CHOP-rituximab based on the results of one randomized trial (9) as this trial has been published in full article form and used an intention-to-treat analysis that included all patients. This analysis detected superior overall survival in the group randomized to receive CHOP-rituximab. In contrast, the German study (10) has been published only in abstract form and used a factorial design to assess two questions; the eventual analysis was performed using different methodology. Given this complexity, the DSG concluded that recommendations should not be made until results are published in article form. When published, the results will be incorporated into the guideline. No changes were made to the recommendations. - The DSG acknowledges the limited quality of the data available for the assessment of risk factors for toxicity in older patients with lymphoma. However, the DSG felt that the most reasonable interpretation of available evidence, in conjunction with clinical experience, was to recommend that "pre-existing infection" and "neutropenia at the time of commencing chemotherapy" should be included as two risk factors leading to a recommendation to use granulocyte-colony stimulating factor as primary prophylaxis. No changes were made to the recommendations. No evidence exists to better guide therapy for those patients with comorbid illness. # Practice Guidelines Coordinating Committee Approval Process The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval at the May 2003 teleconference meeting. Twelve of 16 members of the PGCC attended the meeting, and all 12 approved the practice guideline report as written. The PGCC felt that the guideline covered a lot of questions and the Hematology DSG did a great job handling the questions. One member questioned whether the level of detail was shortchanged given the number of questions and volume of evidence. Other comments included that the guideline was well written overall, the Interpretive Summary was succinct, and 90% practitioner feedback approval indicated great recommendations. # VIII. PRACTICE GUIDELINE This practice guideline reflects the integration of the draft recommendations with feedback obtained from the external review process. It has been approved by the Hematology DSG and the Practice Guidelines Coordinating Committee. # Target Population These recommendations apply to patients older than age 60 who have newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma, an ECOG performance status of less than 4, and no significant comorbid illnesses. - Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is recommended for patients with no apparent cardiac disease or significant comorbidity. Dose and schedule should be the same as that used in younger patients. The addition of rituximab to CHOP is recommended for patients with diffuse large B-cell lymphoma. There is insufficient evidence to support the routine use of granulocyte-colony stimulating factor as primary therapy.  While use of granulocyte-colony stimulating factor shortens the duration of neutropenia and decreases the infection rate in these patients, no differences in disease control or survival have been detected.  The primary use of granulocyte-colony stimulating factor is recommended for older patients who are at a particularly high risk of experiencing neutropenic fever. These patients are best identified as those with a poor performance status (ECOG 2 or greater), neutropenia prior to therapy, or an ongoing infection; there are insufficient data to recommend the primary use of granulocyte-colony stimulating factor for patients whose sole risk factor is bone marrow involvement with lymphoma.  The use of granulocyte-colony stimulating factor as secondary prophylaxis is recommended for patients who have previously experienced an episode of neutropenic fever or a treatment delay resulting from persisting neutropenia. Qualifying Statements Treatment decisions in older patients with aggressive histology lymphoma are complex and may be influenced by comorbidity, patient preferences, quality of life issues, and the goals of the treatment program. These factors may alter recommendations for individual patients and require discussion between health care providers, patients and their families. Radiation therapy is not considered in this guideline and may be an important part of the treatment plan for these patients. CANCERLIT (1983to February 1999, EMBASE (1980 to January 1999), Current Contents (1993 to May 1999), the Cochrane Library (Issue 2, 1999), and Best Evidence (1991 to August 1999) databases were searched without language restriction. This search was updated in April 2000. The following terms were used for MEDLINE and CANCERLIT: "lymphoma, non-Hodgkin" (MESH, text word), "lymphoma" (text word) combined with "aged" (text word) or "older" (text word) combined with "chemo:" (text word). These terms were then combined with search terms: "practice guidelines" (MESH, text word) or "practice guideline?" (text word) or "guideline?" (text word); "meta-analysis" (MESH, text word) or "meta analy:" (text word) or "metaanaly:" (text word) or "systematic review?" (text word) or "systematic overview?" (text word); "random:" (text word) or "random allocation" (MESH, text word). The CANCERLIT search was limited to non-MEDLINE entries. The following headings were used for EMBASE: "lymphoma" or "non-hodgkin lymphoma"; "age" or "old" or "older"; "chemo"; "practice guideline?" or "guideline"; "meta-analysis" or "metaanaly" or "meta analy" or "systematic review?" or "systematic overview?"; "random" or "random allocation?". The Cochrane Library, Current Contents, and Best Evidence were searched using the following terms: "lymphoma" and "older" and "chemotherapy". # Related Guidelines The search strategy for the growth factors question used the following terms for MEDLINE and CANCERLIT (limited to non-MEDLINE entries): "lymphoma" (MESH, text word) or "lymphoma, nonhodgkin" (MESH, text word) and "age?" (text word) or "elder:" (text word) or "old:". These terms were then combined with the following terms: "growth factor?" (text word) or "granulocyte-macrophage colony-stimulating factor" (MESH) or "granulocyte colony-stimulating factor" (MESH) and "review?" or "overview" or "guide:". The following terms were used for EMBASE: "lymphoma" and "older" or "aged" and "granulocyte colony stimulating factor" or "granulocyte macrophage colony stimulating factor". Searches of the Cochrane Library, Current Contents, and Best Evidence were performed using the following terms: "lymphoma" and "older" and "colony stimulating factor". The paucity of randomized trials assessing the role of colony stimulating factors in the elderly led to a broadening of the inclusion criteria to include non-randomized studies. # Study Section Criteria: The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial over-all survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. The baseline characteristics of the pegfilgrastim and filgrastim groups were imbalanced with increased bone-marrow involvement and prior therapy in the former. When the treatment groups were balanced for these risk factors, duration of grade 4 neutropenia was comparable with 2.0 and 3.0 vs. 0.6 and 0.5 days for pegfilgrastim 100 microg/kg and filgrastim patients with and without these risk factors, respectively. The incidence of febrile neutropenia (defined as ANC 38.2degrees C) was low (10% of patients). The Hematology Disease Site Group would like to thank Drs C.T. Kouroukis, G. Browman, K. Imrie, and R. Meyer and Ms. R. Esmail, Ms. J. Makarski, and Ms. A. Stevens for taking the lead in drafting and revising this practice guideline report. For a complete list of the Hematology Disease Site Group members and the Practice Guidelines Coordinating Committee members, please visit our web site at /. # DOCUMENT ASSESSMENT AND REVIEW RESULTS # Question Considered - What are the roles of granulocyte-colony stimulating factor or granulocyte macrophage-colony stimulating factor in combination with chemotherapy in these patients? # Literature Search and New Evidence The new search from October 2001 to January 2013 yielded 19 references representing 17 RCTs (2 RCTs had 2 publications each), evaluating the use of chemotherapy and growth factors in older patients with newly diagnosed, advanced-stage, aggressive histology non-Hodgkin's lymphoma. Sixteen of these references had full text publications and 3 were in abstract form. There were 3 ongoing studies identified from clinicaltrials.gov. Brief results of these searches are shown in the Document Review Tool. # Impact on Guidelines and Its Recommendations # OUTCOMES DEFINITION - ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of our website, each page is watermarked with the phrase "Archived document, not for use in clinical decision making," - ENDORSED -An endorsed document is a document that has been reviewed by the DSG/GDG for currency and relevance, and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way. # DELAY - A Delay means that there is reason to believe new, important evidence will be released within the next year that should be considered before taking further action. # UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.

To provide an updated guideline on the use of rituximab in lymphoma and chronic lymphocytic leukemia (CLL).# For information about this document, please contact Dr. Tom Kouroukis or Dr. Matthew Cheung through the PEBC via: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca: For information about the PEBC and the most current version of all reports, please visit the CCO website at / or contact the PEBC office at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca # INTENDED USERS Intended users of this updated guideline include hematologists and oncologists treating patients with lymphoma or CLL. # RECOMMENDATIONS Recommendation 1 Aggressive histology B-cell lymphomas, including Burkitt lymphoma: first-line, secondline and maintenance treatment and patients with human immunodeficiency virus (HIV)-associated lymphomas. Previously Untreated Patients a. Previously untreated patients with aggressive histology CD20-positive B-cell lymphomas who are candidates for treatment with curative intent and will receive combination chemotherapy with curative intent (including cyclophosphamide, doxorubicin, vincristine, and prednisone CHOP-like, or similar dose-intense regimens) should receive this therapy in combination with rituximab. Patients with Relapsed/Refractory Disease b. For previously treated patients with aggressive histology CD20-positive B-cell lymphomas: There is insufficient evidence at this time to support treatment with a rituximabcontaining chemotherapy regimen in patients who have been previously treated with a rituximab-containing chemotherapy regimen. ii. If patients have not previously received rituximab as part of their treatment regimen, the addition of rituximab to chemotherapy is reasonable. Rituxmab Maintenance Treatment c. There is insufficient evidence at this time to support the use of maintenance rituximab in aggressive histology B-cell lymphomas. Patients with HIV-Associated Lymphomas d. Previously untreated patients with HIV-related lymphoma with a CD4 count ≥50/mm 3 who are candidates for treatment with curative intent and will receive combination chemotherapy with curative intent (including CHOP, CHOP-like, or similar dose-intense regimens), should receive this therapy in combination with rituximab. The addition of rituximab to chemotherapy in patients with CD4 <50/mm 3 is not recommended. # Recommendation 2 Indolent histology B-cell lymphomas: first-line, second-line, and maintenance treatment and patients with asymptomatic CD20-positive B-cell lymphomas Previously Untreated Patients a. Previously untreated patients with indolent histology CD20-positive B-cell lymphomas, excluding small lymphocytic lymphoma (SLL), who are appropriate candidates for chemotherapy, should receive their chemotherapy in combination with rituximab. b. For patients with indolent histology CD20-positive B-cell-histology lymphomas, excluding SLL, who are candidates for therapy, but not combination chemotherapy, rituximab monotherapy is a reasonable option. Patients with Relapsed/Refractory Disease c. For previously treated patients with indolent histology CD20-positive B-cell lymphomas, excluding SLL: i. Patients who have not previously received rituximab and who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab or as rituximab monotherapy. ii. Patients who have previously received rituximab (including combination rituximab chemotherapy, rituximab monotherapy, or maintenance rituximab) and who have achieved a response of at least one year's duration from the last rituximab administration and who are appropriate candidates for therapy should receive this therapy in combination with rituximab or as rituximab monotherapy. Rituxmab Maintenance Treatment d. For patients with indolent histology CD20-positive B-cell lymphomas, excluding SLL, who respond to treatment with combination chemotherapy and/or rituximab, this treatment should be followed by the use of maintenance rituximab. # Patients with Asymptomatic CD20-Positive B-Cell Lymphomas e. There is insufficient evidence at this time to support or refute upfront treatment with rituximab monotherapy for asymptomatic indolent histology CD20-positive B-cell lymphomas. # Recommendation 4 Hepatitis B virus reactivation in all patients treated with rituximab The Hematology Disease Site Group recommends that all patients be screened for surface antigen for hepatitis B (HBsAg) and for hepatitis B core antibody (HBcAb) prior to treatment with rituximab. Consultation with an expert in hepatitis B virus (HBV) should be considered for all patients who test positively for HBV. Patients who are HBsAg positive should receive prophylactic antiviral therapy during and after rituximab. Patients who are HbsAg negative/HBcAb positive should be considered for either prophylactic antiviral therapy, close monitoring for viral reactivation, and/or should be followed by an expert in HBV. In the absence of active hepatitis (elevated transaminases), it is not usually necessary to delay rituximab. In most cases, HBV screening and management can occur in parallel with non-Hodgkin lymphoma/CLL treatment.

Version 2 IN REVIEW. This means that it is undergoing a review for currency and relevance. It is still appropriate for this document to be available while this updating process unfolds. The PEBC has a formal and standardized process to ensure the currency of each document.# Guideline Report History # Target Population These recommendations apply to adult patients with relapsed SCLC. - The evidence for the clinical benefit of second-line chemotherapy in the treatment of patients with relapsed SCLC is limited. The selection of patients for treatment with second-line therapy should be dependent on the treatment-free interval, the extent of response to first-line therapy, residual toxicity from first-line therapy, and the performance status of the patient. - There is insufficient evidence to recommend a specific chemotherapy regimen. However, in the opinion of the Lung Cancer Disease Site Group, patients who relapse three or more months following the completion of first-line chemotherapy may benefit from retreatment with the same regimen that induced their initial response. This would generally mean retreatment with etoposide-cisplatin. Alternative regimens may include cyclophosphamide, doxorubicin, and vincristine (CAV) or carboplatin and etoposide. - Oral topotecan is a possible alternative for patients who initially responded to chemotherapy and had a response duration of 45 days or longer. - There is insufficient evidence to determine whether one mode of administration of topotecan is superior to any other mode of administration. Oral administration is more convenient and may be a treatment option for patients not suitable for intravenous therapy. Oral administration is associated with a higher incidence of grade 3/4 diarrhea, whereas intravenous administration may result in a higher frequency of grade 3/4 neutropenia. - There is currently no standard second-line chemotherapy regimen for patients who fail to respond to or who relapse shortly after first-line therapy. Clinical trials are needed to determine the optimal treatment regimen. # Key Evidence - One randomized phase III trial compared chemotherapy to best supportive care, three randomized trials (one phase II and two phase III) compared different secondline chemotherapy regimens, and two randomized trials (one phase II and one phase III) compared different forms of administration of second-line single-agent chemotherapy. - One recent randomized phase II trial showed that chemotherapy consisting of oral topotecan and best supportive care (BSC) extended survival when compared with BSC alone and improved the quality of life for patients who had relapsed, resistant SCLC. The response rate for patients treated with oral topotecan and BSC was only 7%. - One randomized phase II trial comparing cisplatin and etoposide to carboplatin, cisplatin, and etoposide found no significant differences in response rate (p=0.20) or survival (p=0.11). - One randomized phase III trial that treated patients with CAV or topotecan alone reported no significant differences in response rate (p=0.285) or survival (p=0.795). - One phase III trial randomized patients to either bis-chloro-ethylnitrosourea , thiotepa, vincristine, cyclophosphamide (BTOC) or etoposide and cisplatin; no significant differences in response rate (p=0.91) or survival (p=0.15) were found. - Two randomized trials (phase II and phase III) compared oral to intravenous (IV) administration of topotecan. Response rates were 18.3% and 23.1% for oral administration and 14.8% and 21.9% for IV administration. Survival was not significantly different between the modes of administration (HR, 0.98; 95% CI, 0.77-1.25; and risk ratio, 0.84; 95% CI, 0.53-1.32). # Related Guidelines - # 7-13-1: The Role of Combination Chemotherapy in the Initial Management of Limited-Stage Small-Cell Lung Cancer; - # 7-13-2: Prophylactic Cranial Irradiation in Small Cell Lung Cancer; - # 7-13-3: The Role of Thoracic Radiotherapy as an Adjunct to Standard Chemotherapy in Limited-Stage Small Cell Lung Cancer. The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

The 2014 guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making. Please see Section 4: Document Assessment and Review for a summary of updated evidence published between 2013 and 2022, and for details on how this guideline was ENDORSED. What is the impact of intermittent strategies of administering systemic therapy on length and quality of survival in patients with untreated, unresectable metastatic colorectal cancer? # TARGET POPULATION These recommendations apply to adult patients (≥18 years old) with inoperable, advanced (Stage IV) colorectal cancer. # INTENDED USERS This guideline is intended for use by clinicians and healthcare providers involved in the management of patients with advanced colorectal cancer. # RECOMMENDATIONS AND KEY EVIDENCE Ten trials (1-10) were identified, and seven (1,2,5-9) had published overall survival hazard ratios (HRs) that could be used for the meta-analysis. Meta-analysis demonstrates no clinically significant survival difference between the continuous and intermittent Intermittent strategies of administering first-line systemic therapies to patients with unresectable metastatic colorectal cancer (mCRC) do not result in a statistically significant reduction in overall survival and either improve or maintain quality of life compared to continuous administration of therapy. Patients who want a break from treatment can be reassured that intermittent strategies of administering first-line therapy are a reasonable alternative to continuous administration. Intermittent systemic treatment strategies should be part of an informed discussion of treatment options for this group of patients. chemotherapy strategies (HR, 1.02; 95%CI, 0.95-1.10, p=0.62). No subgroup of trials based on the type of induction or maintenance therapy in the intermittent arm demonstrates a significant difference in overall survival between the two chemotherapy strategies (Figures 2, 3, and 6). Toxicity assessments revealed differential toxicity patterns for the two strategies. However, these toxicity assessments reflect maximal levels of toxicity experienced during exposure to the treatment on that arm of the trial. These measures are important, but for patients on intermittent treatment, duration of exposure to toxicity, or ability of patients to recover from the toxicities after induction treatment, are also important and are likely better captured in quality-of-life (QOL) assessments. Of the two trials that measured quality of life, the Maughan et al. (1) trial demonstrated no difference in QOL, and several benefits were demonstrated for the intermittent chemotherapy arm at 24 weeks in the COIN (6) trial. Specifically, there were statistically significant benefits with respect to role functioning (OR, 0.82; 95%CI, 0.70-0.96, p=0.015) and social functioning (OR, 0.82; 95%CI, 0.70-0.96, p=0.016) as well as for several symptom scales including fatigue, nausea and vomiting, appetite loss, constipation, diarrhea, dry or sore mouth, eating or drinking problems, problems handling small objects, and treatment interfering with activities of daily living (all p<0.04). # QUALIFYING STATEMENTS - Given that the trials included in this systematic review included a variety of maintenance strategies, a definitive recommendation regarding an optimal maintenance strategy is not possible. However, our analyses of strategies that did not use any maintenance systemic therapy did not demonstrate any statistically significant detriment in overall survival. Therefore, this approach may be preferred by patients, as it offers them a complete break from treatment. - All but one of the intermittent strategies offered 12 to 18 weeks of induction treatment and were monitored with imaging at least every 8 to 12 weeks during the intermittent phase of treatment, with reintroduction of the induction chemotherapy at disease progression. These represent reasonable guidelines to consider when using an intermittent strategy, but adaptation of a strategy to individual circumstances should always be considered. A longer induction period or closer clinical monitoring of patients on maintenance therapy or chemotherapy-free interval might be appropriate for patients with very bulky or symptomatic disease. For some patients like this, an intermittent strategy may not be appropriate. - Five of the seven trials that contributed to the meta-analyses were based on treatments with FOLFOX chemotherapy, one of the commonly used first-line chemotherapy regimens for mCRC in Ontario. The other two trials included in the meta-analyses used fluoropyrimidine monotherapy or FOLFIRI as induction chemotherapy regimens. Given the acceptability of fluoropyrimidine monotherapy as one of the options for first-line therapy (see EBS #2-5) and the accepted equivalence of FOLFIRI and FOLFOX as first-line therapies (11,12), extrapolation of our conclusions to all commonly used induction chemotherapy regimens is reasonable. - During maintenance therapy or a chemotherapy-free interval, best supportive care should be continued for patients. # FUTURE RESEARCH Future research should include a population study to evaluate the impact of intermittent strategies of administering first-line therapy for mCRC on outcomes in routine practice. # RELATED GUIDELINES - PEBC Evidence-based Series #2-5: Strategies of Sequential Therapies in Unresectable, Metastatic Colorectal Cancer Treated with Palliative Intent (currently under development) The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

The Ontario Cervical Screening Program (OCSP) is currently being relaunched to incorporate an organized call and recall component. This relaunch has necessitated a review of evidence related to the research questions listed above and an update of the relevant portions of the Program in Evidence-based Care (PEBC) May 2005 guideline Cervical Screening (1). The updated guideline will help the OCSP to realize its long-term goals of reducing the incidence of and mortality from cervical cancer through an organized screening program and improving the capacity of providers to engage in organized cervical screening. It will also address the 2011-2014 Ontario Cancer Plan (2) goal of creating evidence-based guidelines for cervical cancer screening. Evidence clearly indicates that there is a role for HPV testing in primary screening, and, thus, the primary recommendations presented in Part 1 of this guideline are for HPVbased testing for women 30 years of age and over. The proposed algorithm (Figure 1) assumes the existence of an organized province-wide screening program. There is lesser quality evidence at this time for the appropriate screening algorithm for women under 30. For this reason, and because HPV testing is not currently funded in the province and the components of an organized screening program are in the process of being put in place, a set of interim recommendations (Section 1, Part 2) are also provided that include the younger age group and acknowledge the current standard of cytology-based testing. The goal of the interim recommendations is to provide a bridge to the time when HPV testing for primary screening is funded in Ontario. Because screening for cervical cancer is a quickly evolving field, the HPV testing-based algorithm, the optimal age for screening initiation, and a method of screening for women younger than 30 years should be reviewed prior to implementation. A comparison of recommendations contained in this guideline and in the previous version published in 2005 is presented in Table 1. A table of screening test results terminology and a glossary of terms are provided in Appendices 1 and 2, respectively. For more information on HPV and the development of cervical cancer, details of the systematic review, and discussion of the impact of adoption of HPV testing for primary screening, please see Section 2 of this report. # RECOMMENDATION Primary Screening Test HPV DNA testing of cells collected from the cervix is recommended for primary cervical screening. Cytology screening, which was recommended for primary screening in the previous version of this guideline, is now recommended only in the event of a positive HPV DNA test result (see HPV screening algorithm, Figure 1). Interim recommendations are provided in Section 1, Part 2 (Interim Recommendations), because HPV testing is not funded at this time for primary screening in Ontario. # KEY EVIDENCE HPV testing Seven randomized controlled trials (RCTs) (3)(4)(5)(6)(7)(8) have been conducted to assess the performance of HPV testing in primary screening. The trials assessed the rates of cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2 or CIN3), either at a baseline screening round or over two screening rounds. CIN2 is a useful indicator because it is often the threshold for clinical management. CIN3 is less likely than lower grades of CIN to regress or resolve without treatment and so is a useful predictor of the risk for cervical cancer. The results showed that: - HPV testing consistently detected significantly more CIN2 and CIN3 in the baseline screening round than did cytology-based testing. HPV testing detected fewer CIN2 or more severe (CIN2+) cases in the subsequent screening round, indicating a lead time gain with HPV testing. The one trial that had sufficient sample size to report incidence and mortality due to cervical cancer found a significant reduction with HPV testing but not with cytology testing, compared to standard care (9). There was no significant difference in the number of invasive cancers detected in the baseline screening round in the New Technologies in Cervical Cancer trial (8) comparing HPV testing and cytology testing. In the subsequent screening round, no cases of cancer were found in the HPV-testing group, while nine cases were found in the cytology-testing group. A high number of the cancers detected in the second round in the cytology group were adenocarcinomas (10). This is consistent with previous reports that cytology is less effective in preventing adenocarcinomas than squamous cell carcinomas (approximately 20% of cervical cancers in Ontario are adenocarcinomas) (11). # Cytology Triage of HPV Positive Results - Due to the higher sensitivity of HPV testing compared to conventional cytology, the rate of colposcopy referral with HPV testing alone is higher than the rate with conventional cytology. For example, in the Canadian Cervical Cancer Screening Trial (CCCaST) RCT, the rate of referral to colposcopy after a positive HPV test alone was 6.1%, compared to a referral rate of 2.6% for conventional cytology results of atypical squamous cells of undetermined significance (ASCUS) (3). A triage test can reduce the number of colposcopy referrals and increase the specificity of the screening algorithm. In CCCaST, HPV with Pap triage resulted in a 1.1% rate of referral based on ASCUS (3). The Finnish Public Health Trial found the frequency of colposcopy referrals was 1.2% in both the conventional cytology arm at a threshold of low-grade squamous intraepithelial lesions (LSIL) and the HPV with cytology triage arm of their trial (12). # QUALIFYING STATEMENT - The recommendation for HPV testing is applicable only in the context of an organized screening program with an adequate database infrastructure that allows for an invitation to screening at recommended intervals, and a follow-up of women with abnormal test results. HPV testing has been shown to be more effective for women 30 years of age and older (see Age of Screening Initiation below). Women who have never been sexually active 1 do not require cervical screening. # RECOMMENDATION Age of Screening Initiation It is the opinion of the Cervical Screening Guideline Working Group (the Working Group) that there is insufficient evidence at this time to make a recommendation for the age at which to begin cervical screening using HPV testing as the primary screen. HPV testing performs better for women 30 and over compared to younger women because the rate of transient infections is higher in the younger age group; therefore, the screening algorithm in the following recommendation is presented for women 30-65 years of age. # RECOMMENDATION Screening Interval (Women 30-65) Screening interval recommendations are according to the algorithm presented in Figure 1. For women aged 30-65, HPV DNA testing is to occur at five-year intervals after an initial negative result, which is a change from the recommendation for repeat cytology testing every two to three years contained in the 2005 version of this guideline. HPV-positive tests should be assessed with cytology testing and not referred directly to colposcopy. Repeat HPV testing for results of HPV positive/cytology negative should be conducted after one year. # KEY EVIDENCE The proposed HPV testing algorithm is based on a combination of evidence from cohort studies, the natural history of HPV infections, and the consensus of the Working Group. # Five-Year Interval after HPV Negative Results - Six years after a negative HPV test, pooled cohort data found a cumulative incidence rate for CIN3+ of 0.27% (95% CI, 0.12 to 0.45), which was lower than the rate after three years with a negative cytology test (0.51%; 95% CI, 0.23 to 0.77) (14). This indicates that retesting at five-year intervals would entail a low level of risk. The risk of CIN3+ after a negative HPV test is low: in a Danish cohort study the 12-year absolute risk of CIN3+ after a negative HPV DNA test in women with normal cytology was 3.0% (95% CI, 2.5 to 3.5%) (15). # One-Year Interval with HPV Positive/Cytology Negative Results The short-term persistence of HPV infection for at least one year is an important predictor of CIN2+ (16). In women who tested HPV positive at enrolment and negative after about one year (nine-21 months), the cumulative incidence of CIN2+ after three years was 1.2% (95% CI, -0.2 to 2.5). The three-year cumulative incidence of CIN2+ in women who tested positive for carcinogenic HPV at study enrolment and again after approximately one year was 17.0% (95% CI, 12.1 to 22.0) (16). Consequently, referral to colposcopy after two consecutive positive HPV tests occurring a year apart is recommended, even in the event of initially negative cytology results. # QUALIFYING STATEMENTS The screening algorithm (Figure 1) should be reviewed for currency prior to implementation. A variation on this algorithm includes genotyping for HPV 16 and/or HPV 18 immediately after a positive HPV test and cytology results of normal, ASCUS or LSIL, based on the rationale that HPV 16 has been shown to be more persistent and more often associated with high-grade lesions, and HPV 18 is more often associated with difficult to detect lesions in the endocervical canal (13). Positivity for either of these types may require immediate colposcopy. # RECOMMENDATION Age of Screening Cessation Screening may be discontinued after the age of 65 provided there is an adequate negative screening history in the previous 10 years (i.e., two or more negative tests) and a final negative HPV test at age 65. Women who do not meet these requirements should continue with screening at recommended intervals. This is a change from the previous recommendation of cessation at age 70 (1). # KEY EVIDENCE This recommendation is the consensus of the authors, taking into account the low rate of cervical cancer in this age group among women who have previously been adequately screened, the potential discomfort of the procedure, and difficulties with visualization of the squamocolumnar junction in older women. # PART 2: INTERIM RECOMMENDATIONS (TO BE FOLLOWED UNTIL HPV TESTING IS FUNDED) INTERIM RECOMMENDATION Primary Screening Test On an interim basis, the authors endorse the recommendation contained in the 2005 version of this guideline: primary screening with cytology testing (1). # KEY EVIDENCE This recommendation is the opinion of the authors based on the systematic review conducted for the previous version of this guideline (1). # QUALIFYING STATEMENTS - Women with Pap tests that lack transformation zone components (i.e., endocervical and/or metaplastic cells) may continue screening at the regular intervals recommended by the guideline. Repeated samples lacking transformation zone may require further investigation. The above statement does not include women with test results of "unsatisfactory", who should undergo repeat screening in three months. This qualifying statement is the opinion of the Working Group based on the clinical experience that a shorter waiting period may result in the detection of reactive changes as a result of the first screening test. The Working Group maintains the recommendations for screening of special populations contained in the 2005 guideline:  Immunocompromised women (e.g., those currently taking long-term immunosuppressants, those who are HIV positive) should receive annual screening.  Screening can be discontinued in women who have undergone a total hysterectomy for benign causes with no history of cervical dysplasia or HPV. Women who have undergone subtotal hysterectomy (with an intact cervix) should continue screening according to the guidelines.  Indications for screening frequency for pregnant women should be the same as for women who are not pregnant. Manufacturers' recommendations for the use of individual screening tools in pregnancy should be considered.  Women who have sex with women should follow the same cervical screening regimen as women who have sex with men. # INTERIM RECOMMENDATION Age of Screening Initiation Cytology testing should commence at 21 years of age for sexually active women. # KEY EVIDENCE Lower quality evidence was available for the questions regarding the age of initiation of cervical screening. Three case-control studies were found that addressed the questions of initiation (17)(18)(19). The results of these studies were mixed, with a trend towards higher efficacy of screening for older women. There were no studies found that directly assessed the optimal age of initiation of cervical screening with HPV testing as the primary screen. - After weighing the available evidence, the authors of this guideline have concluded that the harms of screening women under 21 years of age significantly outweigh the benefits. In the opinion of the authors, the potential for adverse reproductive outcomes with treatment, anxiety related to the testing procedure, and the anxiety and potential stigma associated with positive test results considerably outweigh the benefits of screening in women younger than 21 years of age (20)(21)(22)(23), given the relatively high rate of HPV infection (24), rarity of cervical cancer in women under 25 years, and the up to decadeslong time period of progression from HPV infection to cervical cancer (25).  In the opinion of the Working Group, evidence regarding the necessity, utility, and/or effectiveness of screening in women 21 to 24 years is not as clear; the authors of this guideline are not convinced that the harms outweigh the benefits of screening for these women. Therefore, the consensus is that lesions in these women should be detected and treated where appropriate in order to minimize the potential for their progression to cervical cancer.  The guideline authors do recognize that there is also a potential for harm with screening. The potential harms related to treatment of CIN are adverse reproductive outcomes, including premature rupture of membranes, low birth weight, and preterm delivery (22). The early detection and treatment of CIN3 in young women, however, might prevent some cancers developing to a stage where treatment could result in compromised fertility. Based on the information available at this time, the authors of this guideline consider that the benefit of eliminating potential cases of invasive cervical cancer in women 21-24 years of age outweighs the reproduction-related harms, as well as the potential anxiety, fear, and uncertainty related to abnormal screening tests, intensified screening, colposcopy, biopsy, and treatment for CIN. # QUALIFYING STATEMENTS - Women who are not sexually active 3 by age 21 may delay cervical screening. Women who have never been sexually active do not require cervical screening. The interim recommendation to begin screening at 21 years of age should be reviewed within 24 months of the publication of this guideline. As HPV-vaccinated women reach the age of screening initiation, there may be impact on the screening recommendations. # KEY EVIDENCE The key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1). # INTERIM RECOMMENDATION Screening Interval Women should be screened every three years. # KEY EVIDENCE The previous guideline recommended three annual negative screens before lengthening the screening interval to two to three years. Evidence presented in the previous version of this guideline showed that the excess risk with screening every three years compared to annually was approximately three additional cases of cervical cancer per 100,000 women (26). A modelling study conducted in Australia found that increasing the recommended screening interval from two years to three years with cytology-based testing would result in no substantial change to incidence and mortality due to cervical cancer (27). # INTERIM RECOMMENDATION Age of Screening Cessation The authors endorse the age of cessation of cytology-based testing presented in the 2005 version of this guideline: Screening may be discontinued after the age of 70 if there is an adequate negative cytology screening history in the previous 10 years (i.e., three to four negative cytology tests). # KEY EVIDENCE Key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1). # Recommended Management for Women with Abnormal Cytology Management recommendations were not included in the scope of the current guideline. The algorithm for the management of abnormal results from the previous version of this guideline has been appended, however, as its recommendations still apply to the interim cytology-based guidelines provided here. Please see Appendix 3 (Section 1, page 19). If the evidence base for these recommendations is required, please email ccopgi@mcmaster.ca. # FUTURE RESEARCH Results from further screening rounds of several of the RCTs included in the evidence base for this guideline are anticipated (Table 2). These results should further inform the optimal screening algorithm for women 30 years of age and older and the optimal age for commencing cervical screening. An international agreement has been reached to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention (28). # NTCC (ISRTCN81678807) February 2002 December 2004 Yes; A cost-benefit analysis is underway (10). Also, the group is updating the follow-up of a third screening round (personal communication, Guglielmo Ronco, May 2011). # ARTISTIC (ISRCTN25417821) June 2001 November 2009 Yes; the ARTISTIC trial is continuing to follow women while maintaining the randomised concealment of HPV testing results for a further three-year round of screening (29). The HPV FOCAL study (Trial Registration No. ISRCTN79347302) is being conducted by the BC (British Columbia) Cancer Agency, in collaboration with the BC Centre for Disease Control, the University of British Columbia, McGill University, and healthcare providers in Metro Vancouver and Greater Victoria. In a Canadian context, this study aims to establish the efficacy of human HPV testing as a stand-alone screening test with cytology triage of HPV positive women, establish an appropriate screening interval for HPV negative women, and determine cost-effectiveness of HPV testing as a primary screening test. Other HPV testing strategies under study are based on molecular markers and include viral load, genotyping, testing for the RNA of the viral oncogenes E6 and E7, and testing for the overexpression of the p16-INK4A protein (31). As research continues into the risk factors for cervical cancers and the different typespecific and other tests evolve, screening algorithms will become increasingly more complex. In response to this, a group is developing a tool to predict the risk for a woman of having or developing cervical precancer. These risk estimates could be used to make referral and screening interval decisions (32) and may be considered for implementation in future update of this guideline. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. # RELATED GUIDELINES

2b. In female patients with locally advanced breast cancer does locoregional irradiation result in higher survival and lower recurrence rates compared with breast/chest wall irradiation alone? 2c. In female patients with locally advanced breast cancer and pathologically complete response to neoadjuvant therapy is radiotherapy indicated? - In female patients with locally advanced breast cancer who receive neoadjuvant chemotherapy is sentinel lymph node biopsy (SLNB) or axillary dissection the most appropriate axillary staging procedure? Is SLNB indicated before neoadjuvant chemotherapy rather than at the time of surgery? 4. How should female patients with locally advanced breast cancer who do not respond to initial neoadjuvant therapy be treated? # TARGET POPULATION This guideline is pertinent to female patients with locally advanced breast cancer (LABC). For purposes of this guideline, LABC includes Stages IIB and IIIABC and inflammatory cancer, as defined in the AJCC Cancer Staging Manual, 6 th edition (1). Most studies in the evidentiary base (see Section 2) included heterogeneous populations spanning Stages IIB -IIIC and sometimes included inflammatory breast cancer. Very few studies dealt only with Stage III or specific subgroups such as patients with T3N0 cancer. As most of the major studies did not report results separately for patients with Stage IIB and Stage III cancers, the evidence did not support recommendations based on a narrower definition of LABC or subdivided by stage. Although some people do not consider Stage IIB to be locally advanced, there is an increasing trend to treat less bulky disease (Stage IIB) in a similar manner, including neoadjuvant therapy; therefore, the recommendations may also be applicable to this group. # INTENDED USERS The intended users are surgeons and medical and radiation oncologists specializing in breast cancer. This guideline addresses several questions related LABC as defined previously. In early breast cancer, breast-conserving surgery (BCS) with adjuvant radiotherapy (RT) has been found equivalent to mastectomy (in patients meeting BCS selection criteria) for long-term outcomes and it is preferred by many patients for cosmetic and psychological reasons. The applicability of BCS to LABC and the use and extent of RT after mastectomy is still a matter of debate. Historically, LABC has had poor outcomes. Although neoadjuvant (preoperative, induction) therapy was first introduced in an attempt to improve tumour resectability and overall survival (OS) rate with early adjuvant treatment, improved OS was not realized (2-6). However, other clinically important outcomes were observed, including disease downstaging and feasibility of breast conservation in select cases, which form the basis for continued use of this approach. Furthermore, neoadjuvant chemotherapy (NACT) 3 may also allow an in vivo assessment of chemosensitivity, potentially allowing a regimen change that would not otherwise be made with traditional postoperative adjuvant treatment. Finally, NACT provides a platform for important biomarker and correlative studies to enhance our understanding of this disease. Although BCS becomes technically feasible in some patients with LABC with good response to NACT, there is uncertainty as to whether mastectomy or BCS is most appropriate. Conversely, optimal treatment when LABC does not respond to initial NACT is unclear. Sentinel lymph node biopsy (SLNB) is used in early breast cancer as an alternative to full axillary lymph node dissection (ALND). The role of SLNB compared with ALND in patients with LABC receiving NACT has not been established. NACT has expanded beyond classically unresectable LABC and it is being used more frequently for some smaller tumours, especially certain clinical subtypes (e.g., triple negative, HER2+. Although this document does not evaluate effectiveness of NACT, its expanded use means that clinical trials often cover a heterogeneous patient population (see Target Population). Communication between oncologists, surgeons, radiologists, and pathologists is essential. A multidisciplinary case conference is the recommended forum for discussion of cases. Any prior use of neoadjuvant therapy should be indicated when specimens are submitted for pathologic examination. Clinical details often affect the pathologic examination and interpretation, whereas details of pathology reports will determine appropriate treatment. Prior therapy (including neoadjuvant therapy) can change the nature of the specimen and what should be reported. The experience of the authors is that use of neoadjuvant treatment is frequently not indicated when submitting specimens. It is recommended that surgical clips marking the original (pretreatment) tumour location be inserted before administration of neoadjuvant therapy. Neoadjuvant therapy may result in a change in the extent or distribution of tumour, including complete disappearance (clinically or pathologically complete response). The consensus reached at the Canadian Consortium for Locally Advanced Breast Cancer (COLAB) in 2011 (7) was that clips should be inserted at the time of diagnosis to mark tumour location and that this should be considered the standard of care. Use of clips allows for more accurate identification of the original tumour site (especially if there is complete response), resection of all (previously) cancerous tissue with adequate margins, pathologic interpretation of the most appropriate area of specimens, and greater accuracy of molecular analyses. # Question 1. In female patients with locally advanced breast cancer (LABC) with good response to neoadjuvant therapy, what is the role of breast-conserving surgery (BCS) compared with mastectomy? # Recommendation 1 For most patients with LABC, mastectomy should be considered to be the standard of care. BCS may be considered for some patients with non-inflammatory LABC on a case-by-case basis when the surgeon deems the disease can be fully resected and there is strong patient preference for breast preservation. # Key Evidence (go to Results in Section 2) - No randomized controlled trials (RCTs) that directly compared BCS with mastectomy in patients with LABC were found in the literature review (see Section 2). - Evidence in early breast cancer is that BCS plus radiation is equivalent to mastectomy alone (8,9). There is a continuum in breast cancer stage, as opposed to a sharp cut-off between early and locally advanced (see Target Population). The Cancer Care Ontario/Program in Evidence-Based Care (CCO/PEBC) guideline (9) included all of Stage I and II, although the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) defined early as "breast cancer in which all clinically apparent disease can be removed surgically" (10). Therefore, at least some cancers defined as LABC in the current guideline (e.g., Stage IIB) are covered in the recommendations of these other guidelines. # Qualifying Statements - Patients should be informed that for LABC as a whole the data are insufficient to recommend BCS as a rule; however, there may be some exceptions that can be considered on a case-by-case basis. - The extent of surgery, including BCS, should be determined after full discussion between the patient and the treating oncologist, taking into consideration the patient's values and the lack of direct evidence regarding the relative benefit of BCS vs mastectomy in this particular situation. Treatment of the axilla is discussed in Recommendations 2 and 3. - When considering between mastectomy and BCS (for those meeting selection criteria), benefits and harms must be weighed. BCS is considered to have generally better cosmetic effects, and for some female patients may have less impact on body image, self-esteem and sexuality than complete breast removal by mastectomy. With BCS there is usually no need for additional reconstructive surgery and the operation may be less complex. In some cases of BCS, there may be positive margins requiring re-excision. In cases of recurrence after BCS, further surgical procedure may be needed, and some patients may wish to reduce this possibility by having mastectomy as initial treatment. - Wide excision of the remaining tumour in the region of the original pre-neoadjuvant treatment tumour bed plus RT is recommended for patients with LABC who strongly desire BCS. The volume of tissue to excise will be decreased if there is response to neoadjuvant therapy. Surgical clips marking the original (pretreatment) tumour location should be inserted before administration of neoadjuvant therapy (see Preamble). - BCS is not advised in inflammatory breast cancer because the extent of tumour involvement cannot be reliably ascertained. - There is continuing evolution in the type of surgical procedures offered (e.g., skin-sparing mastectomy with immediate reconstruction), but these are beyond the scope of this guideline. # Question 2a. In female patients with locally advanced breast cancer who have had a mastectomy is radiotherapy indicated? # Recommendation 2a Radiotherapy following mastectomy is recommended for patients with LABC. # Key Evidence (go to Results in Section 2) - The EBCTCG meta-analyses (15,16) (see Section 2 Table 1) found postmastectomy radiotherapy (PMRT) significantly reduced 5-year and 10-year recurrence risk in patients with positive nodes (including subgroups with 1-3 positive nodes or with ≥4 positive nodes) or who received systemic therapy (primarily cyclophosphamide + methotrexate + fluorouracil and/or tamoxifen; >85% of patients with positive nodes received systemic therapy). This recurrence risk reduction applied to patients who had mastectomy plus ALND, mastectomy plus axillary sampling, or mastectomy only. - In the EBCTCG meta-analyses PMRT significantly improved 20-year breast cancer mortality (including all subgroups). PMRT also significantly improved 20-year overall mortality for node positive patients with ALND (overall or with ≥4 positive nodes) or with axillary sampling. - The benefit of RT in reducing breast cancer recurrence and mortality rates appears to be offset by adverse effects in older trials (primarily cardiovascular and lung adverse effects) especially in female patients with lower risk of recurrence. The ratio of breast cancer mortality rate to other mortality rates was strongly affected by nodal status, age, and decade of follow-up. The absolute benefit still favoured RT overall, but not necessarily in subgroups with particularly low risk of recurrence. More recent reviews found that the effectiveness of RT is increased and cardiopulmonary adverse effects are greatly reduced with modern RT planning and technique; therefore, the non-cancer mortality rate data in the EBCTCG meta-analyses may not be relevant to current practice. # Qualifying Statements - The use of three-dimensional (3D) treatment planning is important to minimize the dose to the lung and heart to ensure improvements in breast-cancer-specific survival rates are not offset by non-breast cancer mortality rates. Treatments provided should conform to accepted standards with respect to tissue coverage and dose. Techniques such as gated RT or active breath-hold are used in some centres to reduce cardiotoxicity, although these were not evaluated in this guideline series. - Radiotherapy after BCS was not part of this review, however guidelines for early breast cancer recommend radiation following BCS (8,9) and this is the current standard of care. In the absence of RCTs to the contrary, it is logical that radiation be used following BCS for LABC as well. Radiotherapy following BCS for LABC is the current standard of care. - The EBCTCG meta-analyses found RT improved recurrence and survival rates in the subgroup of patients with systemic treatment. Several of the studies used older regimens such as CMF. Whelan et al (17) also found RT reduced mortality in patients with nodepositive breast cancer who received systemic treatment. Figure 1 of Section 2 indicates RT significantly improved the local recurrence rate in patients receiving anthracyclinebased chemotherapy but there was no effect on survival rate. No studies were included in the systematic review (Section 2) using taxane-based chemotherapy. Newer chemotherapies and targeted therapies may reduce the absolute benefit of RT for some patients, although in the absence of RCTs, RT is still recommended. - Patients should be informed that improvements in recurrence and disease-specific survival rates have not necessarily translated into advantages in OS, possibly related to radiationinduced adverse effects in older studies. This applies especially in patients at lower risk of recurrence; however, most LABC patients who receive NACT would not be considered at low risk. Of patients with LABC, those with T3N0 confirmed by SLNB as N0 prior to chemotherapy are of lower risk than N+ patients. RT reduced the recurrence rates in all groups reported, but the absolute benefit in patients with very low risk of recurrence due to disease characteristics and systemic therapy may be small, and some may consider the incremental benefit of RT, although statistically significant, to be clinically unimportant. - Lymphedema is more likely when surgical procedures include ALND or/and when RT includes the nodal areas (see Section 2). Decreased shoulder mobility, decreased strength, arm weakness, and paresthesia/hypesthesia have also been reported. The German Breast-Cancer Study Group trial (also referred to as the Bundesministerium für Forschung und Technologie 03 study) (18) found that 25% of RT patients had acute skin reactions, and 28% had long-term skin alterations (1-2 years after RT). Radiation pneumonitis in the MA.20 trial was reported in 1.3% of patients receiving RT and 0.2% without. In some older RT regimens there was a significant increase in contralateral breast cancer and non-cancer mortality rates, primarily from heart disease and lung cancer (15,19). Careful treatment planning is likely to reduce (but not eliminate) risks other than lymphedema and skin effects. - The benefit of PMRT in patients with node-negative LABC (T3-4N0) is less clear because they have not been reported separately from smaller (T2N0) cancers. Additionally, in patients clinically T3N0 the rate of pathological node positivity exceeds 50% and these patients may be considered T3Nx unless deemed N0 by SLNB before NACT or by ALND. The EBCTCG fifth cycle analysis (16) found that patients with node-negative cancer (primarily early cancer) treated with mastectomy + ALND + RT had no difference in recurrence risk (3.0% RT vs 1.6%, p>0.1)due to RT but significantly higher overall mortality rate (47.6% vs 41.6%, p=0.03). Control patients (no RT) with node negative cancer in studies using mastectomy + axillary sampling had higher recurrence than in studies with ALND (17.8% vs 1.6%); RT in patients treated with axillary sampling resulted in significantly lower recurrence risk (3.7% vs 17.8%) and no difference in 20-year mortality (46.1% vs 49.9%, RR=1.0, p>0.1). Patients with T3N0 cancer remain a group with limited data and should be discussed individually with regards to risks and benefits. # Question 2b. In female patients with locally advanced breast cancer does locoregional irradiation result in higher survival and lower recurrence rates compared with breast/chest wall irradiation alone? # Recommendation 2b It is recommended that patients with LABC receive locoregional radiation encompassing the breast/chest wall and local node-bearing areas following breast-conserving surgery or mastectomy. # Key Evidence (go to Results in Section 2) - The recommendation for breast/chest wall irradiation is based on several RCTs as summarized in the EBCTCG meta-analyses (10,15,20-23) and is discussed in Question 2a. - A prospective nonrandomized study (24) in high-risk patients with Stage II-III breast cancer found improved disease-free survival (DFS) rates at median 77 months follow-up (73% with internal mammary (IM) node RT vs 52% without, p=0.02), whereas OS was 78% vs 64%, p=0.08. Subgroups at higher risk of recurrence may have greater benefit, as has been reported for patients with positive nodes. - A meta-analysis of the role of RT to regional nodes included three trials (two abstracts and one full publication) in patients with early/LABC (25) and concluded that regional RT to IM and medial supraclavicular (MS) nodes improves DFS, OS, and distant metastasis-free survival (DMFS) in Stage I-III breast cancer. This analysis did not meet our inclusion criteria because only approximately 36% of patients had LABC; therefore, the results need to be confirmed when the trials are fully published including subgroup data. - The recommendation to include local node-bearing areas is consistent with current practice and other clinical practice guidelines. The NCCN guideline (12) recommends that if IM lymph nodes are clinically or pathologically positive, RT should be administered to the IM nodes; otherwise, treatment to the IM nodes should be strongly considered in patients with node-positive and T3N0 cancer. NCCN also states that RT to the infraclavicular region and supraclavicular area is recommended for patients with ≥4 positive nodes and should be strongly considered if 1-3 nodes are positive, and considered for patients with T3N0 cancer (especially if inadequate axillary evaluation or extensive lymphovascular invasion). - The ACR (26) recommends PMRT for T1-2N2+ and T3-4N+, usually including ipsilateral supraclavicular fossa for patients with positive nodes. There is more variation for IM nodes, but IM RT is considered for patients at risk of IM involvement such as those with medial or centrally located tumours and positive axillary lymph nodes. PMRT treatment of T1-2N1 and T3NO is controversial and should be individualized. # Qualifying Statements - Locoregional treatment (compared with breast/chest wall alone) increases the risk for cardiovascular/pulmonary adverse effects. The additional fields are more technically complex to administer. The use of 3D treatment planning is important to minimize the dose to the lung and heart to ensure improvements in breast-cancer-specific survival are not offset by non-breast cancer mortality. - The risk of long-term adverse effects from locoregional radiation should be weighed against the potential benefits in patients with lower-risk disease, particularly those with left-sided tumours. Ideally, such patients should be discussed in a multidisciplinary setting. - In light of incomplete data, any recommendations regarding the role of regional radiation to specific nodal groups (e.g., IMC, MS, apical axilla, full axilla) in LABC are significantly limited. Although some studies attempted to isolate the role of irradiation to the IM nodes (27,28), others included additional radiation to the MS nodes (29-31) or all locoregional nodes (32,33). - The additional benefit of regional nodal RT is small, but significant for the overall patient groups studied in RCTs (early cancers plus LABC combined). - The incidence and/or severity of lymphedema is higher with locoregional RT. Especially in patients with lower-risk disease, the risk of long-term adverse effects from locoregional radiation should be weighed against the potential benefit of reduced recurrence rates and increased survival rates. - Patients with T3N0 cancer (verified to be node negative pre-and post-neoadjuvant therapy) remain a heterogeneous group with limited data and should be discussed individually with regards to risks and benefits. In patients clinically T3N0 the rate of pathological node positivity exceeds 50% and these patients may be considered T3Nx unless deemed N0 by SLNB before NACT or by ALND. In the latter case, they may be similar to T2N0 patients and less RT to the chest wall may be considered. # Question 2c. In female patients with locally advanced breast cancer and pathologically complete response to neoadjuvant therapy is radiotherapy indicated? # Recommendation 2c It is recommended that postoperative radiotherapy remains the standard of care for patients with LABC who have pathologically complete response to neoadjuvant therapy. # Qualifying Statements (go to Results in Section 2) - No prospective randomized studies were found in the literature review (see Section 2) that compared treatment with vs without RT in female patients with pathologically complete response (pCR) to neoadjuvant therapy. The consensus of the authors is that postoperative RT should therefore remain the standard of care. - When examining the evidence, it is important for the clinician to be aware of the various definitions for pCR that have been used in clinical studies. These range from no microscopic evidence of viable tumour cells, only residual necrotic or nonviable tumour cells, or only residual intraductal tumour cells in the resected specimen. The MD Anderson Cancer Center requires the added disappearance of axillary lymph node metastasis for a pCR. - Randomized trials such as those planned by the Athena Breast Cancer Network (34,35) and the NSABP B51/RTOG 1304 trial may provide data to re-evaluate the recommendation for specific subgroups in the future. # Key Evidence (go to Results in Section 2) - The median sentinel lymph node (SLN) identification rates (SLN ID rates) for the trials in Section 2 were 88% overall, 93% in patients with cN0 cancer and 85% in patients with clinically positive nodes. SLN ID rates depend on the experience of surgeons and the techniques used (see Section 2 for details). - The ACOSOG Z1071 trial (36,37) conducted with patients with positive nodes (>85% LABC) is one of the largest and most recent studies. It found a 93% SLN ID rate for cN1 cancer and 89% for cN2 cancer. This study found detection with radiolabeled colloid much better than blue dye alone (94% colloid + dye, 91% colloid, 79% dye). - For the studies in Section 2, median false negative (FN) rates were 10% overall, 7% cN0, and 13% clinically node positive. The SN FNAC study (38,39) found the FN rate decreased with the number of sentinel nodes removed (FN rate 19% for 1 SN, 7% for 2+ SN) and is consistent with the SENTINA trial findings. Using radiolabelled tracer plus blue dye and removing at least 2-3 SLNs, the best teams achieved FN rates of 5-7%. The FN rate is not dissimilar to the FN rates of 5-10% for early breast cancer surgery (40-42). - Although the studies indicate that SLNB is technically feasible in both early and locally advanced breast cancer, a small percentage of patients will be understaged using SLNB alone. This risk needs to be weighed against the increased adverse effects of ALND. - This recommendation is based on the authors' valuing potentially increased survival rates with use of ALND over increased postoperative complications. Given the results of the Z0011 and EBCTCG studies for early or operable cancers, some patients may decide that for less advanced LABC (e.g, Stages 2b-3a) the adverse effects of ALND are greater than the benefits. # Qualifying Statements - Although the SLNB technique in patients (mostly with LABC) receiving NACT is comparable to that in early breast cancer, the clinical implications of a FN SLNB is not known in these patients (see Discussion in Section 2). - The benefit of ALND is that more nodes are removed and examined, giving more accurate staging for some patients. Provided that locoregional RT is to be administered in all patients, as recommended in Questions 2a and 2b, the staging may have no impact on treatment. However, some patients may value the additional prognostic information. If a patient is not going to receive locoregional RT, then ALND is recommended. Trials in patients with LABC are ongoing. - More than 80% of female patients undergoing ALND have at least one postoperative complication in the arm and psychological distress is common (43). In the Z0011 trial (44,45) ALND added to SLNB resulted in more wound infections, axillary seromas, paresthesias, and subjective reports of lymphedema than SLNB alone. - The NCCN guideline (12) (not specifically on NACT) indicates "in the absence of definitive data demonstrating superior survival the performance of ALND may be considered optional in patients who have particularly favourable tumours, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly, or those with serious comorbid conditions". They recommend that cN0 plus SLN negative (including T3N0) need no further ALND. However, the authors of the current guideline note that most patients with LABC are pathologically node positive before neoadjuvant therapy, even those considered clinically negative; therefore, a high portion may still be pathologically node positive after neoadjuvant therapy. - None of the studies included inflammatory breast cancer; therefore, these findings cannot be extrapolated to that cohort of patients. # Recommendation 3-2 Although SLNB before or after NACT is technically feasible, there is insufficient data to make any recommendation regarding the optimal timing of SLNB with respect to NACT. Limited data suggests higher SLN ID rates and lower FN rates when SLNB is conducted before NACT; however, this must be balanced against the requirement for two operations if SLNB is not performed at the time of resection of the main tumour. # Key Evidence (go to Results in Section 2) - Only three of the studies in Table 6 of the evidence summary (46-48) compared timing of SLNB (before or after NACT) and one additional study (abstract only) performed SLNB before neoadjuvant therapy (49). The rest of the studies performed SLNB and ALND after completion of NACT. Before NACT the SLN ID rate was 98-99%, whereas after NACT it was a median of 93% in patients with clinically node-negative cancer and 88% overall. The studies also suggest FN rates are lower when SLNB is conducted before NACT. - The SENTINA study (46) did not conduct ALND if the SLNB before NACT was negative so FN rates could not be determined for this subgroup. Arm B of the SENTINA trial included patients initially cN0 with a positive SLN (pN1SN) before NACT and conducted a second SLNB plus ALND after NACT. SLN ID rate was 76% in the second SLNB and the FN rate based on the second SLNB was 61% compared with a SLN ID rate of 99% in patients with cN0 cancer when SLNB was performed before NACT. This suggests that SLNB should not be performed both before and after NACT. # Qualifying Statements - It is often considered that adjuvant treatment should be based on the initial stage as determined before any treatment, although the extent of surgery depends on the size/extent of the tumour immediately before the surgical procedure (i.e., after any neoadjuvant treatment). Some studies suggest NACT often eliminates cancer from the SLN but not all the other nodes. For these reasons, there is theoretical justification for performing SLN biopsy before NACT. The very limited data would support this, but is considered insufficient at this time to make a strong recommendation due to the trade-off required in risk and inconvenience of needing to perform two separate operations (one for SLNB and one to remove the main tumour) compared with the normal procedure of removing the tumour and SLN (or ALND) in one operation. # Question 4. How should female patients with locally advanced breast cancer who do not respond to initial neoadjuvant therapy be treated? Recommendation 4-1 It is recommended that patients receiving neoadjuvant anthracycline-taxane-based therapy (or other sequential regimens) whose tumours do not respond to the initial agent(s) or where there is disease progression be expedited to the next agent(s) of the regimen. # Recommendation 4-2 For patients who, in the opinion of the treating physician, fail to respond or who progress on first-line NACT, there are several therapeutic options to consider including second-line chemotherapy, hormonal therapy (if appropriate), radiotherapy, or immediate surgery (if technically feasible). Treatment should be individualized through discussion at a multidisciplinary case conference, considering tumour characteristics, patient factors and preferences, and risk of adverse effects. # Key Evidence (Recommendations 4-1 and 4-2) (go to Results in Section 2) - Anthracycline-taxane is a standard therapy, with the taxane administered either concurrently or consecutively. The NSABP B-27 trial (50-52) found AC followed by docetaxel gave significantly improved clinical and pathological response and lower rates of local recurrence compared with neoadjuvant AC alone. Because most patients were not LABC and patients were not randomized based on response, the trial is not included in the evidence review of Section 2. - The GeparTrio study (53) and a trial by Qi et al (54) evaluated early switching to second-line chemotherapy after nonresponse to two cycles of first-line chemotherapy and demonstrated conflicting findings: the GeparTrio demonstrated no improved response to treatment but better tolerability and DFS; the other trial demonstrated some improved response but worse adverse effects and treatment delays. There is therefore insufficient evidence to switch chemotherapy mid-treatment. - The recommendations are based on current practice and are consistent with the guidelines by NCCN (12), Health Canada (55), and the Consensus Panel for Neoadjuvant Chemotherapy (13). # Qualifying Statements (Recommendation 4-2) - There is a body of literature including patients with locally advanced and metastatic disease (mostly single-arm case series, small pilot studies, or retrospective studies) that supports a variety of second-line single agent and multi-agent NACT and/or RT regimens to improve response (including pCR) and, thus, operability or survival. Although the data are limited and not within the rigorous inclusion criteria of the literature review, Table 8 of Section 2 lists some of these studies as examples of regimens in the medical literature that have been tried in this clinical scenario. These data are not systematically reviewed nor of quality sufficient to make a recommendation as to preferred regimens. It is advised that oncologists individualize the choice of therapy based on the patient and risk of adverse effects. # FUTURE RESEARCH There is a need for prospective randomized clinical trials designed for patients with LABC who fail to respond to NACT so that more definitive treatment recommendations can be developed. # RELATED GUIDELINES The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care. Updating All PEBC documents are maintained and updated as described in the PEBC Document Assessment and Review Protocol.

Recommendation Report SCT-6: Section 1 # Stem Cell Transplantation in the Treatment of Acute Lymphoblastic Leukemia: Recommendations OBJECTIVES 1. To establish the indications for allogeneic stem cell transplantation (allo-SCT) in the management of acute lymphoblastic leukemia (ALL) in adults 2. To identify the role of reduced-intensity conditioning (RIC) regimens for SCT in the management of ALL of adult patients 3. To identify the role of tyrosine-kinase inhibitors (TKIs) for patients undergoing allo-SCT for Philadelphia chromosome-positive ALL (Ph+ ALL) 4. To identify the role of alternative donor transplantation (haploidentical, cord blood) in the management of adult patients with ALL who lack a suitable related or unrelated donor. # TARGET POPULATION All adult ALL patients considered for treatment that involves SCT. Outcomes of interest are relapse, disease-free survival, relapse-free survival, progression-free survival, overall survival, and non-relapse mortality. # INTENDED USERS This recommendation report is targeted for: 1. Healthcare physicians performing SCT in Ontario. - Healthcare institutions and system leaders responsible for providing resources for SCT. # RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1 Allogeneic stem cell transplantation (allo-SCT) is an option for adult patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1). Allo-SCT is recommended in CR2 or greater (refractory or relapsed). # Key Evidence for Recommendation 1 The studies involved patients with Philadelphia chromosome-negative ALL in first complete remission (CR1) and beyond (refractory or relapsed ALL). All patients were treated with total body irradiation (TBI)-based myeloablative conditioning, and sibling donor transplantation. - One evidence-based review with recommendations (1), and two systematic reviews with meta-analysis (2, 3) showed that allo-SCT offers superior overall survival and disease-free survival in patients with chromosome-negative ALL in CR1. - The recommendation surrounding allo-SCT in CR2 or beyond (refractory or relapsed) for adults with ALL represent the consensus of the Working Group members based on guidance provided by the 2012 American Society for Blood and Marrow Transplantation (ASBMT) guideline from USA (1). # Qualifying Statement for Recommendation 1 The studies looking at outcomes of allo-SCT in CR1 were older and many used less intensive regimens that may be currently used in adults with ALL, in particular regarding Lasparaginase. Thus, modern ALL therapy based on pediatric protocols may provide for better outcomes without the need to undergo allo-SCT in CR1. # Interpretation of Evidence for Recommendation 1 The primary outcomes considered to inform this recommendation include relapse, non-relapse mortality, disease-free survival and overall mortality/survival. The certainty of the evidence on the efficacy of allo-SCT compared with other postremission therapy (chemotherapy) is reasonable but with the caveat that current ALL chemotherapy protocols are more intensive than those used in the studies. This recommendation is generalizable to all adult patients with ALL in remission who are eligible for allo-SCT. # Recommendation 2 A myeloablative conditioning is the conventional regimen for most patients with leukemia; however, reduced-intensity conditioning (RIC) is an option for patients with acute lymphoblastic leukemia (ALL) in remission when they are deemed unsuitable for the standard myeloablative conditioning (MAC) regimen. # Key Evidence for Recommendation 2 This recommendation is supported by evidence obtained from the 2012 American Society for Blood and Marrow Transplantation (ASBMT) evidence-based review (1) and a systematic review with meta-analysis (4). - The 2012 ASBMT review (1) recommended RIC regimens only for patients with ALL in remission who are unsuitable for MAC regimens, as it was shown that RIC may produce similar outcomes to MAC regimens. The systematic review (4) stated that RIC may be a potential therapeutic option in patients with high risk of treatment-related mortality (TRM) associated with MAC regimens, as there was a lack of overall survival benefit of MAC over RIC regimens. - One retrospective cohort study (5) detected an improved overall survival for patients undergoing RIC when compared with MAC as conditioning for allo-SCT in ALL. # Qualifying Statement for Recommendation 2 Reduced-intensity conditioning may produce similar outcomes to myeloablative regimens, but available data are limited. Based on the evidence, the members of the Working Group have determined that RIC could be an effective therapeutic option for patients with ALL who are ineligible for MAC allo-SCT. There are important clinical differences in those patients undergoing the two types of conditioning that could affect outcomes. More prospective studies are required to better define the value of reduced versus MAC regimens. # Interpretation of Evidence for Recommendation 2 The primary outcomes considered to inform this recommendation include relapse, disease-free survival, non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of RIC in adults with ALL in remission is non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of haplo-SCT for patients in remission is low and therefore this recommendation cannot be generalized to all patients with ALL. This recommendation is generalizable only to patients with ALL who lack a suitable related or unrelated donor. # IMPLEMENTATION CONSIDERATIONS Should an increase in SCT for ALL result from this recommendation report, there may be issues related to capacity and timeliness of transplant in Ontario centres. Also, the use of haploidentical donors and RIC could increase the number of patients with ALL who may become eligible for a SCT. Due to the nature of the evidence showing improved outcomes in terms of survival and disease control, SCT for ALL would align with patient and provider values. # RELATED GUIDELINES moderate. This recommendation is generalizable to patients with ALL in remission who are not suitable for MAC regimens. # Recommendation 3 Post-transplant use of a BCR-ABL tyrosine-kinase inhibitor (TKI) in patients with Philadelphia chromosome-positive ALL (Ph+ ALL) is a reasonable option. # Key Evidence for Recommendation 3 - One evidence-based review with recommendations (1) and one prospective study ( 6) addressed this question. The consensus is that TKI therapy is useful pre and/or posttransplant. However, the evidence is not as strong as the 2012 ASBMT evidence-based review included one trial that evaluated the use of imatinib (TKI) in only five patients with Ph+ ALL (1). - One prospective, comparative cohort study ( 6) evaluated the administration of imatinib in 62 patients based on BCR-ABL transcript levels after allo-SCT, and it showed a lower relapse rate, lower non-relapse mortality and a survival advantage in favour of imatinib. # Qualifying Statement for Recommendation 3 The standard of care is to administer TKIs in combination with chemotherapy for ALL and before SCT. Demonstrating benefits of TKIs post SCT may therefore be difficult, as most patients will have received TKIs pre-transplant. # Interpretation of Evidence for Recommendation 3 The primary outcomes considered to inform this recommendation include relapse, non-relapse mortality, progression-free survival, and overall survival. The certainty of the evidence on the efficacy of TKIs post SCT is low. However, due to the poor prognosis for patients with Ph+ ALL, the members of the Working Group have determined that the use of TKI post SCT should be an option for this population. # Recommendation 4 Haploidentical hematopoietic Stem Cell Transplantation (haplo-SCT) for patients with ALL in CR1 or later who lack a suitable related or unrelated donor is a reasonable option. # Key Evidence for Recommendation 4 Two retrospective cohort studies compared the efficacy of haplo-SCT with chemotherapy alone when used as post-remission treatment in patients with ALL. Both studies showed improvement in relapse rate, disease control and overall survival in favour of the haplo-SCT patients. Non-relapse mortality was at acceptable levels. Patients in these studies had both standard and high-risk ALL. # Qualifying Statement for Recommendation 4 Haplo-SCT appears to be feasible in patients with ALL and it seems to provide an advantage over chemotherapy. As the evidence is somewhat limited, more prospective comparisons are required. # Interpretation of Evidence for Recommendation 4 The primary outcomes considered to inform this recommendation include relapse,

# GUIDELINE OBJECTIVES - To provide clinical guidance with respect to suitability for breast reconstruction, timing of reconstruction, and optimal reconstruction techniques. - To make recommendations that will inform decisions at the policy and administration level aimed at improving the quality of life of women with breast cancer in Ontario. # TARGET POPULATION - Women who have been diagnosed with breast cancer who have chosen or been recommended for therapeutic mastectomy. - Women who are at high risk for breast cancer who have chosen or been recommended for prophylactic mastectomy. # INTENDED USERS General surgeons practicing breast cancer surgery, plastic surgeons, oncologists, administrators, other referring physicians, and oncology healthcare professionals (e.g., those involved in patient education or psychosocial programs). # RECOMMENDATIONS Recommendation 1: Patient education and preoperative evaluation For women who have chosen or been recommended for therapeutic mastectomy: - The discussion of immediate or delayed breast reconstruction should be initiated at the time that mastectomy is offered by the general surgeon. - For women seeking immediate breast reconstruction for ductal carcinoma in situ (DCIS), preoperative evaluation with a general surgeon and a plastic surgeon should be performed. - For women seeking immediate breast reconstruction for early stage breast cancer who will potentially require adjuvant chemotherapy or radiotherapy (RT), a medical oncologist and/or radiation oncologist should be included in preoperative evaluation, either through a formal consultation or by a multidisciplinary cancer conference. - For women seeking immediate reconstruction, there should be adequate preoperative imaging of the breasts, aligning with existing guideline recommendations. # Qualifying Statement - Please see Cancer Care Ontario guidelines regarding recommendations about the use of mastectomy versus breast-conserving therapy (BCT) in early stage breast cancer (www.cancercare.on.ca). - Advance age is not a contraindication to breast reconstruction. There is no evidence that indicated a specific age cut-off as a contraindication; however, the number of people who received reconstruction after 70 years of age was limited. # Qualifying Statements - If morbid obesity and smoking status have been resolved, then women may be appropriate candidates for breast reconstruction. - None of the two characteristics listed above are absolute contraindications to reconstruction. - There is insufficient evidence to indicate whether diabetes is a contraindication to reconstruction. - Patients with increased (>BMI 30 kg/m 2 are at higher risk for complications and are encouraged to lose weight if undergoing delayed reconstruction. o Small invasive cancers with extensive microcalcifications or atypia that would preclude BCT and there is a low likelihood of nodal disease. - Positive margins following breast-conserving surgery opting for completion mastectomy o Recurrent disease following failed initial BCT and not deemed to be at high risk for metastatic disease - Provisional Recommendation October 2021: In patients expected to require radiotherapy, the timing of breast reconstruction should be determined after multidisciplinary discussion including the general surgeon or surgical oncologist, medical oncologist, radiation oncologist, and plastic surgeon and with full consideration of the values and preferences of the patient. # Qualifying Statement - Provisional Qualifying Statement October 2021: Women who will receive RT and are considering immediate breast reconstruction should be informed of the possibility of increased risk of complications, compromised esthetic outcome, and the potential for increased need for future revisional surgeries. The risk of these may vary depending on type and timing of RT, type of reconstruction, and patient characteristics. Recommendation 4: Skin-sparing, nipple-sparing, and areola-sparing mastectomy - Skin-sparing mastectomy (SSM), nipple-sparing mastectomy (NSM) and areola-sparing mastectomy (ASM) are incisions utilized simultaneously with immediate breast reconstruction - SSM or NSM with immediate breast reconstruction can be offered to women at high risk for breast cancer (>25% lifetime risk) undergoing prophylactic mastectomy and women with known DCIS. - SSM or NSM with immediate breast reconstruction is a reasonable option for women with early breast cancer who are believed to be likely lymph node negative. - SSM, NSM, and ASM are not recommended for women intending to receive postoperative radiation with: - early breast cancer who are lymph node positive, inflammatory breast cancer or locally advanced breast cancer who will require postoperative RT. - any clinical skin or nipple-areolar complex (NAC) involvement by invasive tumour - NSM and ASM are not recommended for women with Paget disease of the breast or women with a retroareolar tumour. - NSM or ASM with immediate reconstruction is reserved for patients with minimal ptosis and do not require skin reducing incisions - Women with multicentric DCIS or early invasive cancer within 2 cm of the NAC) who are contemplating NSM may consider a sampling taken from the base of the nipple for pathological assessment. Women found to have tumour involvement in the NAC either intraoperatively or postoperatively should have the nipple resected. # Qualifying Statements - SSM, NSM, and ASM are oncologically safe when the tumour is resected with clear margins. - Women considering NSM should be made aware that they will experience nipple anesthesia and that there is a risk of nipple necrosis. - Likelihood of lymph node positivity should be determined by consultation with a breast surgeon with oncology expertise or by a multidisciplinary tumour board discussion. When required, for women with invasive breast cancer and clinically negative nodes, a standalone sentinel lymph node biopsy may evaluate lymph node status prior to definitive mastectomy. # Recommendation 5: Delayed breast reconstruction - Delayed reconstruction should be offered as an option for any woman undergoing mastectomy who desires reconstruction, has completed any recommended adjuvant chemotherapy and/or RT, and does not have contraindications to breast reconstruction. # Qualifying Statements - For women who have received RT, it is the opinion of the Expert Panel that reconstruction should not occur sooner than one year after mastectomy. - For women with advanced disease (T4, or N2 or N3), it is the opinion of the Expert Panel that it may be optimal to wait two or three years before undergoing reconstruction when the risk of recurrence is lowered. # Recommendation 6: Autologous tissue versus implant-based reconstruction - Women treated by mastectomy should be made aware that autologous tissue reconstruction and implant-based reconstruction are options for immediate or delayed reconstruction. - Reconstruction methods should be selected based on patient and surgeon factors, because overall patient satisfaction and willingness to recommend reconstruction to others appear to be similar between autologous tissue and tissue-expander implant (TE/I)-based reconstructions. However, if women are candidates for either reconstruction, then they should be informed that TE/I reconstruction may be accompanied by a higher risk of reconstructive failure or soft tissue infection and that there is a trend toward decreased esthetic satisfaction with TE/I reconstruction over time. In patients who have received textured implants, they should be informed of the risk for a rare type of lymphoma called anaplastic large cell lymphoma (ALCL) that is associated with textured implants. - Latissimus dorsi flap with or without implants is another option to TE/I or abdominal autologous tissue reconstruction. # Radiation setting: - For women who have received prior RT to their breast as part of BCT, mastectomy with immediate autologous tissue reconstruction is the recommended option. Current evidence suggests that reconstruction using TE/I alone may be associated with an increased risk of complications. # Qualifying Statement - Women desiring reconstruction in a previously radiated breast should be informed of the increased risk of complications compared with no radiation. # Recommendation 7: Types of autologous tissue reconstruction - In patients who will undergo unilateral autologous tissue reconstruction, pedicled transverse rectus abdominis myocutaneous (TRAM), free TRAM, or deep inferior epigastric perforator (DIEP) flaps are all recommended options that are supported by positive patient-reported outcomes. - In patients who will undergo bilateral autologous tissue reconstruction, DIEP flap is preferred over free or pedicled TRAM flap due to less functional disruption to the abdominal wall following surgery. - Alternative autologous tissue donor types (e.g., gluteal flaps, thigh flaps) are suitable for selected patients in whom abdominal tissue is not available; however, the evidence on these types of reconstructions is very limited. - All patients should be told of the risk of fat necrosis that can present as a nodule or mass after autologous tissue reconstruction, a benign condition that can mimic breast cancer recurrence. The risk of fat necrosis is likely to be greater following DIEP flaps compared with TRAM flaps. - It is the opinion of the Expert Panel that direct-to-implant reconstruction in a single stage using ADM may be used as an adjunct to implant-based breast reconstruction to improve esthetic outcomes in selected women who have smaller and non-ptotic breasts. - Patient selection and surgical technique are critical to good outcomes. - Other than improved esthetic outcomes, ADM has not been shown to have any other benefit for two-staged TE/I reconstruction. - Esthetic outcomes, especially the inframammary fold, are potentially improved with the use of ADM in implant reconstruction. # Recommendation 9: Autologous fat grafting - With the shortage of high-quality studies on the use fat grafting, no recommendation can be made for or against the use of autologous fat grafting as an adjunct to improve esthetic outcomes in breast reconstruction. # Qualifying Statement - Autologous fat grafting is a potential adjunct to improve esthetic outcomes in breast reconstruction following mastectomy; however, more high-quality evidence on the efficacy and safety of this procedure is necessary before its widespread implementation. Recommendation 10: Routine screening for breast cancer recurrence following postmastectomy breast reconstruction - There is insufficient evidence to support the use of postmastectomy surveillance mammography in the reconstructed breast. - Women should be followed with clinical examination of the chest wall and reconstructed breast as per the regular breast cancer follow-up regimen. - Diagnostic mammography, ultrasound, and magnetic resonance imaging may be helpful in the evaluation of symptomatic women with a reconstructed breast (e.g., lumps, skin changes).

# INTENDED PURPOSE To summarize the available evidence regarding provider tools for ACP or GoCD. # INTENDED USERS Healthcare providers who engage in ACP or GoCD with their patients or should engage in ACP or GoCD with their patients and administrators who wish to provide ACP or GoCD training to providers within their institution. This evidence summary was developed by a Working Group, consisting of three family physicians that have an interest in palliative care and who hold palliative care positions within their communities, one family physician who practices comprehensive family medicine, one family physician with clinical focus areas in both emergency and hospitalist medicine, one clinician engagement lead, and one health research methodologist, at the request of CCO"s former Palliative Care Program. The Working Group was responsible for reviewing the identified evidence and drafting the summary. Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy. This evidence review was conducted in two planned stages, including a search for systematic reviews followed by a search for primary literature. These stages are described in subsequent sections. # Search for Existing Guidelines and Systematic Reviews A search was conducted for existing guidelines and systematic reviews from 2010 onwards. The MEDLINE (2010 to June 2015) and EMBASE (2010 to week 26,2015) databases were searched using the literature search strategy found in Appendices 2 and 3. Guidelines and systematic reviews were included if they were published in English, were directly related to one or more of the guideline questions, and reported at least one outcome of interest. Identified systematic reviews were evaluated based on their clinical content and relevance. Relevant systematic reviews were assessed using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) tool to determine whether or not existing systematic reviews met a minimum threshold for methodological quality and could be considered for inclusion in the evidence base. # Search for Primary Literature A search strategy was developed and implemented that captured the primary literature in the following databases: MEDLINE, EMBASE, and American Society for Clinical Oncology (ASCO) Palliative Care Symposium meeting abstracts. # Literature Search Strategy The MEDLINE (1998 to September 2015) and EMBASE (1998 to week 37, 2015) databases were searched using the literature search strategies found in Appendix 4. In addition, ASCO Palliative Care Symposium for 2014 and 2015 were also searched using the following terms: advance care planning or ACP, goals of care or GoC, advance directives or AD, terminal care, and patient care planning. Reference lists of included studies were also searched. # Study Selection Criteria and Process Inclusion Criteria - English language Patients living with chronic illnesses and/or their substitute decision makers OR simulated patients Healthcare provider tools (as opposed to patient tools) Includes at least one outcome of interest (see Appendix 5) Comparative data (randomized trials, cohort, case-controlled, historically controlled trials, etc.) if available Non-comparative data Minimum study size of 30 patients # Exclusion Criteria - Case studies, commentaries, editorials A review of the titles and abstracts that resulted from the search was conducted independently by one reviewer (RC). For items that warranted full-text review, one reviewer (RC) reviewed each item independently. However, if there was any uncertainty regarding a particular paper, the Working Group was consulted. # Data Extraction and Assessment of Study Quality and Potential for Bias Data from the included studies were extracted by one member of the Working Group (RC). All extracted data and information were audited by an independent auditor. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias tool (chapter 8.5) (/) and all non-RCTs were assessed using the Cochrane Risk Of Bias In Non-Randomized Studies -of Interventions (ROBINS-I) tool (/). # Synthesizing the Evidence Meta-analysis was not planned as the studies included in this systematic review were quite varied and included some non-comparative data. # Search for Existing Guidelines and Systematic Reviews A search for guidelines uncovered 1701 documents. Of these, 82 papers (73 adult and nine pediatric) underwent full-text review. No adult guidelines were retained and one pediatric guideline was retained. A search for systematic reviews yielded 824 documents. Of these, 55 papers (47 adult and eight pediatric) underwent full-text review. No adult systematic reviews were retained and one pediatric systematic review was retained. # Search for Primary Literature A search for primary literature was conducted for all guideline questions. # Literature Search Results A search for primary studies yielded 31,105 documents. Of these, 353 (313 adult and 40 pediatric) underwent full text-review. From this, 34 adult studies represented by 36 papers and three pediatric primary studies represented by four papers were retained. In addition, the abstracts from the 2014 and 2015 ASCO Palliative Care in Oncology symposia were searched, resulting in the retention of one abstract of adult ACP. A search of the reference lists of included studies led to the inclusion of a further seven adult studies. For a summary of the full literature search results (including guidelines and systematic reviews), please refer to Figure 1, which is a flow diagram depicting the inclusion and exclusion of all studies for this evidence document. A summary of all included studies can be found in Table 1. Of the 42 included adult primary studies, 10 were RCTs, seven were pre/post designs and four were controlled trials. There were three studies each of the following types of designs: repeated measures, qualitative, chart reviews, and non-comparative studies. There was one or two each of various other study types including one systematic review, which was identified from the search for primary studies and not the search for systematic reviews. Of the three included pediatric primary studies, one was a RCT, one was a survey, and one was a chart review. # ADULT STUDIES Boettcher 2015 Respecting Choices Repeated Measures Davis 2015 Conversation Project Qualitative Evaluation Hickman 2015 POLST Systematic Review Kadlec 2015 Practice Support Program -EOL Module Repeated Measures Detering 2014 Next Steps Pre/Post Study Paladino 2014 abstract Serious Illness Conversation Guide Cluster RCT Pecanac 2014 Respecting Choices Chart Review Slort 2014a ACA Controlled Trial Slort 2014b ACA Controlled Trial Wheeler 2014 Foundation in EOL/Palliative Care Pre/Post Study Wilson 2014 HCM Non-comparative Abel 2013 Planning Ahead Retrospective Cohort Levi 2013 MYWK Qualitative Evaluation Millington-Sanders 2013 Coordinate My Care Non-comparative Slort 2013 ACA Controlled Trial Wilson 2013 EpicCare HER Chart Review Au 2012 NA Cluster-RCT Clayton 2012 PREPARED Pre/Post Study Colville 2012 NA Descriptive Qualitative Study Green 2011 MYWK RCT Resnick 2011 NA Survey Detering 2010 Respecting Choices RCT Hammes 2010 Respecting Choices Chart Review Kirchhoff 2010/2012 PC-ACP RCT Szmuilowicz 2010 NA RCT Newton 2009 Preferred # Study Design and Quality Various study designs are included in this guidance document. All systematic reviews were assessed using AMSTAR (see Table 2). Randomized controlled trials were assessed using the Cochrane Risk of Bias tool (chapter 8.5) (/) (see Table 3) and all non-RCTs were assessed using Risk Of Bias In Non-Randomized Studies -of Interventions (ROBINS-I) tool (/) (see Table 4). No suitable guideline was identified. # Systematic Reviews All systematic reviews used in this guidance document were assessed using the AMSTAR tool. Both systematic reviews provided an a priori design, conducted duplicate study selection and data extraction, performed a comprehensive literature search, provided the characteristics of each included study, combined the findings of the included studies appropriately (e.g., by not combining), and provided conflict of interest statements. (Table 2). # Randomized Controlled Trials Eleven RCTs reported in 14 papers 39,40,44,47,48,50,51] were included in this guidance document and were assessed using Cochrane"s Risk of Bias tool (chapter 8.5) (/) (Table 3). Paladino et al. was only available in abstract form; therefore, risk of bias was unclear because the needed information was not available in the abstract. Six other trials had overall high risks of bias owing to several items being rated as either high risk of bias or unclear risk of bias. Unclear risk of bias may only be a reporting issue; however, it is impossible to know. This tool assesses each trial on seven domains of bias (Table 4) as well as an overall assessment of risk of bias. Almost all of the studies 24,25,27,32,45,46,49,53] had a moderate risk of bias, three studies had low risk of bias and five studies had a serious risk of bias. # Initiating and Facilitating ACP or GoCD Adult Studies No clear distinction has been made between clinical tools that either introduce or facilitate both ACP and GoCDs and, as such, these two search criteria were combined. The ACP provider tool most often encountered in the literature is Respecting Choices® or tools based on the Respecting Choices® program (e.g., patient-centred ACP, Honoring Choices Minnesota) (see Table 5). A key feature of this program is the use of trained facilitators for the ACP process. All studies addressing the Respecting Choices® program describe various patient outcomes. In general, exposure to a Respecting Choices® type of intervention, compared with controls, can result in: increased AD completion ; increased appointment of a surrogate ; more involvement in EOL decisions ; increased consistency between patient wishes and medical interventions undertaken at EOL ; increased patient and surrogate satisfaction with care received ; increased ACP knowledge ; fewer symptoms of anxiety and depression in family members of decedents ; decreased decisional conflict ; and increased consistency between wishes of patients and their surrogates. Only one study described provider outcomes. This study reported that case managers trained and certified by Respecting Choices® demonstrated increased motivation, confidence, preparedness, and skill in facilitating ACP discussions at three months post-training compared with immediately after training. However, no p-values are reported. Although there are different views on its relationship with GoCD, a commonly used provider tool is the Physician Orders for Life Sustaining Treatment (POLST) form. POLST is a standardized form containing medical orders that reflect a patient"s treatment preferences. One recent systematic review of this tool that included 23 studies was identified. It may be prepared by a non-physician facilitator and then reviewed and signed by a physician. Healthcare providers report that POLST expresses patient preferences reliably, guides care, improves communication, and helps in initiating EOL care discussions. POLST has challenges as well including the following difficulties: explaining the form, obtaining physician signatures, and transferring the form between settings, as well as issues regarding the time needed to complete the form. Overall, it has been reported that there is high consistency between code status and treatment received by patients as well as between antibiotic use and wishes of patients. There is general consistency between artificial nutrition use and patient wishes. There are mixed results in terms of the consistency between the level of medical intervention requested and received by patients. Three studies of the Availability, Current Issues and Anticipation (ACA) tool were identified. ACA training is an eight-step program that takes approximately six hours to complete over a six-month time period. Briefly, it is an iterative process of roleplaying and simulated patient interviews, followed by feedback and revision of learning goals. When tested in simulated and real palliative care patients, there were no significant differences between intervention and control groups on any of the outcomes measured (Table 5). Two studies of the Making Your Wishes Known (MYWK) tools were identified. MYWK is an interactive, online decision aid to help adults complete an AD. Providers use the decision aid to facilitate ACP with older patients. Green et al. compared the effectiveness of the MYWK tool with a standard ACP planning package in medical students learning to facilitate ACP discussion with patients. Each student helped an adult aged ≥50 years old engage in ACP discussions. Compared with controls, students in the MYWK intervention group had significantly higher confidence in engaging in ACP and intervention patient-participants were significantly more satisfied with their ACP planning method (Table 5). There were also many one-off-type tools identified, some of which were named and others not. They all measured different and varied outcomes. In general, these various tools resulted in positive patient and provider outcomes (see Table 5 for more detail) including achieving preferred place of death when an ACP document is available. # Pediatric Studies Only a few pediatric ACP (pACP) studies were identified (Table 5). Lyon et al. compared the Family-Centered Advance Care Planning (FACE) intervention with a control group that received current standard of care in teens with cancer and their surrogates. This RCT included 17 intervention and 13 control dyads. FACE consists of three sessions: a survey that assesses the values, beliefs, and experiences with EOL care in patients and their surrogates; a Respecting Choices® interview customized for adolescents; and completion of Five Wishes document (an AD document) customized for adolescents with a trained facilitator. Quality of communication was not different between groups. However, treatment preference congruence between control dyads was low for all scenarios tested whereas treatment preference congruence between intervention dyads was statistically significant for five of the six scenarios. Intervention adolescents thought they were significantly better informed regarding EOL decisions than did control adolescents (p=0.007). Moreover, intervention families all rated the three FACE sessions as worthwhile. Intervention adolescents had significantly lower depression scores at baseline and at the three-month follow-up compared with controls (p=0.0268). There were not significant differences in quality of life between intervention and control adolescents. More intervention than control adolescents completed ADs (100% vs. 0%). A systematic review by Lotz et al. uncovered only three pACP programs: FACE, Footprints, and Respecting Choices®. A review of these interventions revealed that many people are supportive of ADs for children although parents report discomfort of emergency personnel with ADs for children. Parents and adolescents find pACP interventions helpful for ensuring good care, providing time for decision making, facilitating communication among caregivers, and in providing peace of mind. They also found that fears about increasing distress in patients undertaking pACP are unfounded. However, some families do have difficulties thinking about a dismal future (Table 5). A survey conducted by Mitchell et al. found that 58% of pediatric intensive care units (PICUs) in the United Kingdom use a pACP document. All such documents were developed locally. Finally, Walter et al. evaluated prognostic, goals-of-care conversations (PGOCC) in a review of 645 charts of children in the top decile for risk of mortality upon admission to the PICU in a children"s hospital in Michigan. A documented PGOCC was found in 200 (31%) of charts. Patient characteristics significantly associated with a documented PGOCC were length of stay (p<0.001) and cancer diagnosis (p<0.001) (Table 5). o No significant differences between the groups with respect to the mean number of ACA issues (current or anticipated) discussed. o Significant differences between the groups with respect to only 3 types of affective utterances. No other significant differences with respect to quality of communication Computer generated reminders 2x2 factorial RCT Comparison of computer-generated reminders to discuss one or both types of ADs vs. no reminders to increase AD discussions and completion in outpatients # Documenting ACP or GoCD Adult Studies Evidence regarding the documentation of ACP or GoCD is sparse. Overall, storage of ACP documents is varied and inconsistent and the documents can be quite difficult to find even when they exist (Table 6). Wilson et al. conducted a chart review to identify the location of ACP in the electronic health record (EHR) of patients at least 65 years old who were known to have an ACP document in their EHR. Most ACP, POLST, and ADs were not scanned into the EHR. Of those that were, they could be scanned, scanned and in progress notes, scanned and in the problem list, or all three. Patients had a mean of four scanned documents per year but the maximum was 231. Therefore, it was often extremely difficult to locate the ACP documents among them. Colville et al. in a qualitative evaluation, demonstrate the need to document ACP plans such that all providers of care for a given patient have access to them. Resnick et al. surveyed a sample of home, health, and hospice agencies in the USA and found that AD storage varied. Most ADs were stored with the patient"s record at the agency (94.4%), many were stored at the patient"s residence (48.8%), and a few were stored in a special AD file at the agency (3.3%). Bricker et al. describe the development of an AD documentation process within an electronic medical record (EMR). They cite three options for creating an electronic AD: scanning the existing AD into the EMR; dictating an AD note using the existing telephone transcription service; and typing the AD note directly into the EMR. In all cases, the AD note was then highlighted within the list of EMR documents for ease of access. Moreover, singlepage AD forms were developed for ease of completion and ease of scanning into the EMR. All personnel, from healthcare providers to transcriptionists, were made aware of this new system. The result was an increase in the number of completed electronic AD notes. A further benefit was that the patient preferences were accessible throughout the healthcare system. Finally, Pauls et al. describe a model for transferring ADs from a long-term care (LTC) facility to an emergency department (ED). The model consists of three parts: the form, completing the form, and using the form. The form itself is only one or two pages employing simple language and providing a choice of three or four levels of care from which to choose. In terms of form completion, LTC residents and their families were given education sessions regarding ACP and ADs as soon as they entered LTC. The forms are reviewed annually or when there have been changes in a patient"s health. The completion of the forms involves various healthcare providers and they are remunerated. With respect to using the forms, they are kept in an accessible and consistent location and are printed on coloured paper for ease of transferability to the ED via paramedics. # Pediatric Studies No pediatric studies regarding the documentation of ACP or GoCD were identified. # Ongoing, Unpublished, or Incomplete Studies None. NA Descriptive Development of an AD documentation process within one healthcare system Specifically developed an electronic AD note within the EMR Developed short instructional video to increase patient understanding of the importance of ADs 3 options for creating electronic AD o Scan the existing AD document into the EMR o Dictate AD note using existing telephone transcription service o Type AD note directly into EMR The AD note was then highlighted within the list of EMR documents for easy access Single page forms developed for ease of completion of AD and for ease of scanning into EMR Everyone in the system from healthcare providers to transcriptionists had to be aware of the new system Number of completed electronic AD notes increased and continues to increase Informal polling of healthcare providers indicates that they like that patient preferences are available throughout this healthcare system Recently, considerable attention has been given to the important role for ACP conversations and GoCD in decision making for patients not only in the setting of serious illness, but also when there is no illness. Currently, no consensus exists as to the tools or processes clinicians should use to inform or guide ACP and GoCD. The purpose of this evidence summary was to identify existing tools that could be used for each of these clinical encounters. The specific questions that shaped this review were intended to reflect the elements clinicians find particularly challenging, i.e., introducing, facilitating, and documenting both ACP and GoCD. Although a number of studies reported positive findings, there is a lack of consistent patient outcomes evidence to support any one clinical tool for use in either ACP or GoCD. However, despite this, the evidence points to important elements for clinicians to consider when reflecting on their practice around ACP and GoCD. Also, certain evidence emerged that is important for healthcare leaders and system planners to consider. Of note, no clear distinction has been made between clinical tools that either introduce or facilitate both ACP and GoCDs and, as such, these two search criteria were combined. There are common challenges providers encounter in clinical practice relating to ACP and GoCD. There continues to be a lack of widespread agreement on the definitions of ACP and GoCD, their critical elements, and desired outcomes. For example, in some studies and in practice, ACP has been equated with determining a person"s resuscitation status, whereas others define it differently. This is problematic on several levels. However, for the purpose of this review, the lack of standard definitions prevents a unified approach to studying ACP and GoCD and contributes to great difficulty interpreting and comparing the findings among different studies. Improving a shared understanding of these concepts as described in this review is an essential step to establishing evidence for best practice. Similarly, consensus on outcomes are needed. The ideal ACP outcomes may include adequate understanding of the person"s health status by the patient and their SDM, and the SDM understanding the patient"s values, beliefs, and wishes as they relate to the patient"s healthcare. The ideal GoCD outcome would be that current healthcare decisions are informed by the person"s goals and values. This can occur at any point along the illness journey, but will always occur in relation to current, not future, healthcare decisions. Addressing these discrepancies will be beneficial for clinicians, for the development of tools and to guide evidence-informed best practices. A second challenge in attempting to identify tools for clinicians is clarifying what might be considered appropriate tools for the contexts of introducing and facilitating these conversations. Additionally, different tools may be more or less effective for clinicians with varying expertise and competency in advanced communication skills, EOL communication skills, and values-based conversations. Finally, development and evaluation of tools must take into account the relationship of ACP and GoCD with regional laws on capacity, consent, and substituted decision making. It is important to note that tools structured for use by patients or caregivers without immediate clinical support were excluded from this review. Finally, synthesizing evidence for ACP and GoCD is challenging owing to the nature of these two clinical encounters as each has inherent limitations to standardization. ACP is considered to be a process over time, which can lead to a lack of clarity and inconsistent practices around what could or what should be documented for any given clinical encounter. For GoCDs, there are different understandings of the expected outcomes or products of the clinical encounter and one standard approach has yet to be proposed or studied. The majority of studies that met inclusion criteria address ACP-related processes (rather than GoCD), such as the occurrence of any kind of EOL conversation and documentation. Differences in the interpretations of the essential components of ACP are evident, with a key difference being the perceived importance of addressing specific treatments in the conversations. However, it is worth pointing out that the tool with the largest evidence base is Respecting Choices®, which moves away from preferences for specific treatments and shifts toward a greater emphasis on patient values. Although this shift makes the desired outcome of the clinical interaction more challenging to capture, the evidence suggests values-based information is more likely to be help future SDMs than treatment-based or treatment-focused ACP conversations. Considering these emerging themes from the evidence suggests that tool development should focus on enabling healthcare providers to facilitate values-based discussions. Future studies with corresponding valuesbased outcome measures are needed to evaluate the impact on patient care. Irrespective of how ACP effectiveness might be defined, the evidence suggests it is critical to think beyond singular ACP elements in order to meaningfully impact patient care. The evidence related to the Respecting Choices® model outlines the high likelihood that a comprehensive, systematic approach to ACP is necessary. Ideal patient outcomes are unlikely to be achieved in the absence of broad systemic commitments to integrate and deliver ACP as part of routine care. A comprehensive approach to ACP includes community engagement, professional education, development of standard practices, monitoring of these practices through Quality Improvement initiatives, supporting policies and practices, and a technology infrastructures. This approach must be applied across public health and healthcare sectors to support the exchange of clinical information and will involve system-level coordination and planning. Addressing only one, or a few, of these elements creates the risks of leaving critical gaps that could prevent positive impacts on quality patient care. The development of materials, clinical processes, and professional development experiences that improve communication skills, designed to enable clinicians to facilitate a discussion of a person"s values, must be embedded in a system-wide approach to ACP. Evidence from studies addressing the ACA tool serve as important examples of this. The associated education components of the intervention (i.e., simulation and direct feedback) are known to be highly effective from the perspectives of educational design and adult learning theory. However, high-quality education, although essential, on its own is unlikely to improve care or the patient experience in the absence of supporting systemic changes. Important findings for the pediatric population mirror many of the early reports that address ACP in adults. The evidence outlines that, in general, children and their parents are supportive of ACP and find these discussions helpful to ensure good care, to facilitate communication among caregivers, and to provide peace of mind. Concerns that ACP discussions will cause distress in children and parents are not supported by the evidence. However, parents are aware of discomfort among clinicians attempting to navigate ACP discussions. This is an important area for further exploration and discovery. Very few studies specifically address GoCDs and in large part this is likely due to GoCDs having been added to the healthcare lexicon relatively recently. There is a resultant lack of patient outcome evidence and many problematic elements in the research findings. These include a lack of widespread agreement on the expected outcomes, general approach, and components of GoCD. Detailed information regarding the specific clinical interaction was notably absent from studies involving the GoCD. Exploring the elements of GoCD that could be amenable to standardization would uncover important clinician tool-related information. One specific element of the GoCD on which practices differ among clinicians is the perceived relationship with decision making. This ranges from considering GoCD to be separate and distinct from decision-making discussions to considering the two to be one and the same. These differing perspectives may parallel differences in how the POLST is viewed in relation to the GoCD. Some clinicians would likely view the POLST as a tool for use during the GoCD whereas others would not. For the purpose of this evidence review, we include POLST studies with the caveat that this not be considered endorsement for its use as a GoCD or ACP tool. We have chosen to include the POLST to highlight this challenge and enable further discussion. It should be highlighted that the Ontario legal context should preclude the widespread use of tools like the POLST for ACP conversations. Regional variation exists with regard to the completion of orders sets in advance of receiving healthcare. Practitioners should be familiar with their regional laws surrounding consent, capacity, and healthcare decision making. In Ontario, direction and decision making for a person"s current care must come from a capable person (either the patient or their SDM if the patient is not capable), not a previously completed order set. In cases where the patient has been found incapable for a current decision, the SDM will rely on applicable previously expressed wishes or the person"s values. This underscores the importance of ACP conversations as preparation of the SDM for many eventualities of future decision making. The involvement of interprofessional healthcare providers was identified as an important element of the ACP process in a number of positive studies. The shift toward emphasizing patient values in the ACP context has expanded the facilitation of such discussions to include non-physician providers. The Respecting Choices® model demonstrates how the training of interested and willing clinicians, regardless of profession, may be a critical strategy for impacting patient outcomes. An example for GoCDs is the role of clinical nurse specialists and the communication skills they bring to the patient experience. Implementation of ACP as an interprofessional practice is an important consideration in addressing the concern of many physicians about not having adequate time for these discussions. - Outcome evidence for ACP suggests the greatest impact is likely to be made by a system-wide approach to integrating ACP into practice, one that maximizes clinical skills of all interprofessional team members. What is likely to be of greatest value for the GoCD context is to achieve widespread agreement on the specific outcomes that should be expected? The most important patient-related outcome of any future planning or current care decision-making process is a patient receives the care that is wished for or desired. Inconsistencies in definitions and desired outcomes for both ACP and GoCD need to be addressed to enable better understanding of effective healthcare provider tools. # INTERNAL REVIEW The evidence summary was reviewed by the Director of the PEBC. The Working Group is responsible for ensuring the necessary changes are made. The Palliative Care Program and the Working Group would like to thank the following individuals for their assistance in developing this report: - Melissa Brouwers, Sheila McNair, Hans Messersmith, for providing feedback on draft versions. Ruth Chau for conducting a data audit. Sara Miller for copy editing.

# GUIDELINE OBJECTIVES To recommend systemic therapy options for women with recurrent epithelial ovarian cancer including fallopian tube and primary peritoneal cancers. # TARGET POPULATION The target population comprises women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Specific subgroups of interest are identified based on response to therapy. # INTENDED USERS The intended users of this guideline are gynecologic oncologists or medical oncologists in the province of Ontario. # BACKGROUND INFORMATION This guideline was based on an updated systematic review of the 2011 evidence base. New evidence has led to new recommendations in some areas. Recommendations 1, 2, and 3 are endorsements of those found in the 2011 version of this guideline; the original recommendations continue to be valid and have not changed. Recommendations 4 and 5 are new in this current version of the guideline. # Recommendation 1 Systemic therapy for recurrent ovarian cancer is not curative. As such, it is recognized that, to determine the optimal therapy, each patient needs to be assessed individually in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. # Recommendation 2 All patients should be offered the opportunity to participate in clinical trials, if appropriate. # Recommendation 3 Chemotherapy for patients with platinum-sensitive recurrent ovarian cancer: - - If a single platinum agent is not being considered (e.g., because of toxicity or allergy), then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin is a reasonable treatment option. # Recommendation 4 For patients with platinum-sensitive recurrent ovarian cancer: - Women with platinum-sensitive recurrent ovarian cancer should be offered chemotherapy with biologics after a discussion concerning the safety profile Targeted agents: - Bevacizumab combined with combination chemotherapy and as maintenance therapy can be considered. - Cediranib administered during the chemotherapy and maintenance therapy can be considered. - PolyADP-ribose polymerase (PARP) inhibitors are recommended for patients with known BRCA 1 or 2 mutation (somatic and germline) as maintenance treatment post platinum-based chemotherapy for recurrent disease. - Niraparib can be considered for patients who are BRCA wild-type as maintenance post-platinum-based chemotherapy for recurrent disease. # Qualifying Statements for Recommendation 4 - With the increase in evidence supporting the use of PARP inhibitors in patients with homologous recombination deficiency mutations, consideration should be given to testing the BRCA status of all women with ovarian cancer at initial diagnosis. - PARP inhibitors have demonstrated an increase in progression-free survival in patients with BRCA mutations without a significant improvement in overall survival - Women with wild-type BRCA also showed a minor improvement in progression-free survival # Recommendation 5 For patients with platinum-refractory or platinum-resistant recurrent ovarian cancer: - Lower levels of response to treatment are expected for this group; therefore, the goals of treatment should be to improve patient's quality of life by extending the symptom-free interval, reducing symptom intensity, increasing progression-free interval, or if possible, prolonging life. - Monotherapy with a non-platinum agent should be considered since there does not appear to be an advantage in the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine have demonstrated activity in this patient population and are reasonable treatment options. - There is no evidence to support or refute the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrences. There are many treatment options that have shown modest response rates but their benefit over best supportive care has not been studied in clinical trials. - Bevacizumab combined with chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) can be considered for women who meet the eligibility criteria of the Avastin Use in Platinum-Resistant Ovarian Cancer (AURELIA) phase III randomized controlled trial: confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that had progressed within six months of completing ≥4 cycles of platinum-based therapy, age ≥18 years, Eastern Cooperative Oncology Group performance status ≤2, and adequate liver, renal, and bone marrow function. Ineligible patients include those who have received >2 prior anticancer regimens or who had refractory disease, patients with a history of bowel obstruction (including subocclusive disease) related to underlying disease, a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction. # Qualifying Statements for Recommendation 5 - At the time of the writing of this guideline there are numerous targeted agents in addition to vascular endothelial growth factor inhibitors, programmed death-1 and programmed death ligand-1 inhibitors, as well as other immunotherapies that are under investigation and that show promise in early trials. It is likely that one or some of these will become part of the lexicon of treatment protocols in the near future, either independently or in combination with conventional chemotherapy.

Guideline Questions 1. What are the chemotherapeutic and hormonal therapy options for women with advanced or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas)? 2. What are the chemotherapeutic options for women with advanced or recurrent uterine papillary serous carcinoma? # Target Population This practice guideline applies to adult patients diagnosed with advanced stage or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas) or uterine papillary serous carcinoma. For women with advanced or recurrent endometrial cancer: - Combination chemotherapy is favoured over single agent chemotherapy because of higher response rates. Paclitaxel in combination with cisplatin/doxorubicin chemotherapy improves both response rate and median survival; however, the use of this three-drug combination is associated with increased toxicity. Hormonal therapy may be a therapeutic option for those patients with minimal symptoms or non-life threatening advanced or recurrent endometrial cancer. For women with uterine papillary serous carcinoma: - Evidence supporting or refuting various chemotherapy regimens for uterine papillary serous carcinoma is limited. Patients should be encouraged to participate in randomized trials. # Qualifying Statements: - The decision to use the three-drug combination, consisting of cisplatin/doxorubicin/paclitaxel, should be made with consideration of both the greater toxicity and the three-month increase in median survival time in comparison with the two-drug doxorubicin/cisplatin regimen. However, recent data suggest no benefit to the three-drug combination in terms of recurrence-free survival and was associated with increased toxicity. For uterine papillary serous carcinoma treatment, the most studied regimen is a paclitaxel/platinum combination. The addition of paclitaxel in small, non-comparative studies is associated with improved response rates and survival compared to non-platinum containing regimens. Added to Endorsement in June 2017: As mentioned in the Qualifying Statements above, there are data suggesting that a taxaneplatinum drug combination has similar efficacy with better toxicity when compared with the three-drug paclitaxel/cisplatin/doxorubicin combination. The Expert Panel recognizes that this evidence comes from an abstract of an interim analysis of a phase III RCT with no full publication and does not meet the criteria for inclusion in this review. However, practice has changed in light of this evidence with preference for a taxane-platinum drug combination although the three-drug combination is still an option. Added to Endorsement in July 2019: - There has been one small randomized phase II study showing a benefit of adding trastuzumab to carboplatin/paclitaxel in patients with overexpression of Her2/Neu in advanced (stage III or IV) or recurrent uterine serous carcinoma. Please see Section 2 for further details. Entries to MEDLINE (1966to April 2004, CANCERLIT (1975to October 2002, and Cochrane Library (2004, Issue 1) databases and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1997 to 2003) were systematically searched for evidence relevant to this practice guideline report. Evidence was selected and reviewed by four members of the Practice Guidelines Initiative's Gynecology Cancer Disease Site Group and methodologists. This practice guideline report has been reviewed and approved by the Gynecology Cancer Disease Site Group, which comprises gynecologic oncologists, medical oncologists, radiation oncologists, an oncology nurse, a pathologist, and patient representatives. External review by Ontario practitioners is obtained for all practice guidelines through a mailed survey. Final approval of the practice guideline report is obtained from the Practice Guidelines Coordinating Committee. The Practice Guidelines Initiative has a formal standardized process to ensure the currency of each guideline report. This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information. # Key Evidence Seventeen randomized trials (including six abstracts and four phase II randomized trials) provided the evidence for systemic therapy of advanced or recurrent endometrial cancer. There were no randomized trials identified that compared systemic therapy to a control group of patients who received no treatment. Limitations of the evidence include: heterogeneous patient populations with respect to histology; type of previous treatment (surgery, radiation, chemotherapy, or hormonal therapy); results that are still maturing; and non-comparable outcome measurements. Chemotherapeutic options studied for the treatment of advanced or recurrent carcinoma of the endometrium have included single-, double-, and triple-agent therapies. There is limited information available on quality of life and meaningful survival data. Single-agent chemotherapy has reported response rates as follows: doxorubicin 17-27% and platinum agents 21%. For double-agent chemotherapy, randomized trials of doxorubicin/cisplatin reported response rates ranging from 28-45%, other agents in combination with doxorubicin reported response rates of 30% (cyclophosphamide) and 43% (paclitaxel). A randomized trial reported a 57% response rate in the doxorubicin/paclitaxel/cisplatin arm compared to 34% in the doxorubicin/cisplatin arm (p <0.01). One randomized trial has compared doxorubicin/cisplatin to whole abdominal radiotherapy and preliminary reports indicate that doxorubicin/cisplatin is more beneficial than radiotherapy in patients with advanced endometrial cancer in terms of overall survival and progression-free survival (p<0.01). However, recurrence rates are still high (55%) in both treatment arms. Neuropathy, hematological, and gastrointestinal toxicities were the most common adverse effects reported; toxicity increased in incidence with the increase in the number of agents used. One randomized trial comparing two dosages of medroxyprogesterone acetate (hormonal therapy) for advanced or recurrent endometrial cancer detected that patients receiving a lower dosage of medroxyprogesterone acetate had significantly increased overall survival (p=0.026) and response rate (p<0.05) than patients receiving a higher dosage. Hormonal agents were well tolerated: adverse effects were reported at less than 5%. Four non-comparative trials (two retrospective and one abstract) provided the evidence for systemic therapy of advanced or recurrent uterine papillary serous carcinoma. Response rates in the four small non-comparative studies ranged from 50-89% # Future Research In terms of future studies, it is important to be able to control for prognostic factors that affect outcome in these patient populations. Patients should be properly stratified with respect to their disease status (advanced versus recurrent), the amount of previous treatment, type of previous treatment (radiation or chemotherapy), and disease recurrence either in or out of the radiated field. Patients with uterine papillary serous carcinoma should be analyzed separately. Results relating to systemic therapy should be first assessed and proven in those patients with measurable disease so that an accurate assessment of any prolongation in disease-free survival can be made with reasonable assurance that these improvements are due to treatment. Treatment-related toxicity must be studied very carefully in the future in this patient population in order to ensure that the treatment itself has acceptable morbidity in relation to the patient's quality of life, as median survival is generally limited and rarely more than a year in this patient population. Survival, response and toxicity should be studied with regard to impact on quality of life. Comparing tumour responses for both chemotherapy and hormonal agents, stratified by grade, would provide valuable data for making treatment decisions. Added to Endorsement in July 2019: Immunotherapy is an emerging treatment, particularly in patients with tumours with high microsatellite instability, and should be addressed in future guidelines as studies become available. For further information about this practice guideline report, please contact Dr. Michael Fung Kee Fung, the lead author, through the PEBC at: Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca The Practice Guidelines Initiative is sponsored by: Cancer Care Ontario & the Ontario Ministry of Health and Long-term Care. For information about the PEBC and the most current version of all reports, please visit the CCO website at or contact the PEBC office at: Phone: 905-526-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca

# GUIDELINE OBJECTIVES To provide guidance on the optimal systemic therapies for the treatment of advanced gastric and gastro-esophageal junction (GEJ) carcinoma. Optimal systemic therapies were defined as those that provided improved overall survival and improved quality of life. # TARGET POPULATION Adult patients (age ≥18 years) with advanced gastric carcinoma or advanced carcinoma of the GEJ. In this patient population, advanced disease is defined as non-resectable disease that is either locally advanced, recurrent, or metastatic. # INTENDED USERS This guideline is intended for use by clinicians and health care providers involved in the management or referral of the target population. # Recommendation 1a Medical oncologists should prescribe either a fluoropyrimidine-oxaliplatin doublet or a fluoropyrimidine-irinotecan doublet regimen in the first-line treatment of patients with locally advanced, recurrent, or metastatic gastric and GEJ carcinoma. # Qualifying Statements for Recommendation 1a - Based on improved efficacy with fluoropyrimidine-oxaliplatin-taxane when compared with monotherapy, this triplet regimen may be discussed with selected patients as an alternative to a doublet regimen. - Medical oncologists should individualize treatment based on the different toxicities associated with the preferred regimens, patient characteristics, and patient preferences when choosing the appropriate therapy. # Recommendation 1b In patients with metastatic gastric cancer or GEJ carcinoma not overexpressing human epidermal growth factor receptor 2 (HER2), medical oncologists should not prescribe a biological agent in addition to a first-line chemotherapy regimen # Recommendation 2 In patients with recurrent or metastatic gastric and GEJ carcinoma, medical oncologists should prescribe an immune checkpoint inhibitor (ICI) in addition to a fluoropyrimidine doublet chemotherapy regimen in the first-line setting. # Qualifying Statements for Recommendation 2 - A positive association was observed between programmed cell death ligand 1 (PD-L1) combined positive score (CPS) and the magnitude of treatment benefit. In Checkmate-649, the overall survival benefit of nivolumab was confined to patients with a CPS of ≥5. To aid clinicians in informed decision making and counseling, we recommend that the CPS score be obtained, and the recommendation for the use of nivolumab be restricted to those patients whose tumours have a CPS of ≥5. # Recommendation 3 In patients with HER2 overexpressing gastric or GEJ carcinoma, medical oncologists should prescribe the addition of trastuzumab to a fluoropyrimidine doublet chemotherapy regimen in the first-line setting. # Qualifying Statements for Recommendation 3 - Trastuzumab should be prescribed until disease progression or intolerance in HER2 overexpressing patients # Recommendation 4 In patients with gastric or GEJ adenocarcinoma being considered for second-line therapy, medical oncologists may prescribe paclitaxel plus ramucirumab. # Qualifying Statements for Recommendation 4 - Single agent irinotecan or taxane is a reasonable alternative for patients not eligible for paclitaxel plus ramucirumab # Recommendation 5 In patients with gastric or GEJ adenocarcinoma being considered for third-line therapy, medical oncologists may prescribe trifluride-tipiracil monotherapy. # Recommendation 6 In patients with gastric or GEJ carcinoma undergoing later lines of therapy, medical oncologists should not prescribe ICI in addition to standard of care. # IMPLEMENTATION CONSIDERATIONS Although testing for PD-L1 CPS is available in Ontario through local laboratories or the industry funded access programs, CPS is not routinely included on the tumor pathology report. Medical oncologists will need to request CPS testing from available resources. Until reporting of the CPS is routine, requesting the score may result in treatment decision delays.

The purpose of the memorandum is to exchange information and expertise in the area of occupational safety and health. One product of this agreement is the development of documents to provide the scientific basis for establishing recommended occupational exposure limits. These limits will be developed separately by the two countries according to their different national policies. This document on the health effects of occupational exposure to acrylamide is the fourth product of that agreement. The document was written by Vlasta Molak, Ph.D., D.A.B.T. (DSDTT/NIOSH), and was reviewed by the Criteria Group and by DSDTT/NIOSH.# BACKGROUND # CHEMICAL AND PHYSICAL PROPERTIES Acrylamide is an odorless, white, crystalline solid used as a monomer or as a raw material in the production of polyacrylamides and other compounds. Chemical and physical properties of acrylamide are given in Table 1. Because most of the aciylamide monomer is produced and used as an aqueous solution, the physical properties of a 50% aqueous solution of acrylamide are also given (Table 2). # PRODUCTION AND USE OF ACRYLAMIDE In 1985,140 million lb (63,600 metric tons) of acrylamide were produced in the United States, and predictions in 1988 indicated that 164 million lb (74,500 metric tons) of this chemical would be produced in 1989 . Total acrylamide production capacity in western Europe was 93.5 million lb (42,500 metric tons) in 1984, and the estimated production in Japan was 90 million lb (41,000 metric tons) in 1982 . Acrylamide is also used and produced in the Soviet Union and China, but production estimates have not been reported . The reactive acrylamide monomer is used in the production of other compounds (mostly polymers of acrylamide) and as a grouting agent in the construction or rehabilitation of dams, buildings, sewers, tunnels, and other structures. Acrylamide grouts are used predominantly as barriers against groundwater seepage into sewers. About 95% of the acrylamide produced in the United States is consumed in the production of other compounds and polyacrylamide products that are widely used as (1) flocculents in potable water and wastewater treatment, mineral ore processing, and sugar refining, (2) water flow control agents in oil well operations, and (3) adhesives in papermaking and construction . The remaining 5% is used as a monomer . # POTENTIAL FOR OCCUPATIONAL EXPOSURE Data on worldwide occupational exposures to acrylamide are unavailable. However, since exposure occurs during aciylamide production and use, the potential for occupational exposure exists in all countries that produce or import acrylamide. The National Institute for Occupational Safety and Health (NIOSH) estimates that more than 10,000 U.S. workers were potentially exposed to acrylamide monomer during the period 1981-83, either in acrylamide manufacturing and processing or in grouting operations (particularly in sewer grouting) . Other workers that are potentially exposed to variable and intermittent airborne concentrations and possible dermal contact with acrylamide are the researchers and technicians involved in the preparation of polyacrylamide estimates that 100,000 to 200,000 of these U.S. workers have the potential for exposure. Because acrylamide is produced by catalytic or sulfuric acid hydration of acrylonitrile (identified by the International Agency for Research on Cancer as a probable human carcinogen ), acrylamide production workers may also be exposed to acrylonitrile. Evaluation of exposure data from industrial settings indicates that in all four U.S. acrylamide production plants, airborne concentrations were generally below 0.3 mg/m3-the occupational exposure limit set by many countries (see the Appendix). Of the ninety 8-hr time-weighted average (TWA) personal samples collected in the four U.S. acrylamide production plants, only two samples from one of the plants were above 0.3 mg/m3 (0.38 and 0.39 mg/m3). However, many samples exceeded the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 0.03 mg/m3 adopted in 1989 . # Hills and Greife # EXISTING STANDARDS AND RECOMMENDATIONS Many international standards for workplace exposures to acrylamide are 0.3 mg/m3 with a skin notation. The current American Conference of Governmental Hygienists (ACGIH) threshold limit value (TLV») and the current OSHA PEL are both 0.03 mg/m3. The current Swedish occupational exposure limit is 0.3 mg/m3 with a skin notation and a short-term exposure limit (STEL) of 0.9 mg/m3. See the Appendix for a list of the occupational exposure limits for airborne acrylamide in various countries and a discussion of the bases for recommendations that depart from the frequently cited limit of 0.3 mg/m3. # TOXICOLOGY # METABOLISM Acrylamide is a small organic molecule that is very soluble in water and can react at both its amide group and its double-bond vinyl group. This reactivity and ease of transport may account for the toxic effects of acrylamide. Studies show that the toxicokinetics and tissue distribution of acrylamide are not significantly dependent on the dose and route of exposure. The parent compound is rapidly eliminated from the tissues. The uptake, distribution, biotrans formation, and elimination, which are summarized below, have been discussed in detail by Dearfield et al. . # Uptake No studies were found on the absorption of acrylamide by inhalation. All animal studies involved either oral or dermal exposure, and intraperitoneal (i.p.) or intravenous (i.v.) dosing. The uptake of acrylamide through the gastrointestinal tract of rats was rapid and complete, as indicated by similar excretion profiles of the chemical whether it was administered by i.v. injection or by gavage . Dermal absorption in the rat is less than complete. By comparing blood concentrations after i.v. or dermal administration of acrylamide, Ramsey et al. calculated that 25% of the applied doses (2 or 50 mg/kg) of acrylamide were absorbed through the skin of rats during the first 24 hr. Frantz et al. reported that 26% of a 0.5% aqueous solution of acrylamide was absorbed through the skin of rats in 24 hr and that, after the skin was washed, an additional 35% remained in the skin. The data from in vitro experiments were similar . These researchers used excised skin preparations to show that 67% of the applied acrylamide was either absorbed or available for absorption (that is, 54% was absorbed and 13% remained in the skin after washing). # Distribution and Toxicokinetics After rats received various doses of acrylamide (0.5 to 100 mg/kg) by i. 1970]. Miller et al. reported that high percentages of the wC-labeled chemical were found in muscle (48%), skin (15%), blood (12%), and liver (7%), whereas the neural tissues (brain, spinal cord, and sciatic nerve) contained less than 1%. However, when the data were expressed as micromoles (¿tmoles) of acrylamide/g of tissue, the concentrations of acrylamide in the tissues were similar. In the neural tissues of rats there appears to be no preferential bioconcentration of acrylamide and/or its metabolites that can account for its neurotoxic effects . Acrylamide has also been reported to distribute readily in the tissues of other animal species. For example, acrylamide was found in the blood, brain, heart, liver, kidneys, and lungs of miniature swine and beagle dogs, with the highest concentrations found in the liver and kidneys . Because the authors did not analyze skin, muscle, and other tissues, it is difficult to compare the results with those reported by Miller et al. . In addition, autoradiographic studies have demonstrated a similar distribution of acrylamide in male and pregnant female mice . Acrylamide was found to cross the placentas of rats, rabbits, dogs, pigs, and mice and to be uniformly distributed in those fetuses . Ramsey et al. have examined the effects of multiple oral doses on tissue distribution. When rats were given acrylamide at 0.05 or 30 mg/kg for 13 consecutive days, the ratio of the 14C-labeled chemical in the tissues at the two doses was proportional to the ratio of the doses administered (that is, 600) except in the red blood cells (304), blood plasma (1,089), and testes (934). These data demonstrate that multiple doses of acrylamide do not greatly alter its distribution except at those three sites. Miller et al. used rats in a detailed study of the pharmacokinetics and distribution of acrylamide, both as the parent compound and as the total "¿-labeled chemical after an i.v. dose of 10 mg/kg. The elimination of the parent acrylamide was represented by a single compartment model. In the blood, the parent compound had a half-life of 1.7 hr, and the clearance of the unmetabolized acrylamide from all other tissues but the testes was similar. The testes showed a delay in the time necessary to reach peak concentration-an event attributed to their fat content. After the peak was attained, the parent acrylamide was cleared from the testes in a manner similar to that for other tissues . # Biotransformation and Elimination The distribution and the elimination of the total 14C-labeled chemical (representing acrylamide and its metabolites) was slower than that of the parent compound and was best represented by a biphasic curve . In addition, four tissues (liver, kidney, fat, and testes) demonstrated absorptive phases for the total 14C-labeled chemical. Since no absorption phases were noted for the parent acrylamide in the liver and kidney, the increases in the 14C-labeled chemical in these two tissues were attributed to metabolite accumulation. The higher lipid content of the fat and testes and the polar nature of acrylamide were reported by Miller et al. to have delayed the absorption in these two tissues. The initial portion (half-life of 5 hr) of the biphasic curve was attributed to the metabolism of acrylamide and the binding of its metabolites to biological macromolecules, since only 2% of the total dose of administered acrylamide was excreted as the parent compound. The terminal portion (half-life of 8 days) of the biphasic curve was thought to be the result of the release of acrylamide metabolites from tissue depots and the degradation of acrylamide-protein adducts . Support for these suppositions was provided by Ramsey et al. , who analyzed urine, plasma, and tissue samples in male Fisher 344 rats following either i.v., gavage, or dermal administration of 14C-labeled acrylamide. Their data indicated that the initial phase was due to the loss of the parent compound and that the latter phase resulted from the clearance of acrylamide metabolites. Because acrylamide affects reproduction, the very slow release of acrylamide or its metabolites from the testes is of particular interest. Although the fat content of the testes may have decreased the uptake of the parent acrylamide, it would not appear to account for its slow excretion. It is possible that acrylamide is metabolized and binds to constituents of the testes. Marlowe et al. reported that radioactivity appeared in the testes 1 hr after administration and migrated to the seminiferous tubules and head of the epididymis after 9 hr. After 9 days, radioactivity remained only in the tail of the epididymis and in the epithelium of the penis. Marlow et al. correlated this movement with that of the spermatids. # Factors That Can Affect Metabolism Studies of the effects of altering microsomal mixed-function oxidase activity on the expression of acrylamide-induced neuropathy have given disparate results. Pretreatment of rats with phenobarbital (PB) or DDT Srivastava et al. found that pretreatment of rats with PB or DDT decreased the time necessary for onset of acrylamide-induced hind-limb paralysis. This disparity does not appear to be due to variations in experimental protocol, but it may be explained by differences in the animal strains. The results of using drug metabolism inhibitors are difficult to interpret. For example, SKF 525A (which inhibits microsomal oxidation) has been reported to prevent acrylamide-induced enhance ment of striatal dopamine receptor activity and to increase the acute toxicity of acrylamide in rats , whereas cobalt chloride has been shown to cause a significant delay in the development of hindlimb paralysis in rats . Presently, no correlation exists between the effects of modifying microsomal metabolism of acrylamide and expression of its toxic effects. Accordingly, identification of metabolic factors important in the toxic manifestations of acrylamide is not possible. Khanna et al. studied the role of protein deficiency on the neurobehavioral effects of acrylamide in rat pups exposed during pregnancy and early infancy. They demonstrated that acrylamide was more toxic in protein-deficient animals because it decreased the dopamine and benzodiazepam receptor binding and delayed the development of reflexes and other physical milestones in pups. # TOXICOLOGIC MECHANISMS Because the most noticeable and earliest detectable effects of acrylamide exposures are neurological effects, numerous studies have attempted to find the mechanism of its action in neural tissues. found that acrylamide inhibits succinic dehydrogenase (SDH) activity in mitochondrial preparations from rat brain and causes changes in levels of biogenic amines and activities of monoamine oxidase and acetylcholine esterase. Biochemical changes may be responsible for the functional changes observed in neural tissues-for example, changes in membrane capacitance and sodium permeability remains to be established. However, the fact that acrylamide has been shown to interact with genetic material may have implications for its genotoxic and carcinogenic effects. # TOXICITY IN HUMANS AND ANIMALS # Neurotoxic Effects The # Developmental and Reproductive Effects Data on developmental and reproductive effects in animals are summarized in Tables 3 and 4 # GENOTOXIC EFFECTS The major concern about the genotoxicity of acrylamide is its clastogenic activity (that is, chromosomal breakage and other chromosomal abnormalities). The clastogenic effect of acrylamide appears more pronounced in the germ cells compared with somatic cells. The interaction with germinal tissues suggests the possible heritabUity of acrylamide-induced DNA alterations. # Gene Mutation Assays # Chromosomal Assays Studies that have examined the chromosomal effects of acrylamide have confirmed its clastogenic potential. This effect appears to be more pronounced in the germ cells than in somatic cells. The suggestive reciprocal translocation results raise the possibility that acrylamide-induced alterations to DNA may be transmissible to future generations. A study of heritable translocation in mice demonstrated that acrylamide is an effective inducer of translocations in postmeiotic germ cells. This result demonstrates that acrylamide may be capable of affecting heritable germ cells in a mammalian system. # CARCINOGENIC EFFECTS # Epidemiologic Findings Collins et al. studied the mortality of workers in acrylamide production plants. This study was performed by scientists at major production plants. Mortality was tracked for a cohort of 8,854 males from 1925 to 1983. This cohort (2,293 of whom were exposed to acrylamide) consisted of four plant populations in the United States and the Netherlands. Followup was completed for 95% of the cohort. At the end of the study 2,148 individuals were deceased, and death certificates were obtained for 95%. The underlying cause of death was coded by a nosologist. Exposure estimates were developed for all jobs at each of the four plants using exposure data collected at each plant and information obtained from plant personnel who had knowledge of past jobs and processes. Exposure to acrylamide was defined as a cumulative exposure greater than 0.001 mg/m3-years, which is approximately equivalent to a 1-day exposure to an average concentration of 0.3 mg/m3. Data on smoking history were available for only a third of the cohort. Standardized mortality ratios (SMRs) and internally standardized rate ratios were employed to estimate the risk. According to the authors, a particular strength of their study was the ability to detect a 25% increase in total cancer, a 50% increase in respiratory cancer, and a threefold increase in brain and other central nervous system cancers based on a two-tailed, 5% significance level with a power of 80%. The SMRs for all causes for both exposed and unexposed groups were significantly less than expected, which may be the result of both initial selection and the ongoing benefits of employment (i.e., the healthy worker effect). An excess of total cancer deaths was not observed among the exposed workers. A slight increase in cancer of the respiratory system (30 observed versus 26.3 expected) was not statistically significant. Analyses of trends by cumulative exposure showed no increased risk of mortality with increasing exposure. Because smoking history was obtained for only a third of the cohort, it was impossible to determine whether smoking habits had confounded the results. # Sobel et al. examined mortality in a group of 371 workers assigned to acrylamide monomer or polyacrylamide operations. Exposure to acrylamide was categorized on the basis of a review of job classifications. Before 1957, personal TWA exposures to acrylamide in the monomer production areas were 0.1 to 1.0 mg/m3. The data from 1957 to 1970 indicated that exposures to acrylamide were 0.1 to 0.6 mg/m3. After 1970, personal exposures to acrylamide were <0.1 mg/m3 for all job classifications. Associated with the production of acrylamide monomer is the potential for exposure to acrylonitrile. The possible confounding effect of this exposure was not formally addressed in this study; but in a previous epidemiologic study , no effects could be directly related to acrylonitrile under the conditions of exposure. The total number of deaths from malignancies was slightly elevated (11 observed versus 7.9 expected ), but this result was apparently due to the excess in a subgroup that was also exposed to organic dyes . Overall, the results did not indicate an excess of cancers from exposures to acrylamide. However, these results may be due to the small cohort size, limited followup, and short duration of exposure (274 workers were exposed for less than 5 years). Given the size of the total cohort and the period of observation, the study had only an 80% likelihood (power) of detecting a twofold or greater increase in total cancer incidence. # Evidence of Carcinogenicity in Animals Studies in rats and mice indicate that acrylamide is an animal carcinogen . Acrylamide was tested for skin-tumor-initiating activity in Senear mice and for the ability to induce lung adenomas in A /J mice . In a mouse skin initiation-promotion assay, 6-to 8-week old female Senear mice were divided into groups of 40 and treated topically, by gavage, or by i.p. injection with acrylamide dissolved in water. Acrylamide was tested at doses of 12.5, 25, and 50 mg/kg for six applications by the three routes over a 2-week period, resulting in total doses of 75, 150, and 300 mg/kg. Ethyl carbamate, a known initiator, was used for a comparison in doses of 30,100, and 300 mg/kg in one application administered topically, by gavage, or i.p. A tumor promotion regimen was started 2 weeks after the last of the tumor-initiating doses of acrylamide. One microgram of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a known tumor promoter, was applied topically 3 times/week for 20 weeks. Tumor incidences were charted from weekly observation. Surviving animals were sacrificed at 52 weeks and histopathological evaluations were done on all gross lesions. A highly significant (p<0.01) dose-response relationship existed for time to first tumor and for the total number of tumors in treated animals. The effect was more pronounced with i.p. and gavage treatment than with topical application. However, without application of TPA promotion, no increase occurred in tumor yield, either with acrylamide or ethyl carbamate treatment. In this assay system, acrylamide was therefore confirmed as being a tumor initiator. In a bioassay for lung adenoma in mice, groups of 40 male and 40 female, 8-week-old A /J mice received doses of 6.25, 12.5, or 25 mg/kg of acrylamide by gavage in an aqueous solution three times/week for 8 weeks . Animals were sacrificed at 7 months of age. Acrylamide increased the yield of lung adenomas in both sexes in a dose-related manner; the average number of tumors per animal increased from 0.2 to 1.4. The dose-response relationship was statistically significant (p<0.01) when both the number of animals with tumors and the multiplicity of tumors in each dose group were tested using logit regression model analysis. In the same investigation, groups of 16 male and 16 female, 8-week-old A /J mice received i.p. injections of 1, 3, 10, 30, or 60 mg/kg acrylamide three times/week for 8 weeks. The average number of tumors per animal increased from 0.4 to 2.2. The number of lung adenomas increased with the dose up to 30 mg/kg. The dose-response relationship was statistically significant (p<0.01) by the logit regression model. Because acrylamide increased the lung tumor yield by two routes of administration in the absence of a promoter, the authors concluded that acrylamide acted as a complete carcinogen in this test system. In a subsequent study , groups of 40 female Swiss-ICR mice were administered an oral dose of 0, 12.5, 25, or 50 mg/kg acrylamide six times in a 2-week period. Ethyl carbamate served as a positive control and was administered in the same way at concentrations of 50 mg/kg. Two weeks after the last dose, a tumor promotion regimen was started. The regimen consisted of 3 weekly applications of 2.5 fig TPA dissolved in acetone to the shaved back of each animal. Another group of mice treated with 50 mg/kg acrylamide did not receive promotion treatment. The appearance of skin tumors was observed weekly, and after 52 weeks of study, the surviving animals were sacrificed and evaluated histologically for skin and lung tumors. When TPA treatment followed, acrylamide produced a dose-related increase in the number of animals that bore skin tumors (33% in the high-dose group versus none in the control group). Without TPA treatment there was no significant increase. The number of lung tumors (adenoma and carcinoma) was increased by acrylamide treatment in a dose-related manner (4 tumors in the control group and 11 tumors in the 50-mg/kg group). This increase was also observed in the absence of TPA (14 tumors in the 50 mg/kg group). This study confirms the initiating effects of acrylamide on the skin of Senear mice and the carcinogenic effects of acrylamide on the lungs of A /J mice. Acrylamide administered in drinking water to female and male F344 rats for 2 years caused a statistically significant increase in the incidence of benign and malignant tumors at several sites in both sexes . Groups of 90 male and 90 female rats were maintained on drinking water providing acrylamide intakes of 0, 0.01, 0.1, 0.5, or 2.0 mg/kg per day. Ten rats per sex per treatment group were randomly selected for examination after 6, 12, or 18 months of study. Cumulative mortality showed no apparent dose relationship until the 21st month of study. From that time to the conclusion of the study at 24 months, mortality increased in the group receiving 2.0 mg/kg per day. No overt signs of neurotoxicity or other effects were attributable to acrylamide treatment. Rats in the group receiving the highest dose had an increased number of palpable masses, subsequently identified as subcutaneous or skin tumors. The number of tumors by site is listed in Table 5. In females, tumor incidence increased in the mammary glands, CNS, thyroid gland follicular epithelium, oral tissues, uterus, and clitoral gland. In males, tumor incidence increased in the CNS, the thyroid gland follicular epithelium, and the scrotal mesothelium. These increases occurred in the group receiving the highest dose (2.0 mg/kg per day). The only statistically significant increases (p<0.05) at the 0.5-mg/kg per day dose were the incidence of scrotal mesotheliomas in male rats and the incidence of combined mammary and clitoral gland tumors in female rats . 1 Includes only adrenal benign tumors. Tumors only (no "proliferations"). # METHODS FOR MONITORING EXPOSURES # EXPOSURE MONITORING A worker's exposure to airborne acrylamide should be determined by using a personal sampling train consisting of a glass-fiber filter in a Swinnex cassette (13-mm) followed by a silica gel tube. Plastic cassettes (37-mm) yielded poor recoveries of acrylamide and are therefore unsuitable. Samples should be collected at a maximum flowrate of 1 liter/min for a minimum of 2 hr; the maximum air volume should be 120 liters. The silica gel tube should then be treated with methanol to extract the acrylamide. An important step in this method is the transfer of the glass-fiber filters to glass vials containing 1 ml of methanol immediately after sampling to avoid losses of acrylamide from the filter by evaporation. Analysis should be conducted by gas chromatography using a nitrogen/phosphorus detector. The limit of detection for this procedure is 1.3 parts per billion (ppb) (0.004 mg/m3). This method is described in Method 21 of the OSHA Analytical Methods Manual . # BIOLOGICAL MONITORING The International Programme on Chemical Safety (IPCS) has recommended that a biological monitoring method for acrylamide be developed based on the determination of the adduct formed with hemoglobin . However, no biological monitoring test acceptable for routine use has yet been developed for acrylamide. # RELATIONSHIP BETWEEN EXPOSURE AND ADVERSE HEALTH EFFECTS No data are available from studies in humans to establish an occupational exposure limit for acrylamide on the basis of neurotoxic, developmental, reproductive, or carcinogenic effects. However, many studies demonstrate a relationship between exposure and adverse health effects in animals. These studies are the bases for occupational exposure limits recommended by many organizations and government agencies. A few of these studies are described here. 5 NOEL = no-observable-effect level; LOEL = lowest-observable-effect level. The linearized multistage procedure was followed by EPA , with GLOBAL 86 as the computer program. Among the models that showed adequate fit with one to six stages, the model that gave the least q^ (slope factor) was selected as the model with which to calculate carcinogenic risks using the lifetime average daily exposures provided by the exposure assessment for acrylamide. For the female rats with tumors of the thyroid, oral cavity, uterus, CNS, or mammary glands, this model had two stages. The cancer potency factor obtained for acrylamide by the linearized multistage procedure was 4.5 (mg/kg per day)'1. The cancer potency factor describes the increased risk of developing cancer over a 70-year lifetime per unit of exposure where the unit of exposure is expressed as mg chemical/kg body weight per day. When based on an experimental animal study, the cancer potency factor is the 95% upper confidence limit slope of the dose-response relationship for a carcinogen as the dose approaches zero. Calculated upper-bound excess risks for individuals exposed to acrylamide are presented in Table 7. The highest risks were estimated for sewer repair workers, whose excess risks ranged from 10'1 to 10'2. EPA calculated that exposure to airborne concentrations of 0. # RESEARCH NEEDS Very few studies address dermal absorption o f acrylamide, although the dermal route may be the most significant one for acrylamide exposure in the workplace . Therefore, quantitative studies should be performed to assess the absorption o f aciylam ide through the skin. Because dermal exposure appears to be a significant route o f acrylamide uptake and it is difficult to monitor dermal exposures routinely, it is important to develop biom onitoring that can accurately reflect total exposure to acrylamide. A valid biomonitoring technique for acrylamide is presently unavailable. However, the literature on the toxicokinetics o f acrylamide indicates that biom oni toring may be feasible either in urine or blood. M ore than 50% o f the given dose is reported to be excreted in urine as the m etabolite N-acetyl-S-(3-amino-3-oxy-propyl)cysteine . By collecting the urine o f workers whose exposure is monitored, it may be feasible to correlate the total exposure (that is, both inhalation and skin) to acrylamide with measured concentrations or total amounts o f m etabolites in 24-hr urine samples. Another possibility for biomonitoring is measurement o f acrylamide binding to red blood cells. Hashimoto and Aldridge observed that after rats received a single i.v. dose o f UC acrylamide, the radioactivity in blood after 24 hr was entirely associated with red blood cells. Miller et al. found that the concentration o f 14C in whole blood reached a plateau at 12% o f the total dose after 1 hr and remained constant throughout the time period examined (7 days). The binding to erythrocytes accounted for essentially all o f the remaining radioactivity in the w hole blood. In vitro studies showed that acrylamide was covalently bound to cysteine residues in protein and, on acidic hydrolysis, the adduct yielded a compound with chromatographic properties identified as S-( 2 # SUMMARY Acrylamide is an odorless, white, crystalline solid used as a monomer or as a raw material in the production o f polyacrylamides. Workers potentially exposed to acrylamide monomer are employed in acrylamide manufacturing and processing, grouting operations, and research and analytical laboratories. Only the acrylamide monomer is toxic; polyacrylamide products are generally nontoxic. Acrylamide monomer may be neurotoxic, carcinogenic, genotoxic, and hazardous to reproduction. Recent studies confirm that acrylamide exposures cause cancer and reproductive effects in animals, but epidem iologic studies have not demonstrated these effects in humans. Key Words: Acrylamide, carcinogenicity, dermal exposures, grouting, neurotoxic effects, occupational exposure, polyacrylamide, reproductive effects. # APPENDIX. INTERNATIONAL STANDARDS FOR WORKPLACE EXPOSURES TO ACRYLAMIDE This appendix lists occupational exposure lim its for airborne acrylamide in various countries (Table A -

# Table of Contents List of Tables, Figures , and Boxes # Summary Preexposure Prophylaxis for HIV Prevention in the United States -2013: A Clinical Practice Guideline provides comprehensive information for the use of daily oral antiretroviral preexposure prophylaxis (PrEP) to reduce the risk of acquiring HIV infection in adults. The key messages of the guideline are as follows:  Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, o PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA) 1 o PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) o PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) o PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB)  Currently the data on the efficacy and safety of PrEP for adolescents are insufficient. Therefore, the risks and benefits of PrEP for adolescents should be weighed carefully in the context of local laws and regulations about autonomy in health care decision-making by minors. (IIIB)  Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is prescribed. (IA)  The only medication regimen approved by the Food and Drug Administration and recommended for PrEP with all the populations specified in this guideline is daily TDF 300 mg co-formulated with FTC 200 mg (Truvada) (IA) o TDF alone has shown substantial efficacy and safety in trials with IDUs and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied. (IC) o The use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended. (IIIA) o The prescription of oral PrEP for coitally-timed or other noncontinuous daily use is not recommended. (IIIA)  HIV infection should be assessed at least every 3 months while patients are taking PrEP so that those with incident infection do not continue taking it. The 2-drug regimen of TDF/FTC is inadequate therapy for established HIV infection, and its use may engender resistance to either or both drugs. (IA)  Renal function should be assessed at baseline and monitored at least every 6 months while patients are taking PrEP so that those in whom renal failure is developing do not continue to take it. (IIIA)  When PrEP is prescribed, clinicians should provide access, directly or by facilitated referral, to proven effective risk-reduction services. Because high medication adherence is critical to PrEP efficacy but was not uniformly achieved by trial participants, patients should be encouraged and enabled to use PrEP in combination with other effective prevention methods. (IIIA) # Introduction Recent findings from several clinical trials have demonstrated safety 1 and a substantial reduction in the rate of HIV acquisition for men who have sex with men (MSM) 2 , men and women in heterosexual HIV-discordant couples 3 , and heterosexual men and women recruited as individuals 4 who were prescribed daily oral antiretroviral preexposure prophylaxis (PrEP) with a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). In addition, one clinical trial among injection drug users (IDU) 5 and one among men and women in heterosexual HIV-discordant couples 3 have demonstrated substantial efficacy and safety of daily oral PrEP with TDF alone. The demonstrated efficacy of PrEP was in addition to the effects of repeated condom provision, sexual risk-reduction counseling, and the diagnosis and treatment of sexually transmitted infection (STI), all of which were provided to trial participants, including those in the drug treatment group and those in the placebo group. In July 2012, after reviewing the available trial results, the U.S. Food and Drug Administration (FDA) approved an indication for the use of Truvada † (TDF/FC) "in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk" 6,7 . On the basis of these trial results and the FDA approval, the U.S. Public Health Service recommends that clinicians evaluate their male and female patients who are sexually active or who are injecting illicit drugs and consider offering PrEP as one prevention option to those whose sexual or injection behaviors and epidemiologic context place them at substantial risk of acquiring HIV infection. The evidence base for these recommendations is derived from a systematic search and review of published literature. To identify all PrEP safety and efficacy trials pertaining to the prevention of sexual and injection acquisition of HIV, a search of the clinical trials registry () was performed by using combinations search terms (preexposure prophylaxis, pre-exposure prophylaxis, PrEP, HIV, Truvada, tenofovir, and antiretroviral). In addition, the same search terms were used to search conference abstracts for major HIV conferences (e.g., International AIDS Conference, Conference on Retroviruses and Opportunistic Infections) for the years 2009-2013. These same search terms were used to search PubMed and Web of Science databases for the years 2006-2013. Finally, a review of references from published PrEP trial data and the data summary prepared by FDA for its approval decision 8 confirmed that no additional trial results were available. This publication provides a comprehensive clinical practice guideline for the use of PrEP for the prevention of HIV infection in the United States. It incorporates and extends information provided in interim guidance for PrEP use with MSM 9 , with heterosexually active adults 10 , and with IDU (also called persons who injection drugs ) 11 . Currently, prescribing daily oral PrEP with TDF/FTC is recommended as one prevention option for MSM, heterosexual men, heterosexual women, and IDU at substantial risk of HIV acquisition. As the results of additional PrEP clinical trials and studies in these and other populations at risk of HIV acquisition become known, this guideline will be updated. The intended users of this guideline include  primary care clinicians who provide care to persons at risk of acquiring HIV infection  clinicians who provide substance abuse treatment  infectious disease and HIV treatment specialists who may provide PrEP or serve as consultants to primary care physicians about the use of antiretroviral medications  health program policymakers. # Evidence of Need for Additional HIV Prevention Methods Approximately 50,000 people in the United States are infected with HIV each year 12 . From 2008 through 2010, HIV incidence remained stable or declined among IDU and heterosexuals of all races and Hispanic/Latino ethnicity, but incidence increased among MSM (12% increase), especially among adolescent and young adult MSM (aged 13-24 years) (22% increase) 12 . The greatest number of new HIV infections among MSM occurred in young African American MSM (4,800). In 2010, 63% of the estimated 47,500 new infections were attributed to male-male sexual activity without injection drug use, 4% to male-male sexual activity with injection drug use, 25% to male-female sexual contact without injection drug use, and 8% to injection drug use. Among the 25% of persons newly infected through heterosexual activity, 66% were African-American women and men. These data indicate a need for additional methods of HIV prevention to further reduce new HIV infections, especially (but not exclusively) among young adult and adolescent MSM of all races and Hispanic/Latino ethnicity and for African American heterosexuals (populations with higher HIV prevalence and at higher risk of HIV infection among those without HIV infection). # Evidence of the Safety and Efficacy of Antiretroviral Prophylaxis The biological plausibility and the short-term safety of antiretroviral use to prevent HIV acquisition in other exposure situations have been demonstrated in 2 studies conducted prior to the PrEP trials. In a randomized placebo-controlled trial, perinatal transmission was reduced 68% among the HIV-infected women who received zidovudine during pregnancy and labor and whose infants received zidovudine for 6 weeks after birth 13 . That is, these infants received both preexposure and postexposure prophylaxis. In 1995, investigators used case-control surveillance data from health-care workers to demonstrate that zidovudine provided within 72 hours after percutaneous exposure to HIV-infected blood and continued for 28 days (PEP, or postexposure prophylaxis) was associated with an 81% reduction in the risk of acquiring HIV infection . Evidence from these human studies of blood-borne and perinatal transmission as well as studies of vaginal and rectal exposure among animals suggested that PrEP (using antiretroviral drugs) could reduce the risk of acquiring HIV infection from sexual and drug-use exposures. Clinical trials were launched to evaluate the safety and efficacy of PrEP in populations at risk of HIV infection through several routes of exposure. The results of completed trials published as of August 2013 are summarized below. See also Tables 2-6. # PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG MEN WHO HAVE SEX WITH MEN # IPREX (PREEXPOSURE PROPHYLAXIS INITIATIVE) TRIAL The iPrEx study 2 was a phase 3, randomized, double-blind, placebo-controlled trial conducted in Peru, Ecuador, Brazil, Thailand, South Africa, and the United States among men and male-tofemale transgender adults who reported sex with a man during the 6 months preceding enrollment. Participants were randomly assigned to receive a daily oral dose of either the fixeddose combination of TDF and FTC or a placebo. All participants (drug and placebo groups) were seen every 4 weeks for an interview, HIV testing, counseling about risk-reduction and adherence to PrEP medication doses, pill count, and dispensing of pills and condoms. Analysis of data through May 1, 2010, revealed that after the exclusion of 58 participants (10 later determined to be HIV-infected at enrollment and 48 who did not have an HIV test after enrollment), 36 of 1,224 participants in the TDF/FTC group and 64 of 1,217 in the placebo group had acquired HIV infection. Enrollment in the TDF/FTC group was associated with a 44% reduction in the risk of HIV acquisition (95% CI, 15-63). The reduction was greater in the as-treated analysis: at the visits at which adherence was ≥50% (by self-report and pill count/dispensing), the reduction in HIV acquisition was 50% (95% CI, . The reduction in the risk of HIV acquisition was 73% at visits at which self-reported adherence was ≥90% (95% CI, 41-88) during the preceding 30 days. Among participants randomly assigned to the TDF/FTC group, plasma and intracellular drug-level testing was performed for all those who acquired HIV infection during the trial and for a matched subset who remained HIV-uninfected: a 92% reduction in the risk of HIV acquisition (95% CI, 40-99) was found in participants with detectable levels of TDF/FTC versus those with no drug detected. Generally, TDF/FTC was well tolerated, although nausea in the first month was more common among participants taking medication than among those taking placebo (9% versus 5%). No differences in severe (grade 3) or life-threatening (grade 4) adverse laboratory events were observed between the active and placebo group, and no drug-resistant virus was found in the 100 participants infected after enrollment. Among 10 participants who were HIV-negative at enrollment but later found to have been infected before enrollment, FTC-resistant virus was detected in 2 of 2 men in the active group and 1 of 8 men in the placebo group. Compared to participant reports at baseline, over the course of the study participants in both the TDF/FTC and placebo groups reported fewer total numbers of sex partners with whom the participants had receptive anal intercourse and higher percentages of partners who used condoms. # US MSM SAFETY TRIAL The US MSM Safety Trial 1 was a phase 2 randomized, double-blind, placebo-controlled study of the clinical safety and behavioral effects of TDF for HIV prevention among 400 MSM in San Francisco, Boston, and Atlanta. Participants were randomly assigned 1:1:1:1 to receive daily oral TDF or placebo immediately or after a 9-month delay. Participants were seen for follow-up visits 1 month after enrollment and quarterly thereafter. Among those without directed drug interruptions, medication adherence was high: 92% by pill count and 77% by pill bottle openings recorded by Medication Event Monitoring System (MEMS) caps. Temporary drug interruptions and the overall frequency of adverse events did not differ significantly between TDF and placebo groups. In multivariable analyses, back pain was the only adverse event associated with receipt of TDF. In a subset of men at the San Francisco site (n=184) for whom bone mineral density (BMD) was assessed, receipt of TDF was associated with small decrease in BMD (1% decrease at the femoral neck, 0.8% decrease for total hip) 20 . TDF was not associated with reported bone fractures at any anatomical site. Among 7 seroconversions, no HIV with mutations associated with TDF resistance was detected. No HIV infections occurred while participants were being given TDF; 3 occurred in men while taking placebo, 3 occurred among men in the delayed TDF group who had not started receiving drug; 1 occurred in a man who had been randomly assigned to receive placebo and who was later determined to have had acute HIV infection at the enrollment visit. Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for sexuallyactive MSM at substantial risk of HIV acquisition because the iPrEx trial presents evidence of its safety and efficacy in this population, especially when medication adherence is high. (IA) # PUBLISHED TRIALS OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG HETEROSEXUAL MEN AND WOMEN # PARTNERS PREP TRIAL The Partners PrEP trial 3,21 was a phase 3 randomized, double-blind, placebo-controlled study of daily oral TDF/FTC or TDF for the prevention of acquisition of HIV by the uninfected partner in 4,758 HIV-discordant heterosexual couples in Uganda and Kenya. The trial was stopped after an interim analysis in mid-2011 showed statistically significant efficacy in the medication groups (TDF/FTC or TDF) compared with the placebo group. In 48% of couples, the infected partner was male. HIV-positive partners had a median CD4 count of 495 cells/µL and were not being prescribed antiretroviral therapy because they were not eligible by local treatment guidelines. Participants had monthly follow-up visits and the study drug was discontinued among women who became pregnant during the trial. Adherence to medication was very high: 98% by pills dispensed, 92% by pill count, and 82% by plasma drug-level testing among randomly selected participants in the TDF and TDF/FTC study groups. Rates of serious adverse events and serum creatinine or phosphorus abnormalities did not differ by study group. Modest increases in gastrointestinal symptoms and fatigue were reported in the antiretroviral medication groups compared with the placebo group, primarily in the first month of use. Among participants of both sexes combined, efficacy estimates for each of the 2 antiretroviral regimens compared with placebo were 67% (95% CI, 44-81) for TDF and 75% (95% CI, 55-87) for TDF/FTC. Among women, the estimated efficacy was 71% for TDF and 66% for TDF/FTC. Among men, the estimated efficacy was 63% for TDF and 84% for TDF/FTC. Efficacy estimates by drug regimen were not statistically different among men, women, men and women combined, or between men and women. In a Partners PrEP substudy that measured plasma TDF levels among participants randomly assigned to receive TDF/FTC, detectable drug was associated with a 90% reduction in the risk of HIV acquisition. TDF-or FTC-resistant virus was detected in 3 of 14 persons determined to have been infected when enrolled (2 of 5 in the TDF group; 1 of 3 in the TDF/FTC group) 8 . No TDF or FTC resistant virus was detected among those infected after enrollment. Among women, the pregnancy rate was high (10.3 per 100 person -years) and rates did not differ significantly between the study groups. # TDF2 TRIAL The Botswana TDF2 Trial 22 , a phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF/FTC, enrolled 1,219 heterosexual men and women in Botswana, and follow-up has been completed. Participants were seen for monthly follow-up visits, and study drug was discontinued in women who became pregnant during the trial. Among participants of both sexes combined, the efficacy of TDF/FTC was 62% (22%-83%). Efficacy estimates by sex did not statistically differ from each other or from the overall estimate, although the small number of endpoints in the subsets of men and women limited the statistical power to detect a difference. Compliance with study visits was low: 33.1% of participants did not complete the study per protocol. However, many were re-engaged for an exit visit, and 89.3% of enrolled participants had a final HIV test. Among 3 participants later found to have been infected at enrollment, TDF/FTC-resistant virus was detected in 1 participant in the TDF/FTC group and a low level of TDF/FTC-resistant virus was transiently detected in 1 participant in the placebo group. No resistant virus was detected in the 33 participants who seroconverted after enrollment. Medication adherence by pill count was 84% in both groups. Nausea, vomiting, and dizziness occurred more commonly, primarily during the first month of use, among those randomly assigned to TDF/FTC than among those assigned to placebo. The groups did not differ in rates of serious clinical or laboratory adverse events. Pregnancy rates and rates of fetal loss did not differ by study group. # FEM-PREP TRIAL The FEM-PrEP trial 23 was a phase 3 randomized, double-blind, placebo-controlled study of the HIV prevention efficacy and clinical safety of daily TDF/FTC among heterosexual women in South Africa, Kenya, and Tanzania. Participants were seen at monthly follow-up visits, and study drug was discontinued among women who became pregnant during the trial. The trial was stopped in 2011, when an interim analysis determined that the trial would be unlikely to detect a statistically significant difference in efficacy between the two study groups. Adherence was low in this trial: study drug was detected in plasma samples of <50% of women randomly assigned to TDF/FTC. Among adverse events, only nausea and vomiting (in the first month) and transient, modest elevations in liver function test values were more common among those assigned to TDF/FTC than those assigned to placebo. No changes in renal function were seen in either group. Initial analyses of efficacy results showed 4.7 infections per 100/ personyears in the TDF/FTC group and 5.0 infections per 100 person-years in the placebo group. The hazard ratio 0.94 (95% CI, 0.59-1.52) indicated no reduction in HIV incidence associated with TDF/FTC use. Of the 68 women who acquired HIV infection during the trial, TDF or FTC resistant virus was detected in 5 women: 1 in the placebo group and 4 in the TDF/FTC group. In multivariate analyses, there was no association between pregnancy rate and study group. # PHASE 2 TRIAL OF PREEXPOSURE PROPHYLAXIS WITH TENOFOVIR AMONG WOMEN IN GHANA, CAMEROON, AND NIGERIA A randomized, double-blind, placebo-controlled trial of oral tenofovir TDF was conducted among heterosexual women in West Africa -Ghana (n = 200), Cameroon (n = 200), and Nigeria (n = 136) 24 . The study was designed to assess the safety of TDF use and the efficacy of daily TDF in reducing the rate of HIV infection. The Cameroon and Nigeria study sites were closed prematurely because operational obstacles developed, so participant follow-up data were insufficient for the planned efficacy analysis. Analysis of trial safety data from Ghana and Cameroon found no statistically significant differences in grade 3 or 4 hepatic or renal events or in reports of clinical adverse events. Eight HIV seroconversions occurred among women in the trial: 2 among women in the TDF group (rate=0.86 per 100 person-years) and 6 among women receiving placebo (rate, 2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% CI, 0.03-1.93; P=0.24). Blood specimens were available from 1 of the 2 participants who seroconverted while taking TDF; standard genotypic analysis revealed no evidence of drug-resistance mutations. # VOICE (VAGINAL AND ORAL INTERVENTIONS TO CONTROL THE EPIDEMIC) TRIAL VOICE (MTN-003) 25 was a phase 2B randomized, double-blind study comparing oral (TDF or TDF/FTC) and topical vaginal (tenofovir) antiretroviral regimens against corresponding oral and topical placebos among 5,029 heterosexual women enrolled in eastern and southern Africa. Of these women, 3,019 were randomly assigned to daily oral medication (TDF/FTC, 1,003; TDF, 1,007; oral placebo, 1,009). In 2011, the trial group receiving oral TDF and the group receiving topical tenofovir were stopped after interim analyses determined futility 26 . The group receiving oral TDF/FTC continued to the planned trial conclusion. After the exclusion of 15 women later determined to have had acute HIV infection when enrolled in an oral medication group and 27 with no follow-up visit after baseline, 52 incident HIV infections occurred in the oral TDF group, 61 in the TDF/FTC group, and 60 in the oral placebo group. Effectiveness was not significant for either oral PrEP medication group; −49%% for TDF (hazard ratio 1.49; 95% CI, 0.97-2.29) and −4.4% for TDF/FTC (HR, 1.04; 95% CI, 0.73-1.49) in the modified-intent-to-treat analysis. Face-to-face interview, audio computer-assisted self-interview, and pill-count medication adherence were high in all 3 groups (84%-91%). However, among 315 participants in the random cohort of the case-cohort subset for whom quarterly plasma samples were available, tenofovir was detected, on average, in 30% of samples from women randomly assigned to TDF and in 29% of samples from women randomly assigned to TDF/FTC. No drug was detected at any quarterly visit during study participation for 58% of women in the TDF group and 50% of women in the TDF/FTC group. The percentage of samples with detectable drug was less than 40% in all study drug groups and declined throughout the study. In a multivariate analysis that adjusted for baseline confounding variables (including age, marital status), the detection of study drug was not associated with reduced risk of HIV acquisition. The number of confirmed creatinine elevations (grade not specified) observed was higher in the oral TDF/FTC group than in the oral placebo group. However, there were no significant differences between active product and placebo groups for other safety outcomes. Of women determined after enrollment to have had acute HIV infection at baseline, two women from the TDF/FTC group had virus with the M184I/V mutation associated with FTC resistance. One woman in the TDF/FTC group who acquired HIV infection after enrollment had virus with the M184I/V mutation; No participants with HIV infection had virus with a mutation associated with tenofovir resistance. In summary, although low adherence and operational issues precluded reliable conclusions regarding efficacy in 3 trials (VOICE, FEM-PrEP and the West African trial) 27 , 2 trials (Partners PrEP and TDF2) with high medication adherence have provided substantial evidence of efficacy among heterosexual men and women. All 5 trials have found PrEP to be safe for these populations. Daily oral PrEP with TDF/FTC is recommended as one HIV prevention option for heterosexually-active men and women at substantial risk of HIV acquisition because these trials present evidence of its safety and 2 present evidence of efficacy in these populations, especially when medication adherence is high. (IA). # PUBLISHED TRIAL OF ANTIRETROVIRAL PREEXPOSURE PROPHYLAXIS AMONG INJECTION DRUG USERS # BANGKOK TENOFOVIR STUDY (BTS) BTS 5 was a phase 3 randomized, double-blind, placebo-controlled study of the safety and efficacy of daily oral TDF for HIV prevention among 2,413 IDUs in Bangkok, Thailand. The study was conducted at drug treatment clinics; 22% of participants were receiving methadone treatment at baseline. At each monthly visit, participants could choose to receive either a 28-day supply of pills or to receive medication daily by directly-observed therapy. Study clinics (n=17) provided condoms, bleach (for cleaning injection equipment), methadone, primary medical care, and social services free of charge. Participants were followed for 4.6 years (mean) and received directly-observed therapy 87% of the time. In the modified intent-to-treat analysis (excluding 2 participants with evidence of HIV infection at enrollment), efficacy of TDF was 48.9% (95% CI, 9.6-72.2; P = .01). A post-hoc modified intent-to-treat analysis was done, removing 2 additional participants in whom HIV infection was identified within 28 days of enrollment, including only participants on directly observed therapy who met pre-established criteria for high adherence (taking a pill at least 71% of days and missing no more than two consecutive doses), and had detectable levels of tenofovir in their blood. Among this set of participants, the efficacy of TDF in plasma was associated with a 73.5% reduction in the risk for HIV acquisition (95% CI, 16.6-94.0; P = .03). Among participants in an unmatched case-control study that included the 50 persons with incident HIV infection and 282 participants at 4 clinics who remained HIV uninfected, detection of TDF in plasma was associated with a 70.0% reduction in the risk for acquiring HIV infection (95% CI, 2.3-90.6; P = .04). Rates of nausea and vomiting were higher among TDF than among placebo recipients in the first 2 months of medication but not thereafter. The rates of adverse events, deaths, or elevated creatinine did not differ significantly between the TDF and the placebo groups. Among the 49 HIV infections for which viral RNA could be amplified (of 50 incident infections and 2 infections later determined to have been present at enrollment), no virus with mutations associated with TDF resistance were identified. Among participants with HIV infection followed up for a maximum of 24 months, HIV plasma viral load was lower in the TDF than in the placebo group at the visit when HIV infection was detected (P = .01), but not thereafter (P = .10). Daily oral PrEP with TDF/FTC (or TDF alone) is recommended as one HIV prevention option for IDUs at substantial risk of HIV acquisition because this trial presents evidence of the safety and efficacy of TDF as PrEP in this population, especially when medication adherence is high. (IA) # Identifying Indications for PrEP Taking a sexual history is recommended for all adult and adolescent patients as part of ongoing primary care, but the sexual history is often deferred because of urgent care issues, provider discomfort, or anticipated patient discomfort. This deferral is common among providers of primary care 29 , STI care, 30 and HIV care . Routinely taking a sexual history is a necessary first step to identify which patients in a clinical practice are having sex with same-sex partners, which are having sex with opposite-sex partners, and what specific sexual behaviors may place them at risk for, or protect them from, HIV acquisition. The clinician can introduce this topic by stating that taking a brief sexual history is routine practice, go on to explain that the information is necessary to the provision of individually appropriate sexual health care, and close by reaffirming the confidentiality of patient information. # ASSESSING RISK OF SEXUAL HIV ACQUISITION Because offering PrEP is currently indicated for MSM at substantial risk of HIV acquisition, it is important to consider that although 76% of MSM surveyed in 2008 in 21 US cities reported a health care visit during the past year 34 , other studies reported that health care providers do not ask about, and patients often do not disclose, same-sex behaviors 35 . Box A1 contains a set of brief questions designed to identify men who are currently having sex with men and to assess a key set of sexual practices that are associated with the risk of HIV acquisition. In studies to develop scored risk indexes predictive of incident HIV infection among MSM 36,37 (see Providers' Supplement, Section 5), several critical factors were identified. BOX A1: RISK BEHAVIOR ASSESSMENT FOR MSM 36 Box A2 contains a set of brief questions designed to identify women and men who are currently having sex with opposite-sex partners (heterosexually active) and to assess a key set of sexual practices that are associated with the risk of HIV acquisition as identified both in PrEP trials and epidemiologic studies . In the past 6 months:  Have you had sex with men, women, or both?  (if men or both sexes) How many men have you had sex with?  How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom?  How many of your male sex partners were HIV-positive?  (if any positive) With these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing a condom?  Have you used methamphetamines (such as crystal or speed)? # BOX A2: RISK BEHAVIOR ASSESSMENT FOR HETEROSEXUAL MEN AND WOMEN In addition, for all sexually active patients, clinicians may want to consider reports of diagnoses of bacterial STIs (chlamydia, syphilis, gonorrhea) during the past 6 months as evidence of sexual activity that could result in HIV exposure. For heterosexual women and men, sex without a condom (or its correct use) may also be indicated by recent pregnancy of a female patient or sexual partner of a male patient. Clinicians should also briefly screen all patients for alcohol abuse 41 (especially before sexual activity) and the use of illicit non-injection drugs (e.g., amyl nitrite, stimulants). 42,43 The use of these substances may affect sexual risk behavior 44 , hepatic or renal health, or medication adherence, any of which may affect decisions about the appropriateness of prescribing PrEP medication. In addition, if substance abuse is reported, the clinician should provide referral for appropriate treatment or harm-reduction services acceptable to the patient. Lastly, clinicians should consider the epidemiologic context of the sexual practices reported by the patient. The risk of HIV acquisition is determined by both the frequency of specific sexual practices (e.g., unprotected anal intercourse) and the likelihood that a sex partner has HIV infection. The same behaviors when reported as occurring in communities and demographic populations with high HIV prevalence or occurring with partners known to have HIV infection, are more likely to result in exposure to HIV and so will indicate greater need for intensive riskreduction methods (PrEP, multisession behavioral counseling) than when they occur in a community or population with low HIV prevalence (see or /). After assessing the risk of HIV acquisition, clinicians should discuss with the patient which of several effective prevention methods (e.g., PrEP, behavioral interventions) 45 will be pursued. When supporting consistent and correct condom use is feasible and the patient is motivated to achieve it, high levels of protection against both HIV and several STIs 46,47 are afforded without the side effects or cost of medication. A clinician can support consistent condom use by providing brief clinical counseling (see Providers' Supplement, Section 7), by referring the patient to behavioral medicine or health education staff in the clinical setting, or by referring the patient to community-based or local health department counseling and support services. # In the past 6 months:  Have you had sex with men, women, or both?  (if opposite sex or both sexes) How many men/women have you had sex with?  How many times did you have vaginal or anal sex when neither you nor your partner wore a condom?  How many of your sex partners were HIV-positive?  (if any positive) With these HIV-positive partners, how many times did you have vaginal or anal sex without a condom? Reported consistent ("always") condom use is associated with an 80% reduction in HIV acquisition among heterosexual couples 48 . However, inconsistent condom use is less effective, 37,49 and studies have reported low rates of recent consistent condom use among MSM 50 and other sexually active adults 51 . Especially low rates have been reported when condom use was measured over several months rather than during most recent sex or the past 30 days 52 . Therefore, unless the patient reports confidence that consistent condom use can be achieved, additional HIV prevention methods, including the consideration of PrEP should be provided while continuing to support condom. A patient who reports that 1 or more regular sex partners is of unknown HIV status should be offered HIV testing for those partners, either in the clinician's practice or at a confidential testing site (see zip code lookup at /). Lastly, for any regular sex partner reported to be HIV-positive, clinicians should determine whether the partner is receiving antiretroviral therapy and whether a recent evaluation indicates an undetectable viral load. In addition to the known health benefits of viral load suppression, a recent clinical trial (HPTN 052 53 ) demonstrated that viral load suppression is highly, but not completely, protective against HIV transmission to a heterosexual partner (96% reduction). No similar trial has been done with MSM in HIV-discordant couples, so it is unknown how much viral load suppression reduces HIV transmission among partners who are MSM. Persons who know they have HIV infection may not be in care, may not be receiving antiretroviral therapy, may not be receiving highly effective regimens, may not be adherent to their medications, or for other reasons may not have viral loads that are associated with the least risk of transmission to an uninfected sex partner 54 . 56 substantial proportions of IDU report sharing syringes (34%) and sharing injection equipment (58%). In addition, in NHBS and epidemiologic studies conducted with IDU, most IDU report sexual behaviors that also confer risk of HIV acquisition 57 . Because of the efficacy and safety demonstrated in the PrEP trial with IDU, providing PrEP to those who report injection behaviors that place them at substantial risk of acquiring HIV infection could contribute to HIV prevention for IDU at both the individual and the population level. Although current evidence is insufficient for a recommendation that all patients be screened for injection or other illicit drug use, the US Preventive Services Task Force recommends that clinicians be alert to the signs and symptoms of illicit drug use in patients. 26 Clinicians should determine whether patients who are currently using illicit drugs are in (or want to enter) behavioral, medication-assisted, or in-patient drug treatment. For persons with a history of injecting illicit drugs but who are currently not injecting, clinicians should assess the risk of relapse along with the patients' use of relapse prevention services (e.g., a drug-related behavioral support program, use of mental health services, 12-step program). Box A3 contains a set of brief questions that may help identify persons who are injecting illicit drugs, and to assess a key set of injection practices that are associated with the risk of HIV acquisition as identified in the PrEP trial with IDU 5 and in epidemiologic studies 56,58 . PrEP or other HIV prevention should be integrated with prevention and clinical care services for the many health threats IDU may face (e.g., hepatitis B and C infection, abscesses, septicemia, endocarditis, overdose) 59 . In addition, referrals for drug treatment, mental health services, and social services may be indicated 59 . # LABORATORY TESTS AND OTHER DIAGNOSTIC PROCEDURES All patients whose sexual or drug injection history indicates consideration of PrEP and who are interested in taking PrEP must undergo laboratory testing to identify those for whom this intervention would be harmful or for whom it would present specific health risks that would require close monitoring. # HIV TESTING HIV testing and the documentation of results are required to confirm that patients do not have HIV infection when they start taking PrEP medications. For patient safety, HIV testing and should be repeated at least every 3 months (before prescriptions are refilled or reissued). This requirement should be explained to patients during the discussion about whether PrEP is appropriate for them. The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force recommends that MSM, IDUs, patients with a sex partner who has HIV infection, and others at substantial risk of HIV acquisition undergo an HIV test at least annually or for those  Have you ever injected drugs that were not prescribed to you by a clinician?  (if yes), When did you last inject unprescribed drugs?  In the past 6 months, have you injected by using needles, syringes, or other drug preparation equipment that had already been used by another person?  In the past 6 months, have you been in a methadone or other medication-based drug treatment program?  Adult person  Without acute or established HIV infection  Any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following  Any sharing of injection or drug preparation equipment in past 6 months  Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months  Risk of sexual acquisition (also evaluate by criteria in Box B1 or B2) with additional risk factors, every 3-6. 60 However, outside the context of PrEP delivery, testing is often not done as frequently as recommended. 61 At a minimum, clinicians should document a negative antibody test result within the week before initiating (or reinitiating) PrEP medications. # ACUTE HIV INFECTION In the iPrEx trial, drug-resistant virus developed in 2 persons with unrecognized acute HIV infection at enrollment and for whom TDF/FTC had been dispensed. These participants had negative antibody test results before they started taking PrEP, tested positive at a later study visit, and PCR (polymerase chain reaction) on stored specimens from the initial visit detected the presence of virus. When questioned, most of the 10 acutely infected participants (8 of whom had been randomly assigned the placebo group) reported signs and symptoms consistent with a viral syndrome 2 . Both acutely infected patients to whom TDF/FTC had been dispensed had the M184V/I mutation associated with emtricitabine resistance, but not the K65R mutation associated with tenofovir resistance 2 . Among participants who were dispensed PrEP medication in the US MSM Safety Trial and in the Partners PrEP, TDF2, and VOICE trials (see Table 6), the M184V mutation, developed in several persons who were enrolled and had started taking medication with unrecognized acute HIV infection but K65R developed in only one (in the TDF2 study). However, no mutations emerged in persons who acquired infection after baseline. In the one trial with very low medication adherence that has published its resistance testing results, the emtricitabine resistance mutation, but not the K65R mutation was found in a few persons with incident infection after baseline (4 persons in the FEM-PrEP trial). PrEP is indicated for MSM, heterosexual men and women, and IDUs who report injection or sexual behaviors that place them at substantial risk of HIV acquisition. Therefore clinicians should suspect acute HIV infection in persons known to have been exposed recently (e.g., a condom broke during sex with an HIV-infected partner, relapse to injection drug use with shared injection equipment). In addition, clinicians should solicit a history of nonspecific signs or symptoms of viral infection during the preceding month or on the day of evaluation (Table 7) in all PrEP candidates with a negative or an indeterminate result on an HIV antibody test. Optional adjustment for low actual body weight 71 If the actual body weight is less than the IBW (ideal body weight) use the actual body weight for calculating the eCrCl. # Optional adjustment of high actual body weight 71 Used only if the actual body weight is 30% greater than the IBW. Otherwise, the IBW is used. # HEPATITIS SEROLOGY Sexually active adults (especially MSM), and persons who inject illicit drugs, are at risk of acquiring HBV infection 74 and hepatitis C virus (HCV) infection 75 . Vaccination against HBV is recommended for all adolescents and adults, especially for MSM 76 . Therefore, HBV and HCV infection status should be documented by screening serology before TDF/FTC is prescribed as PrEP (see Table 8). Those patients determined to be susceptible to HBV infection should be vaccinated. In addition, both TDF and FTC are active against HBV. This has 2 implications for PrEP use. First, if patients with active HBV infection stop taking these medications, liver function must be closely monitored because reactivated HBV infection can result in hepatic damage 77 . In addition, a recent study demonstrated a lower rate of incident HBV infections among HIV-infected MSM whose treatment regimens included TDF or lamivudine (closely related to FTC) than among men whose regimens did not contain these drugs (0.7 vs 6.7 infections per 100 person-years). 78 # Providing PrEP # GOALS OF PREP THERAPY The ultimate goal of PrEP is to reduce the acquisition of HIV infection with its resulting morbidity, mortality, and cost to individuals and society. Therefore clinicians initiating the provision of PrEP should Prescribe medication regimens that are proven safe and effective for uninfected persons who meet recommended criteria to reduce their risk of HIV acquisition Educate patients about the medications and the regimen to maximize their safe use Provide support for medication-adherence to help patients achieve and maintain protective levels of medication in their bodies Provide HIV risk-reduction support and prevention services or service referrals to help patients minimize their exposure to HIV Provide effective contraception to women who are taking PrEP and who do not wish to become pregnant Monitor patients to detect HIV infection, medication toxicities, and levels of risk behavior in order to make indicated changes in strategies to support patients' long-term health # INDICATED MEDICATION The medication proven safe and effective, and currently approved by FDA for PrEP in healthy adults at risk of acquiring HIV infection, is the fixed-dose combination of TDF and FTC in a single daily dose (see Table 9). Therefore, TDF/FTC is the recommended medication that should be prescribed for PrEP for MSM, heterosexually active men and women, and IDU who meet recommended criteria. Because TDF alone has been proven effective in trials with IDU and heterosexually active men and women, it can be considered as an alternative regimen for these specific populations. As PrEP for MSM, TDF alone is not recommended because no trials have been done, so the efficacy of TDF alone for MSM is unknown. In addition to the safety data obtained in PrEP clinical trials, data on drug interactions and longer-term toxicities have been obtained by studying the component drugs individually for their use in treatment of HIV-infected persons. Studies have also been done in small numbers of HIVuninfected, healthy adults (see Table 10). # No data WHAT NOT TO USE No antiretroviral regimens should be used for PrEP other than a daily oral dose of TDF/FTC, or a daily dose of TDF alone as an alternative only for IDU and heterosexually active adults. Other medications and other dosing schedules have not yet been shown to be safe or effective in preventing HIV acquisition among otherwise healthy adults and are not approved by FDA for PrEP.  Do not use other antiretroviral medications (e.g., 3TC), either in place of, or in addition to, TDF/FTC or TDF.  Do not use other than daily dosing (e.g., intermittent, episodic , or other discontinuous dosing)  Do not provide PrEP as expedited partner therapy (i.e., do not prescribe for an uninfected person not in your care). # TIME TO ACHIEVING PROTECTION The time from initiation of daily oral doses of TDF/FTC to maximal protection against HIV infection is unknown. There is not scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues. It has been shown that the pharmacokinetics of TDF and FTC vary by tissue 80 . Data from exploratory pharmacokinetic studies conducted with HIV-uninfected men and women does provide preliminary data on the lead-time required to achieve steady state levels of tenofovir diphosphate (TFV-DP, the activated form of the medication) in blood (PBMCs ), rectal, and vaginal tissues 81,82 . These data suggest that maximum intracellular concentrations of TFV-DP are reached in blood after approximately 20 days of daily oral dosing, in rectal tissue at approximately 7 days, and in cervicovaginal tissues at approximately 20 days. No data are yet available about intracellular drug concentrations in penile tissues susceptible to HIV infection to inform considerations of protection for male insertive sex partners. # MANAGING SIDE EFFECTS Patients taking PrEP should be informed of side effects among HIV-uninfected participants in clinical trials (see Table 5). In these trials, side effects were uncommon and usually resolved within the first month of taking PrEP ("start-up syndrome"). Clinicians should discuss the use of over-the-counter medications for headache, nausea, and flatulence should they occur. Patients should also be counseled about signs or symptoms that indicate a need for urgent evaluation (e.g., those suggesting possible acute renal injury or acute HIV infection). # CLINICAL FOLLOW-UP AND MONITORING Once PrEP is initiated, patients should return for follow-up approximately every 3 months. Clinicians may wish to see patients more frequently at the beginning of PrEP (e.g., 1 month after initiation, to assess and confirm HIV-negative test status, assess for early side effects, discuss any difficulties with medication adherence, and answer questions. All patients receiving PrEP should be seen as follows:  At least every 3 months to o Repeat HIV testing and assess for signs or symptoms of acute infection to document that patients are still HIV negative (see Figure) o Repeat pregnancy testing for women who may become pregnant o Provide a prescription or refill authorization of daily TDF/FTC for no more than 90 days (until the next HIV test) o Assess side effects, adherence, and HIV acquisition risk behaviors o Provide support for medication adherence and risk-reduction behaviors o Respond to new questions and provide any new information about PrEP use  At least every 6 months to o Monitor eCrCl If other threats to renal safety are present (e.g., hypertension, diabetes), renal function may require more frequent monitoring or may need to include additional tests (e.g., urinalysis for proteinuria) A rise in serum creatinine is not a reason to withhold treatment if eCrCl remains ≥60 ml/min. If eCrCl is declining steadily (but still ≥60 ml/min), consultation with a nephrologist or other evaluation of possible threats to renal health may be indicated. o Conduct STI testing recommended for sexually active adolescents and adults (i.e., syphilis, gonorrhea, chlamydia) 83  At least every 12 months to o Evaluate the need to continue PrEP as a component of HIV prevention OPTIONAL ASSESSMENTS # BONE HEALTH Decreases in bone mineral density (BMD) have been observed in HIV-infected persons treated with combination antiretroviral therapy (including TDF-containing regimes) 84,85 . However, it is unclear whether this 3%-4% decline would be seen in HIV-uninfected persons taking fewer antiretroviral medications for PrEP. The iPrEx trial (TDF/FTC) and the CDC PrEP safety trial in MSM (TDF) conducted serial dual-emission x-ray absorptiometry (DEXA) scans on a subset of MSM in the trials and determined that a small (~1%) decline in BMD that occurred during the first few months of PrEP either stabilized or returned to normal 20,86 . There was no increase in fragility (atraumatic) fractures over the 1-2 years of observation in these studies comparing those persons randomized to receive PrEP medication and those randomized to receive placebo. Therefore, DEXA scans or other assessments of bone health are not recommended before the initiation of PrEP or for the monitoring of persons while taking PrEP. However, any person being considered for PrEP who has a history of pathologic or fragility bone fractures or who has significant risk factors for osteoporosis should be referred for appropriate consultation and management. # THERAPEUTIC DRUG MONI TORING Similar to the limited use of therapeutic drug monitoring (TDM) in the treatment of HIV infection 66 , several factors mitigate against the routine use of TDM during PrEP. These factors include (1) a lack of established concentrations in blood associated with robust efficacy of TDF or FTC for the prevention of HIV acquisition in adults after exposure during penile-rectal or penile-vaginal intercourse 87 and (2) the limited but growing availability of clinical laboratories that perform quantitation of antiretroviral medicine concentrations under rigorous quality assurance and quality control standards. However, some clinicians may want to use TDM periodically to assess adherence to PrEP medication. If so, a key limitation should be recognized. The levels of medication in serum or plasma reflect only very recent doses, so they are not valid estimates of consistent adherence 88 . However, if medication is not detected or is detected at a very low level, support to reinforce medication adherence would be indicated. # Persons with Documented HIV Infection All persons with HIV-positive test results whether at screening or while taking TDF/FTC or TDF alone as PrEP should be provided the following services 66 .  Laboratory confirmation of HIV status (see Figure )  Determination of CD4 lymphocyte count and viral load to guide therapeutic decisions  Documentation of results of genotypic HIV viral resistance testing to guide future treatment decisions  Provision of, or referral to, an experienced provider for the ongoing medical management of HIV infection  Counseling about their HIV status and steps they should take to prevent HIV transmission to others and to improve their own health  Assistance with, or referral to, the local health department for the identification of sex partners who may have been recently exposed to HIV so that they can be tested for HIV infection, considered for nonoccupational postexposure prophylaxis (nPEP), and counseled about their risk-reduction practices 89 In addition, a confidential report of new HIV infection should be provided to the local health department. # Discontinuing PrEP Patients may discontinue PrEP medication for several reasons, including personal choice, changed life situations resulting in lowered risk of HIV acquisition, intolerable toxicities, chronic nonadherence to the prescribed dosing regimen despite efforts to improve daily pill-taking, or acquisition of HIV infection. Upon discontinuation for any reason, the following should be documented in the health record:  HIV status at the time of discontinuation  Reason for PrEP discontinuation  Recent medication adherence and reported sexual risk behavior For persons with incident HIV infection, see Persons with Documented HIV Infection. For persons with active hepatitis B infection, see Special Clinical Considerations. Any person who wishes to resume taking PrEP medications after having stopped should undergo all the same pre-prescription evaluation as a person being newly prescribed PrEP. In addition, a frank discussion should clarify the changed circumstances since discontinuing medication that indicate the need to resume medication, and the commitment to, take it, # Special Clinical Considerations The patient with certain clinical conditions requires special attention and follow-up by the clinician. # WOMEN WHO BECOME PREGNANT OR BREASTFEED WHILE TAKING PREP MEDICATION Women without HIV infection who have sex partners with documented HIV infection are at substantial risk of HIV acquisition during attempts to conceive (i.e., without a condom). In addition, pregnancy is associated with an increased risk of HIV acquisition 90 . PrEP use periconception and during pregnancy by the uninfected partner may offer an additional tool to reduce the risk of sexual HIV acquisition. Both the FDA labeling information 6 and the perinatal antiretroviral treatment guidelines 91 permit this use. However, data directly related to the safety of PrEP use for a developing fetus are limited. Providers should discuss available information about potential risks and benefits of beginning or continuing PrEP during pregnancy so that an informed decision can be made. (See Clinical Providers' Supplement, Section 5 at ). In the PrEP trials with heterosexual women, medication was promptly discontinued for those who became pregnant, so the safety for exposed fetuses could not be adequately assessed. A single small study of periconception use of TDF in 46 uninfected women in HIV-discordant couples found no ill effects on the pregnancy and no HIV infections. 92 Additionally, because TDF and FTC are widely used for the treatment of HIV infection and continued during pregnancies that occur, 76,77,93 The data on pregnancy outcomes in the Antiretroviral Pregnancy Registry provide no evidence of adverse effects among fetuses exposed to these medications 94 . Providers should educate HIV-discordant couples who wish to become pregnant about the potential risks and benefits of all available alternatives for safer conception 95 and if indicated make referrals for assisted reproduction therapies. Whether or not PrEP is elected, the HIVinfected partner should be prescribed effective antiretroviral therapy before conception attempts 96 : if the infected partner is male, to reduce the risk of transmission-related viral load in semen; and in both sexes, for the benefit of their own health 53 . In addition, health care providers are strongly encouraged to prospectively and anonymously submit information about any pregnancies in which PrEP is used to the Antiretroviral Pregnancy Registry at /. The safety of PrEP with TDF/FTC or TDF alone for infants exposed during lactation has not been adequately studied. However, data from studies of infants born to HIV-infected mothers and exposed to TDF or FTC through breast milk suggest limited drug exposure. 93,97 Additionally, the World Health Organization has recommended the use of TDF/FTC or 3TC/efavirenz for all pregnant and breastfeeding women for the prevention of perinatal and postpartum mother-tochild transmission of HIV 98 . Therefore, providers should discuss current evidence about the potential risks and benefits of beginning or continuing PrEP during breastfeeding so that an informed decision can be made. # PATIENTS WITH CHRONIC ACTIVE HEPATITIS B VIRUS INFECTION TDF and FTC are each active against both HIV infection and HBV infection and thus may prevent the development of significant liver disease by suppressing the replication of HBV. Only TDF, however, is currently FDA-approved for this use. Therefore, in persons with substantial risk of both HIV acquisition and active HBV infection, daily doses of TDF/FTC may be especially indicated. All persons screened for PrEP who test positive for hepatitis B surface antigen (HBsAg) should be evaluated by a clinician experienced in the treatment of HBV infection. For clinicians without this experience, co-management with an infectious disease or a hepatic disease specialist should be considered. Patients should be tested for HBV DNA by the use of a quantitative assay to determine the level of HBV replication 99 before PrEP is prescribed and every 6-12 months while taking PrEP. TDF presents a very high barrier to the development of HBV resistance. However, it is important to reinforce the need for consistent adherence to the daily doses of TDF/FTC to prevent reactivation of HBV infection with the attendant risk of hepatic injury, and to minimize the possible risk of developing TDF-resistant HBV infection 100 . If PrEP is no longer needed to prevent HIV infection, a separate determination should be made to about whether to continue TDF/FTC as a means of providing TDF to treat HBV infection. Acute flares resulting from the reactivation of HBV infection have been seen in HIV-infected persons after the cessation of TDF and other medications used to treat HBV infection. Such flares have not yet been seen in HIV-uninfected persons with chronic active HBV infection who have stopped taking TDF-containing PrEP regimens. Nonetheless, when such patients discontinue PrEP, they should continue to receive care from a clinician experienced in the management of HBV infection so that if flares occur, they can be detected promptly and treated appropriately. # PATIENTS WITH CHRONIC RENAL FAILURE HIV-uninfected patients with chronic renal failure, as evidenced by an eCrCl of <60 ml/min, should not take PrEP because the safety of TDF/FTC for such persons was not evaluated in the clinical trials. TDF is associated with modestly reduced renal function when used as part of an antiretroviral treatment regimen in persons with HIV infection (which itself can affect renal function). Because other HIV prevention options are available, the only PrEP regimen proven effective to date (TDF/FTC) and approved by FDA for PrEP is not indicated for persons with chronic renal failure. 6 ADOLESCENT MINORS 101 As a part of primary health care, HIV screening should be discussed with all adolescents who are sexually active or have a history of injection drug use. Parental/guardian involvement in an adolescent's health care is often desirable but is sometimes contraindicated for the safety of the adolescent. However, laws and regulations that may be relevant for PrEP-related services (including HIV testing), such as those concerning consent, confidentiality, parental disclosure, and circumstances requiring reporting to local agencies, differ by jurisdiction 5 . Clinicians considering providing PrEP to a person under the age of legal adulthood (a minor) should be aware of local laws, regulations, and policies that may apply 102 . Although the FDA labeling information specifies PrEP indications for "adults," an age above which an adolescent is considered an adult is not provided. 6 None of the completed PrEP trials have included persons under the age of 18. Therefore, clinicians should consider carefully the lack of data on safety and effectiveness of PrEP taken by persons under 18 years of age, the possibility of bone or other toxicities among youth who are still growing, and the safety evidence available when TDF/FTC is used in treatment regimens for HIV-infected youth 103 . These factors should be weighed against the potential benefit of providing PrEP for an individual adolescent at substantial risk of HIV acquisition. # NONOCCUPATIONAL POSTEXPOSURE PROPHYLAXIS Persons not receiving PrEP who seek care within 72 hours after an isolated sexual or injectionrelated HIV exposure should be evaluated for the potential need for nPEP 104 . If such exposures are not isolated, and the person is determined not to have HIV infection, clinicians should consider beginning PrEP immediately because PrEP during the first 28 days is consistent with a recommended nPEP regimen 104 . If the exposure is isolated (e.g., sexual assault, infrequent condom failure), nPEP should be prescribed, but continued antiretroviral medication is not indicated after completion of the 28-day PEP course. Persons who repeatedly seek nPEP should be evaluated for possible PrEP use after confirming they have not acquired HIV infection 105 . Because HIV infection has been reported in association with exposures soon after an nPEP course 98 , daily PrEP may be more protective than repeated episodes of nPEP. # Improving Medication Adherence Data from the published studies of daily oral PrEP indicate that medication adherence is critical to achieving the maximum prevention benefit (see Table 4) and reducing the risk of selecting for a drug-resistant virus if non-adherence leads to HIV acquisition 106,107 . Three additional studies reinforce the need to prescribe, and support adherence to uninterrupted daily doses of TDF/FTC. A study of the pharmacokinetics of directly observed TDF dosing in MSM in the STRAND trial found that the intracellular levels of the active form of TDF (tenofovir diphosphate), when applied to the drug detection-efficacy statistical model with iPrEx participants, corresponded to an HIV risk reduction efficacy of 99% for 7 doses per week, 96% for 4 doses per week, and 76% for 2 doses per week 87 . This finding adds to the evidence that despite some "forgiveness" for occasional missed doses, a high level of prevention efficacy requires a high level of adherence to daily medication. A pilot study of daily TDF/FTC as PrEP with young MSM was stopped when the iPrEx trial results were reported. 108 Among the 68 men enrolled (mean age, 20 years; 53% African American; 40% Hispanic/Latino) plasma specimens were tested to objectively measure medication adherence. At week 4, 63% had detectable levels of tenofovir, but at week 24, only 20% had detectable levels of tenofovir. In addition, a study with MSM and commercial sex workers in Kenya evaluated adherence to daily, fixed-interval (Mondays and Fridays), and coitally-timed (single post-coital) TDF/FTC dosing schedules by the use of pill bottles with caps monitored by an electronic medication event monitoring system (MEMS) and monthly interviews about sexual behavior 12 . Among the 67 men and 5 women in this study, 83% adhered to daily dosing, 55% to fixed-interval dosing, and 26% to post-coital dosing regimens. These findings suggest that adherence is better with daily dosing, as currently recommended, than with non-daily regimens (not yet proven effective as PrEP). These data confirm that medication education and adherence counseling (also called medication self-management) will need to be provided to support daily PrEP use. A recent review of the antiretroviral treatment adherence studies over the past 15 years and adherence data from the completed PrEP trials suggests various approaches to effectively support medication adherence 109 . These approaches include educating patients about their medications; helping them anticipate and manage side effects; helping them establish dosing routines that mesh with their work and social schedules; providing reminder systems and tools; addressing financial, substance abuse, or mental health needs that may impede adherence; and facilitating social support. Although many published articles address antiretroviral medication adherence among persons being treated for HIV infection, these findings may be only partially applicable to PrEP users. HIV treatment regimens include more than 2 drugs (commonly including more than 1 pill per day), resulting in an increased pill burden, and the possibility of side effects and toxicities with 3 or more drugs may occur that would not occur with TDF/FTC alone. The motivations of persons being treated for HIV infection and persons trying to prevent HIV infection may differ. Because PrEP will be used in otherwise healthy adults, studies of the use of medications in asymptomatic adults for the prevention of potential serious future health outcomes may also be informative for enhancing adherence to PrEP medications. The most cost-effective interventions for improving adherence to antihypertensive and lipid-lowering medications were initiated soon after the patients started taking medication and involved personalized, regularly scheduled education and symptom management (patients were aware that adherence was being monitored) 110 . Patients with chronic diseases reported that the most important factors in adherence to medications were incorporating medication into their daily routines, knowing that the medications work, believing that the benefits outweigh the risks, knowing how to manage side effects, and low out-of pocket costs. 111,112 When initiating a PrEP regimen, clinicians must educate patients so that they understand clearly how to take their medications (i.e., when to take them, how many pills to take at each dose) and what to do if they experience problems (e.g., what constitutes a missed dose , what to do if they miss a dose). Patients should be told to take a single missed dose as soon as they remember it, unless it is almost time for the next dose. If it is almost time for the next dose, patients should skip the missed dose and continue with the regular dosing schedule. Side effects can lead to non-adherence, so clinicians need a plan for addressing them. Clinicians should tell patients about the most common side effects and should work with patients to develop a specific plan for handling them, including the use of specific over-the-counter medications that can mitigate symptoms 113 . The importance of using condoms during sex, especially for patients who decide to stop taking their medications, should be reinforced. # Box D: Key Components of Medication Adherence Counseling Using a broad array of a health care professionals (e.g., physicians, nurses, case-managers, physician assistants, clinic-based and community pharmacists) that work together on a health care team to influence and reinforce adherence instructions 114 significantly improves medication adherence and may alleviate the time constraints of individual providers. 115,116 This broad-team approach may also provide a larger number of providers to counsel patients about selfmanagement of behavioral risks. For additional information on adherence counseling, see the Clinical Providers' Supplement, Section 6 at . # Reducing HIV Risk Behaviors The adoption and the maintenance of safer behaviors (sexual, injection, and other substance abuse) are critical for the lifelong prevention of HIV infection and are important for the clinical management of persons prescribed PrEP. 117 have reduced STI incidence in a general clinic population. However, they take a general approach, so they do not allow tailoring to the sexual risk-reduction needs of individual patients (e.g., as partners change, PrEP is initiated or discontinued). # Establish trust and bidirectional communication Interactive, client-centered counseling (in which content is tailored to a patient's sexual risk behaviors and the situations in which risks occur), in conjunction with goal-setting strategies is effective in HIV prevention 105, . An example of this method is Project Respect: although this counseling protocol alone did not reduce HIV incidence significantly 20-minute clinical counseling sessions to develop and review patient-specific, incremental risk-reduction plans led to reduced incidence of STIs in a heterosexual population, 121 . Project Aware included MSM and heterosexuals attending STD clinics and provided a single brief counseling session (using the Respect-2 protocol) while conducting rapid HIV testing. There was no reduction in the incidence of STIs attributed to counseling 122 . However, in the context of PrEP delivery, brief, repeated counseling sessions can take advantage of multiple visits for follow-up care 123 while addressing the limited time available for individual visits 124 and the multiple prevention 115,116 and treatment topics that busy practitioners need to address. Reducing or eliminating injection risk practices can be achieved by providing access to drug treatment and relapse prevention services (e.g., methadone, buprenorphine for opiate users) for persons who are willing to participate 125 . For persons not able (e.g., on a waiting list or lacking insurance) or not motivated to engage in drug treatment, providing access to unused injection equipment through syringe service programs (where available), prescriptions for syringes or purchase from pharmacies without a prescription (where legal) can reduce HIV exposure. In addition, providing or referring for cognitive or behavioral counseling and any indicated mental health or social services may help reduce risky injection practices. See the Substance Abuse Treatment and Mental Health Treatment Locators at /. For additional information on risk reduction interventions, see Clinical Providers' Supplement, Section 7 at . # Box E: Key Components of Behavioral Risk-Reduction Counseling # Financial Case-Management Issues for PrEP One critical component in providing PrEP medications and related clinical and counseling services is identifying insurance and other reimbursement sources. Although some commercial insurance and employee benefits programs have defined policies for the coverage of PrEP, others have not yet done so. Similarly, public insurance sources vary in their coverage policy. For patients who do not have health insurance, whose insurance does not cover PrEP medication, and whose personal resources are inadequate to pay out-of-pocket, Gilead Sciences has established a PrEP medication assistance program. In addition to providing Truvada to providers for eligible patients and access to free HIV testing, the program provides co-pay assistance for medical care visits and free condoms to patients on request 126 . Providers may obtain applications for their patients at /. # Decision Support, Training and Technical Assistance Decision support systems (electronic and paper), flow sheets, checklists (see Clinical Providers' Supplement, Section 1 for a PrEP provider/patient checklist at ), feedback reminders, and involvement of nurse clinicians and pharmacists will be helpful in managing the many steps indicated for the safe use of PrEP and to increase the likelihood that patients will follow them. Often these systems are locally developed but may become available from various sources including training centers and Web sites funded by government agencies; professional associations, or interested private companies. Examples include downloadable applications (widgets) to support the delivery of nPEP or locate nearby sites for confidential HIV tests (); and confidential commercial services to electronically monitor # Related DHHS Guidelines This document is consistent with several other guidelines from several DHHS agencies related to sexual health, HIV prevention, and the use of antiretroviral medications. Clinicians should refer to these other documents for detailed guidance in their respective areas of care. # III. Expert opinion The quality of scientific evidence ratings in Table 2 are based on the GRADE rating system. 28 # Appendices # APPENDIX 1 HIV TEST TABLES The working groups and expert panels listed here were convened by teleconference before trial results were available (2009-2010) and some were reconvened after each trial results for each population group was published. As technical experts, prevention partners, and key stakeholders, they were asked to assist us to identify relevant scientific/medical literature and share thoughts on topics that would inform the development of possible future guidelines for PrEP use in the US. They did not participate in the writing of these guidelines. No financial disclosures were sought. See Providers' Supplement section 10 for a description of the criteria use for constitution of the working groups. Institutional associations listed for participants are those at the time of the group discussions and may have changed since.

This report is being published as a courtesy to both the National Association of State Public Health Veterinarians, Inc., and to the MMWR readership. Its publication does not imply endorsement by CDC.# Copies also can be accessed at the CDC website at and the American Veterinary Medical Association website at . # Compendium of Measures To Control Chlamydia psittaci Infection Among Humans (Psittacosis) and Pet Birds (Avian Chlamydiosis), 2000 # INTRODUCTION Chlamydia psittaci is a bacterium that can be transmitted from pet birds to humans. In humans, the resulting infection is referred to as psittacosis (also known as parrot fever and ornithosis). Psittacosis typically causes influenza-like symptoms and can lead to severe pneumonia and nonrespiratory health problems. With appropriate treatment, the disease is rarely fatal. From 1988 through 1998, CDC received reports of 813 cases of psittacosis (1 ), which is an underrepresentation of the actual number of cases because psittacosis is difficult to diagnose and cases often go unreported. During the 1980s, approximately 70% of the psittacosis cases with a known source of infection resulted from exposure to pet birds. The largest group affected (43%) included bird fanciers and owners of pet birds. Pet shop employees accounted for an additional 10% of cases. Other persons at risk include pigeon fanciers and persons whose occupation places them at risk for exposure (e.g., employees in poultry slaughtering and processing plants, veterinarians, veterinary technicians, laboratory workers, workers in avian quarantine stations, farmers, wildlife rehabilitators, and zoo workers). Because human infection can result from brief, passing exposure to infected birds or their contaminated droppings, persons with no identified leisure-time or occupational risk can become infected. In this report, C. psittaci infection in birds is referred to as avian chlamydiosis (AC). C. psittaci has been isolated from approximately 100 bird species but is most commonly identified in psittacine (parrot-type) birds, especially cockatiels and parakeets. Among caged, nonpsittacine birds, infection with C. psittaci occurs most frequently in pigeons, doves, and mynah birds. AC is less frequently diagnosed in canaries and finches. The recommendations in this compendium provide standardized procedures for controlling AC in the pet bird population, an essential step in efforts to control psittacosis among humans. Development of and participation in aviary and pet shop accreditation programs is encouraged. This compendium is intended to guide public health officials, physicians, veterinarians, the pet bird industry, and others concerned with the control of C. psittaci infection and the protection of public health. # PART I. INFECTION AMONG HUMANS (PSITTACOSIS) Transmission Because several diseases affecting humans can be caused by other species of Chlamydia, the disease resulting from the infection of humans with C. psittaci is referred to as psittacosis. Most C. psittaci infections in humans result from exposure to pet psittacine birds. However, transmission has been documented from free-ranging birds, including doves, pigeons, birds of prey, and shore birds. Infection with C. psittaci usually occurs when a person inhales the organism, which has been aerosolized from dried feces or respiratory secretions of infected birds. Other means of exposure include mouth-to-beak contact and the handling of infected birds' plumage and tissues. Even brief exposures can lead to symptomatic infection; therefore, some patients with psittacosis might not recall or report having any contact with birds. Mammals occasionally transmit C. psittaci to humans. Certain strains of C. psittaci infect sheep, goats, and cattle, causing chronic infection of the reproductive tract, placental insufficiency, and abortion in these animals. These strains of C. psittaci are transmitted to persons when they are exposed to the birth fluids and placentas of infected animals. Another strain of C. psittaci, feline keratoconjunctivitis agent, typically causes rhinitis and conjunctivitis in cats. Transmission of this strain from cats to humans rarely occurs. Person-to-person transmission has been suggested but not proven. Standard infection-control precautions are sufficient for patients with psittacosis, and specific isolation procedures (e.g., private room, negative pressure air flow, and masks) are not indicated. # Clinical Signs and Symptoms The onset of illness typically follows an incubation period of 5-14 days, but longer periods have been reported. The severity of this disease ranges from inapparent illness to systemic illness with severe pneumonia. Before antimicrobial agents were available, 15%-20% of persons with C. psittaci infection died. However, <1% of properly treated patients now die as a result of the infection. Persons with symptomatic infection typically have abrupt onset of fever, chills, headache, malaise, and myalgia. They usually develop a nonproductive cough that can be accompanied by breathing difficulty and chest tightness. A pulse-temperature dissociation (fever without elevated pulse), enlarged spleen, and rash are sometimes observed and are suggestive of psittacosis in patients with community-acquired pneumonia. Auscultatory findings can underestimate the extent of pulmonary involvement. Radiographic findings include lobar or interstitial infiltrates. The differen-tial diagnosis of psittacosis-related pneumonia includes infection with Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses such as influenza. C. psittaci can affect organ systems other than the respiratory tract and result in endocarditis, myocarditis, hepatitis, arthritis, keratoconjunctivitis, and encephalitis. Severe illness with respiratory failure, thrombocytopenia, hepatitis, and fetal death has been reported among pregnant women. # Case Definitions In 1997, CDC and the Council of State and Territorial Epidemiologists established case definitions for confirmed and probable psittacosis for epidemiologic purposes (2 ). These definitions should not be used as the sole criteria for establishing clinical diagnoses. A patient is considered to have a confirmed case of psittacosis if clinical illness is compatible with psittacosis and the case is laboratory confirmed by one of three methods: a) C. psittaci is cultured from respiratory secretions; b) antibody against C. psittaci is increased by fourfold or greater (to a reciprocal titer of 32 between paired acute-and convalescent-phase serum specimens collected at least 2 weeks apart) as demonstrated by complement fixation (CF) or microimmunofluorescence (MIF); or c) immunoglobulin M antibody is detected against C. psittaci by MIF (to a reciprocal titer of 16). A patient is considered to have a probable case of psittacosis if clinical illness is compatible with psittacosis and a) the patient is epidemiologically linked to a confirmed human case of psittacosis or b) a single antibody titer of 32, demonstrated by CF or MIF, is present in at least one serum specimen obtained after onset of symptoms. # Diagnosis Most diagnoses are established by using serologic methods in which paired sera are tested for chlamydial antibodies by CF test. However, because chlamydial CF antibody is not species-specific, high CF titers also can result from C. pneumoniae and C. trachomatis infections. Acute-phase serum specimens should be obtained as soon as possible after onset of symptoms, and convalescent-phase serum specimens should be obtained 2 weeks after onset of symptoms. Because antibiotic treatment can delay or diminish the antibody response, a third serum sample might help confirm the diagnosis. All sera should be tested simultaneously at the same laboratory. If the patient's epidemiologic and clinical history indicate a possible diagnosis of psittacosis, MIF and polymerase chain reaction (PCR) assays can be used to distinguish C. psittaci infection from infection with other chlamydial species. The infectious agent also can be isolated from the patient's sputum, pleural fluid, or clotted blood during acute illness and before treatment with antimicrobial agents; however, culture of C. psittaci is performed by few laboratories because of technical difficulty and safety concerns. # Laboratories that Test Human Specimens for C. psittaci Information about laboratory testing is available from most state public health laboratories. Few commercial laboratories have the capability to differentiate Chlamydia species. The following laboratories (Table 1) accept human specimens to confirm C. psittaci. Other sources might be available. # Treatment Tetracyclines are the drugs of choice (3 ). Most patients respond to oral therapy (100 mg of doxycycline administered twice a day or 500 mg of tetracycline hydrochloride administered four times a day). For initial treatment of severely ill patients, doxycycline hyclate can be administered intravenously at a dosage of 4.4 mg/kg (2 mg/lb) body weight per day divided into two infusions per day (up to 100 mg per dose). Remission of symptoms usually is evident within 48-72 hours. However, relapse can occur, and treatment must continue for at least 10-14 days after fever abates. Although its in vivo efficacy has not been determined, erythromycin probably is the best alternative agent in patients for whom tetracycline is contraindicated (e.g., children aged <9 years and pregnant women). # PART II. INFECTION AMONG BIRDS (AVIAN CHLAMYDIOSIS) Transmission C. psittaci is excreted in the feces and nasal discharges of infected birds. The organism is resistant to drying and can remain infectious for several months. If infected, birds can appear healthy and shed the organism intermittently. Shedding can be activated by stress factors, including shipping, crowding, chilling, and breeding (3 ). # Clinical Signs The time between exposure to C. psittaci and onset of illness ranges from 3 days to several weeks. However, active disease can appear years after exposure. Whether the bird exhibits acute or chronic signs of illness or dies depends on the species of bird, virulence of the strain, infectious dose, stress factors, age, and extent of treatment or prophylaxis (4 ). Signs of AC include lethargy, anorexia, and ruffled feathers, similar to signs of other systemic illnesses. Other signs include serous or mucopurulent ocular or nasal discharge, diarrhea, and excretion of green to yellow-green urates. Anorectic birds can produce sparse, dark green droppings, followed by emaciation, dehydration, and death. # Case Definitions A confirmed case of AC is defined on the basis of at least one of the following laboratory results: a) isolation of C. psittaci from a clinical specimen, b) identification of chlamydial antigen by immunofluorescence (fluorescent antibody ) of the bird's tissues, c) a greater than fourfold change in serologic titer in two specimens from the bird obtained at least 2 weeks apart and assayed simultaneously at the same laboratory, or d) identification of C. psittaci within macrophages in smears stained with Gimenez or Macchiavellos stain or sections of the bird's tissues. A probable case of AC is defined as compatible illness and at least one of the following laboratory results: a) a single high serologic titer in one or more specimens obtained after the onset of signs or b) the presence of C. psittaci antigen (identified by enzyme-linked immunosorbent assay , PCR, or FA) in feces, a cloacal swab, or respiratory or ocular exudates. A suspected case of AC is defined as a) compatible illness that is epidemiologically linked to another case in a human or bird but that is not laboratory confirmed, b) a subclinical infection with a single high serologic titer or detection of chlamydial antigen, c) compatible illness with positive results from a nonstandardized test or a new investigational test, or d) compatible illness that is responsive to appropriate therapy. # Diagnosis Several diagnostic methods are available for identifying AC in birds (Appendix A). # Treatment Treatment should be supervised by a licensed veterinarian (Appendix B). # PART III. RECOMMENDATIONS AND REQUIREMENTS # Recommendations for Controlling Infection Among Humans and Birds To prevent transmission of C. psittaci to persons and birds, the following control measures are recommended: - Protect persons at risk. Inform all persons in contact with infected birds about the nature of the disease. Instruct them to wear protective clothing, gloves, a disposable surgical cap, and a respirator with an N95 rating or a higher-efficiency respirator when cleaning cages or handling infected birds. Surgical masks might not be effective in preventing transmission of C. psittaci. When necropsies are performed on potentially infected birds, wet the carcass with detergent and water to prevent aerosolization of infectious particles and work under a biological safety cabinet (or equivalent). - Maintain accurate records of all bird-related transactions to aid in identifying sources of infected birds and potentially exposed persons. Records should include the date of purchase, species of birds purchased, source of birds, and any identified illnesses or deaths among birds. In addition, the seller should record the name, address, and telephone number of the customer and the band numbers if applicable. - Avoid purchasing or selling birds that have signs of AC. Signs include ocular or nasal discharge, diarrhea, or low body weight. - Isolate newly acquired birds. Isolate the birds -including those that have been to shows, exhibitions, fairs, and other events -for 30-45 days, and test or prophylactically treat them before adding them to a group. - Test birds before they are to be boarded or sold on consignment. House them in a room separate from other birds. - Practice preventive husbandry. Position cages to prevent the transfer of fecal matter, feathers, food, and other materials from one cage to another. Do not stack cages, and be sure to use solid-sided cages or barriers if cages are adjoining. The bottom of the cage should be made of a wire mesh. Litter that will not produce dust (e.g., newspapers) should be placed underneath the mesh. Clean all cages, food bowls, and water bowls daily. Soiled bowls should be emptied, cleaned with soap and water, rinsed, placed in a disinfectant solution, and rinsed again before reuse. Between occupancies by different birds, cages should be thoroughly scrubbed with soap and water, disinfected, and rinsed in clean, running water. Exhaust ventilation should be sufficient to prevent accumulation of aerosols. - Prevent the spread of infection. Isolate birds requiring treatment. Rooms and cages where infected birds were housed should be cleaned immediately and disinfected thoroughly. When the cage is being cleaned, transfer the bird to a clean cage. Thoroughly scrub the soiled cage with a detergent to remove all fecal debris, rinse the cage, disinfect it (allowing at least 5 minutes of contact with the disinfectant), and rerinse the cage to remove the disinfectant. Discard all items that cannot be adequately disinfected (e.g., wooden perches, ropes, nest material, and litter). Minimize the circulation of feathers and dust by wetmopping the floor frequently with disinfectants and preventing air currents and drafts within the area. Reduce contamination from dust by spraying the floor with a disinfectant or water before sweeping it. Do not use a vacuum cleaner, as it can aerosolize infectious particles. Frequently remove waste material from the cage (after moistening the material), and burn or double-bag the waste for disposal. Care for healthy birds before handling isolated or sick birds. - Use disinfection measures. C. psittaci is susceptible to most disinfectants and detergents as well as heat; however, it is resistant to acid and alkali. A 1:1,000 dilution of quaternary ammonium compounds (e.g., Roccal ® or Zephiran ® ) is effective, as is 70% isopropyl alcohol, 1% Lysol ® , 1:100 dilution of household bleach (i.e., 2.5 tablespoons per gallon), or chlorophenols. Many disinfectants are respiratory irritants and should be used in a well-ventilated area. Avoid mixing disinfectants with any other product. # Recommendations for Treating and Caring for Infected Birds All birds with confirmed or probable AC should be isolated and treated, preferably under the supervision of a veterinarian (Appendix B). Birds with suspected AC or birds previously exposed to AC should be isolated and retested or treated. Because treated birds can be reinfected, they should not be exposed to untreated birds or other potential sources of infection. To prevent reinfection, contaminated aviaries should be thoroughly cleaned and sanitized. No AC vaccines are available. The following general recommendations should be followed when treating and caring for birds with confirmed, probable, or suspected cases of AC: - Protect birds from undue stress (e.g., chilling or shipping), poor husbandry, and malnutrition. These problems reduce the effectiveness of treatment and promote the development of secondary infections with other bacteria or yeast. - Observe the birds daily, and weigh them every 3-7 days. If the birds are not maintaining weight, have them reevaluated by a veterinarian. - Avoid high dietary concentrations of calcium and other divalent cations because they inhibit the absorption of tetracyclines. Remove oyster shell, mineral blocks, and cuttlebone. - Isolate birds that are to be treated in clean, uncrowded cages. - Clean up all spilled food promptly; wash food and water containers daily. - Provide fresh water and appropriate vitamins daily. - Continue medication for the full treatment period to avoid relapses. Birds can appear clinically improved and have reduced chlamydial shedding after 1 week. # Responsibilities of Physicians and Veterinarians Persons exposed to birds with AC should seek medical attention if they develop influenza-like symptoms or other respiratory illness. The physician should collect specimens for laboratory analysis (see Part I) and initiate early and specific treatment for psittacosis. Most states require physicians to report cases of psittacosis to the appropriate state or local health authorities. Timely diagnosis and reporting can help identify the source of infection and control the spread of disease. Local and state authorities may conduct epidemiologic investigations and institute additional disease control measures (see Local and State Epidemiologic Investigations). Birds that are suspected sources of human infection should be referred to veterinarians for evaluation and treatment. Veterinarians should be aware that AC is not a rare disease among pet birds. They should consider a diagnosis of AC for any lethargic bird that has nonspecific signs of illness, especially if the bird was purchased recently. If AC is suspected, the veterinarian should submit appropriate laboratory specimens to confirm the diagnosis. Laboratories and attending veterinarians should follow local and state regulations or guidelines regarding case reporting. Veterinarians should work closely with authorities on investigations and inform clients that infected birds should be isolated and treated. In addition, they should educate clients about the public health hazard posed by AC and the appropriate precautions that should be taken to avoid the risk for transmission. # Quarantine of Birds The appropriate animal and public health authorities may issue a quarantine for all affected and susceptible birds on a premises where C. psittaci infection has been identified. The purpose of imposing a quarantine is to prevent further disease transmission. Reasonable options should be made available to the owners and operators of pet stores. For example, with the approval of state or local authorities, the owner of quarantined birds may choose to a) treat the birds in a separate quarantine area to prevent exposure to the public and other birds, b) sell the birds if they have completed at least 7 days of treatment, provided that the new owner agrees in writing to continue the quarantine and treatment and is informed of the disease hazards, or c) euthanize the infected birds. After completion of the treatment or removal of the birds, a quarantine can be lifted when the infected premises are thoroughly cleaned and disinfected. The area can then be restocked with birds. # Bird Importation Regulations The Veterinary Services of the Animal and Plant Health Inspection Service, U.S. Department of Agriculture (USDA), regulates the importation of pet birds to ensure that exotic poultry diseases are not introduced into the United States. These regulations are set forth in the Code of Federal Regulations, Title 9, Chapter 1 (5 ). Current minimum treatment protocols under these regulations are not always sufficient to clear AC from all birds. Illegally smuggled birds are also a source of new AC infection to domestic flocks. In general, current USDA regulations regarding the importation of birds include the following requirements: - Before shipping the birds, the importer must obtain an import permit from the USDA and a health certificate issued and/or endorsed by a veterinarian of the national government of the exporting country. - A USDA veterinary inspection must be conducted at the first port of entry in the United States and a quarantine be imposed for a minimum of 30 days at a USDAapproved facility to determine whether the birds are free of evidence of communicable diseases of poultry. In addition, the birds must be tested to ensure they are free of exotic Newcastle disease and pathogenic avian influenza. - During the 30-day U.S. quarantine, psittacine birds must receive a balanced, medicated feed ration containing >1% chlortetracycline (CTC) with <0.7% calcium for the entire quarantine period as a precautionary measure against AC. The USDA recommends that importers continue CTC prophylactic treatment of psittacine birds for an additional 15 days (i.e., for 45 continuous days). # Local and State Epidemiologic Investigations Public health or animal health authorities at the local or state level might need to conduct epidemiologic investigations to help control the transmission of C. psittaci to humans and birds. An epidemiologic investigation should be initiated if a) a bird with confirmed or probable AC was procured from a pet store, breeder, or dealer within 60 days of the onset of signs of illness, b) a person has confirmed or probable psittacosis, or c) several suspect avian cases have been identified from the same source. Other situations can be investigated at the discretion of the appropriate local or state public health department or animal health authorities. Investigations involving recently purchased birds should include a visit to the site where the infected bird is located and identification of the location where the bird was originally procured (e.g., pet shop, dealer, breeder, or quarantine station). During such investigations, authorities should consider documenting the number and types of birds involved, the health status of potentially affected persons and birds, locations of facilities where birds were housed, relevant ventilation-related factors, and any treatment protocol. Examination of sales records for other birds that had contact with the infected bird may be considered. To help identify multistate outbreaks of C. psittaci infection, local and state authorities should report suspected outbreaks to the Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, telephone (404) 639-2215. # METHODS FOR DIAGNOSING AVIAN CHLAMYDIOSIS # Pathologic Findings In birds that have avian chlamydiosis (AC), cloudy air sacs and an enlarged liver and spleen usually are observed, but no specific gross lesion is pathognomonic. The chromatic or immunologic staining of tissue-impression smears can be used to identify organisms. # Culture Technique Isolation of the etiologic agent, Chlamydia psittaci, from the bird's spleen, liver, air sacs, pericardium, heart, or intestines is the optimal means for verifying the diagnosis. Chlamydia species are obligate intracellular bacteria that must be isolated in tissue culture, mice, or chick embryos. Specialized laboratory facilities and training are necessary for reliable identification of chlamydial isolates and adequate protection of microbiologists. Consequently, few laboratories perform chlamydial cultures. In live birds, depending on which clinical signs they exhibit, combined choanal and cloacal swab specimens should be collected, refrigerated, and sent to the laboratory packed in ice but not frozen. The proper handling of samples is critical for maintaining the viability of organisms for culture, and a special transport medium is required. The diagnostic laboratory should be contacted for specific procedures required for collection and submission of specimens. Live birds being screened for C. psittaci might not shed the microorganism daily. Therefore, to reduce laboratory costs, serial specimens should be collected for 3-5 consecutive days and pooled before being cultured. Tissue samples from the bird's liver and spleen are the preferred necropsy specimens for isolation of C. psittaci. Use of culture is recommended to avoid limitations associated with other tests. # Tests for Antibody A positive serologic test result is evidence that the bird was infected by C. psittaci at some point, but it might not indicate that the bird has an active infection. False-negative results can occur for birds that have acute infection when they are sampled before seroconversion. Treatment with an antimicrobial agent can diminish the antibody response. A single testing method might not be adequate because of the diversity of reactions with immunoglobulins from the various avian species. Therefore, use of a combination of antibody-and antigen-detection methods is recommended, particularly when only one bird is tested. When specimens are obtained from a single bird, serologic testing is most useful when a) signs of disease and the history of the flock or aviary are considered and b) serologic results are compared with the white blood cell counts and liverenzyme activities. A greater than fourfold increase in titer of paired samples or a combination of a titer and antigen identification is needed to confirm a diagnosis of AC. Some of the advantages and disadvantages of two serologic tests for antibodies are described in the following sections. # Direct Complement Fixation (CF) Direct CF is more sensitive than agglutination methods. False-negative results are possible in specimens from small psittacine birds (e.g., budgerigars, young African grey parrots, and lovebirds). High titers can persist after treatment and complicate interpretation of subsequent tests. Modified direct CF is more sensitive than direct CF. # Elementary-Body Agglutination (EBA) EBA is commercially available and can detect early infection. Titers >10 in budgerigars, cockatiels, and lovebirds and titers >20 in larger birds are frequently seen in cases of recent infection. However, elevated titers can persist after treatment is completed. # Tests for Antigen Enzyme-Linked Immunosorbent Assay (ELISA) ELISA tests (e.g., QuickView ® ) were originally developed for identification of Chlamydia trachomatis in humans. The exact sensitivity and specificity of these tests for identifying C. psittaci are not known. They are now used to identify C. psittaci in birds. These tests give rapid results and do not require live, viable organisms; however, falsepositive results from cross-reacting antigens can occur. False-negative results can occur if insufficient antigen is present. As with all nonculture tests, the results must be evaluated in conjunction with clinical findings. If a bird has a positive ELISA result but is clinically healthy, the veterinarian should attempt to verify that the bird is shedding antigen through isolation of the organism. When a clinically ill bird has a negative ELISA result, a diagnosis of AC cannot be excluded without further testing (e.g., culture, serologic testing, or polymerase chain reaction). # Immunofluorescent Antibody Tests (IFA) Monoclonal or polyclonal antibodies, fluorescein-staining techniques, and fluorescent microscopy are used to identify the organism in impression smears or other specimens. These tests have similar advantages and disadvantages as ELISA. # Polymerase Chain Reaction (PCR) Numerous laboratories offer diagnostic testing using PCR technology. The PCR test promises to be sensitive and specific for detection of target DNA sequences in collected specimens (e.g., choanal and cloacal swabs, blood). Results from tests that have not been validated can be difficult to interpret. # Additional Tests Additional diagnostic techniques are in use or under development. Readers are encouraged to research peer-reviewed reports on such tests before use. Although these treatment protocols are usually successful, knowledge is evolving and no protocol assures safe treatment or complete elimination of infection. Therefore, treatment for avian chlamydiosis (AC) should be supervised by a licensed veterinarian. In quarantine situations, compliance might be easiest to monitor when treatment is provided by medicated feed. All birds with AC should be treated for 45 days, except as noted in the following sections. # Medicated Feed Medicated feed should be the only food provided to the birds during the entire treatment. Birds' acceptance of medicated feed is variable. Thus, food consumption should be monitored. Acceptance can be enhanced by first adapting the birds to a similar, nonmedicated diet. Treatment begins when the birds accept the medicated feed as the sole food in their diet. The following options are available: q Medicated mash diets (i.e., >1% chlortetracycline with <0.7% calcium) prepared with corn, rice, and hen's scratch can be used. - Pellets and extruded products containing 1% CTC can be used. They are available and appropriate for use with most pet birds. Select a pellet size appropriate for the size of bird being treated. - A special diet might be necessary for lories and lorikeets, which feed on nectar and fruit in the wild. # Medicated Water Limited pharmacological studies indicate that dosages of 400 mg doxycycline hyclate/liter of water in cockatiels and 400-600 mg/liter of water in African grey parrots, blue-fronted Amazon parrots, and Goffin's cockatoos will maintain therapeutic concentrations (Keven Flammer, North Carolina State University, unpublished data, 2000). Research data are lacking for other species, but empiric use of 400-mg/liter of water has been successful for many psittacine birds (excluding budgerigars). Drug toxicity can occur when using this regimen, so an experienced avian veterinarian should monitor birds during treatment. Signs of toxicity include general signs of illness (depression, inactivity, decreased appetite), green or yellow stained urine, and altered hepatic tests (elevated aspartate aminotransferase , lactate dehydrogenase , and bile acids). If toxicity occurs, medication should be immediately stopped and supportive care provided until the bird recovers. Treatment with a different regimen can be started at a later date. # Oral Doxycycline Doxycycline is the drug of choice for oral treatment; either the monohydrate or calcium-syrup formulations can be used. Dosage recommendations are as follows: 40-50 mg/kg body weight by mouth once a day for cockatiels, Senegal parrots, and bluefronted and orange-winged Amazon parrots; and 25 mg/kg body weight by mouth once a day for African grey parrots, Goffin's cockatoos, blue and gold macaws, and greenwinged macaws. Precise dosages cannot be extrapolated for other species; however, 25-30 mg/kg body weight administered by mouth once a day is the recommended starting dosage for cockatoos and macaws, and 25-50 mg/kg by mouth once a day is recommended for other psittacine species. If the bird regurgitates the drug, another treatment method should be used. # Injectable Doxycycline Intramuscular (IM) injection into the pectoral muscle is often the easiest method of treatment, but not all injectable doxycycline formulations are suitable for IM injection. All available formulations can cause irritation at the injection site. The Vibrovenos® formulation (Pfizer Laboratories, London) is available in Europe and is effective if administered at doses of 75-100 mg/kg body weight IM every 5-7 days for the first 4 weeks and subsequently every 5 days for the duration of treatment. The injectable hyclate formulation labeled for intravenous (IV) use in humans can be used IV in birds. This formulation is not suitable for IM use because severe tissue reactions will occur at the site of injection. # Injectable Oxytetracycline Limited information exists for the use of an injectable, long-acting oxytetracycline product (LA-200®; Pfizer Laboratories, Exton, Pennsylvania). Current dosage recommendations are as follows: subcutaneous injection of 75 mg/kg body weight every 3 days in Goffin's cockatoos, blue-fronted and orange-winged Amazon parrots, and blue and gold macaws. This dosage might be suitable for but has not been tested on other species. This product causes irritation at the site of injection and is best used to initiate treatment in ill birds or those that are reluctant to eat. After stabilization with oxytetracycline treatment, the birds should be switched to another form of treatment to reduce the muscle irritation that is caused by repeated oxytetracycline injection. # Experimental Methods Treatment protocols using late-generation macrolides and pharmacist-compounded injectable doxycycline are under investigation. Information about these treatment protocols might be available in the scientific literature or from avian veterinary specialists. # Sources of Medications The following sources (Table B) are not listed as an endorsement of the companies or products. Other sources might be available. 1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk for infection, provided that liberal portions of the exposed area are discarded. Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months. 2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption. Pasteurization temperatures will inactivate rabies virus; therefore, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure. 3) Having more than one rabid animal in a herd or having herbivore-toherbivore transmission is rare; therefore, restricting the rest of the herd if a single animal has been exposed to or infected by rabies might not be necessary. c. Other Animals. Other animals bitten by a rabid animal should be euthanized immediately. Animals maintained in USDA-licensed research facilities or accredited zoological parks should be evaluated on a case-by-case basis. 6. Management of Animals That Bite Humans. a. A healthy dog, cat, or ferret that bites a person should be confined and observed daily for 10 days; administration of rabies vaccine is not recommended during the observation period. Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be euthanized, its head removed, and the head shipped under refrigeration (not frozen) for examination of the brain by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted as described above for rabies examination. b. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Prior vaccination of an animal might not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species. Management of animals other than dogs, cats, and ferrets depends on the species, the circumstances of the bite, the epidemiology of rabies in the area, and the biting animal's history, current health status, and potential for exposure to rabies. # C. Control Methods in Wildlife The public should be warned not to handle wildlife. Wild mammals and hybrids that bite or otherwise expose persons, pets, or livestock should be considered for euthanasia and rabies examination. A person bitten by any wild mammal should immediately report the incident to a physician who can evaluate the need for antirabies treatment (See current rabies prophylaxis recommendations of the ACIP*). State-regulated wildlife rehabilitators may play a role in a comprehensive rabies-control program. Minimum standards for persons who rehabilitate wild mammals should include receipt of rabies vaccination, appropriate training, and continuing education. 1. Terrestrial Mammals. The use of licensed oral vaccines for the mass immunization of free-ranging wildlife should be considered in selected situations, with the approval of the state agency responsible for animal rabies control. Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis. However, limited control in high-contact areas (e.g., picnic grounds, camps, or suburban areas) may be indicated for the removal of selected high-risk species of wildlife. The state wildlife agency and state health department should be consulted for coordination of any proposed vaccination or population-reduction programs. 2. Bats. Indigenous rabid bats have been reported from every state except Hawaii and have caused rabies in at least 33 humans in the United States. Bats should *CDC. Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(No. RR-1). # Appendix A Laboratories that Test Avian Specimens for C. psittaci Many state diagnostic laboratories and veterinary colleges perform routine chlamydial diagnostics. Additional laboratories are included in the following list (Table A). Other sources might be available. Inclusion in Table A does not imply endorsement by the Committee of the National Association of State Public Health Veterinarians or constituent institutions. The purpose of this Compendium is to provide rabies information to veterinarians, public health officials, and others concerned with rabies prevention and control. These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies-control program. This document is reviewed annually and revised as necessary. Immunization procedure recommendations are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control. # Part I: Recommendations for Parenteral Immunization Procedures # A. Vaccine Administration All animal rabies vaccines should be restricted to use by, or under the direct supervision of, a veterinarian. # B. Vaccine Selection Part II lists all vaccines licensed by USDA and marketed in the United States at the time of publication. New vaccine approvals or changes in label specifications made subsequent to publication should be considered as part of this list. Vaccines used in state and local rabies-control programs should have a 3-year duration of immunity. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in any population. # C. Route of Inoculation All vaccines must be administered in accordance with the specifications of the product label or package insert. Adverse reactions and vaccine failures should be reported to USDA, Animal and Plant Health Inspection Service, Center for Veterinary Biologics at (800) 752-6255 or by e-mail at CVB@usda.gov. # D. Vaccination of Wildlife and Hybrid Animals The efficacy of parenteral rabies vaccination of wildlife and hybrids (the offspring of wild animals crossbred to domestic dogs and cats) has not been established, and no such vaccine is licensed for these animals. Zoos or research institutions may establish vaccination programs that attempt to protect valuable animals, but these programs should not replace appropriate public health activities that protect humans. # E. Accidental Human Exposure to Vaccine Accidental inoculation might occur during administration of animal rabies vaccine. Such exposure to vaccines listed in Part II constitutes no rabies hazard. # F. Identification of Vaccinated Animals All agencies and veterinarians should adopt the standard tag system. This practice will aid the administration of local, state, national, and international control procedures. Animal license tags should be distinguishable in shape and color from rabies tags. Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. 1. Rabies Tags. be excluded from houses and adjacent structures to prevent direct association with humans. Such structures should then be made bat-proof by sealing entrances used by bats. Controlling rabies in bats by programs designed to reduce bat populations is neither feasible nor desirable. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # IU.S. Government Printing Office: 2000-533-206/28022 Region IV

Chairman/Criteria Group NIOH In an Italian factory for production of n-butyl phthalate, isobutyl phthalate, and DEHP, G ilioli et al (36) measured to tal phthalate exposure 3 concentrations between 1 and 60 mg/m with an average air concentration 3 (not stated whether arithmetic or geometric) around 5 mg/m . Nielsen et al (64) measured total phthalic acid esters in air in a PVCprocessing industry in Sweden where diisodecyl phthalate, DEHP, and some 3 butylbenzylphthalate were used. Concentrations between 0.01 and 2.0 mg/m were recorded in 96 2-hour personal samples from 54 workers. Air concentrations of to tal phthalates were measured in a Russian PVCprocessing plant using mainly dibutyl phthalate and higher alkyl phthalates but also some DEHP and other phthalates. Concentrations between 1.7 and 66 3 mg/m were recorded (59). 3 DEHP a ir concentrations between 0.09 and 0.16 mg/m were reported from a German factory for phthalate production (110).Experiments with radioactive (^C-labeled) DEHP have indicated that at least 50% of the radioactivity of a single oral dose (2.9 mg/kg) is absorbed in the rat intestine since 42 % and 14 % were excreted in urine and in bile, respectively (27). The same authors also found that DEHP was rapidly hydrolyzed by pancreatic lipase, indicating the possibility that DEHP is hydrolyzed in the gut before absorption. DEHP analysis in liver further supported this supposition in that no unmetabolized DEHP was found in liver after administration of smaller (0.5 g/kg) the analyses were positive (8). At a dose of 2 g/kg given p.o. to rats the bioavailability of DEHP was 14% as measured with a HPLC technique in blood. When a higher dose (4 g/kg) was given i.p ., only 5% was recovered in blood, again indicating a role for hydrolysis in the gut in the kinetics of DEHP (77). Experiments with p.o. administration of MEHP indicated that this metabolite was well absorbed (109). Radioactive MEHP or# Mention of the name of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health. (The literatu re is followed to August, 1987.) Diethylhexylphthalate (DEHP), a diester of phthalic acid, is used primarily as a softener in plastics, primarily for polyvinyl chloride (PVC). Smaller amounts are used as lubricants. Occupational exposure occurs during the production of DEHP, during the addition of DEHP to plastics, and in the processing of softened plastics. (20 °C) 0.0013 kPa DEHP is a colourless to yellow, oily liquid at room temperature and normal atmospheric pressure. DEHP is available in a variety of technical grades. # D I S C L A I M E R The solubility of DEHP in water is low, 0.3-0.4 mg/1 at 20-25 °C, it is much less soluble in sa lt water. DEHP is miscible with most common organic solvents and it is more soluble in blood than water. DEHP is lipophilic and the distribution ratio in dichloromethane -Krebs bicarbonate buffer is 1130. The log n-octanol-water partition coefficient is 3-4. # OCCUPATIONAL EXPOSURE TO DEHP DURING MANUFACTURE, FORMULATION, OR USE Few data on occupational exposure to DEHP have been reported. In a phthalate manufacturing industry where DEHP was produced from phthalic anhydride and alcohols, Liss et al (56) DEHP was given to rats and 16 times more radioactivity from MEHP than from DEHP was recovered in plasma. P.o. administration of DEHP to young rats (1 g/kg) lead to a larger MEHP area under the plasma concentration time curve than in older rats when measured with gas chromatography (103), indicating either a more rapid hydrolysis of DEHP or a more efficient absorption of MEHP in young rats. The systemic availability of DEHP is low (5% when 4 g/kg was given) after i.p . administration. Relatively low amounts of MEHP were recovered in blood in these experiments (77). # Distribution Intravenously (i.v .) administered DEHP is rapidly eliminated from blood. This has been demonstrated in experiments where radioactive DEHP was injected i.v . and blood levels were followed by TLC (92). At' a low dose (0.1 mg/kg) there was an in itia l phase with a half-time of 4.5 min and a second phase with a half-time of 22 min. At a higher dose (200 mg/kg) the in itia l phase had a half-time of 9 min. This indicated that DEHP was taken up in a tissue compartment by a saturable process (92). Radioactivity from DEHP was rapidly distributed to liver, carcass, lung and spleen when administered i.v. (27,92). Perorally administered DEHP is mainly distributed as MEHP (77,109). In the liver unmetabolized DEHP was recovered only after high doses (>0.5 g/kg) of DEHP, indicating a threshold phenomenon in its absorption and distribution (1,8 (77,109). The in vitro plasma protein binding of MEHP is extensive (103). Newborn infants receiving exchange transfusions may reach plasma levels of about 10 Mg/ml of DEHP (104). This level is about twice as high as those found in leukaemia patients receiving p latelet concentrates and about five times as high as levels found in haemodialysed patients. After treatment this level rapidly fe ll to about 3 Mg/ml within 2 hours, and then a further drop with a half-time of about 12 hours (104). # Metabolism DEHP is hydrolyzed in vitro by pancreatic lipase to MEHP (27), indicating that this metabolism mainly occurs in the gut lumen. In rats about 80% of a p.o. dose of DEHP undergoes mono-de-esterification (77), while in traarterially administered DEHP was only slowly converted to MEHP (77). The hydrolysis in rat liver has been studied with both negative (27) and positive ( 6) results. MEHP may be further metabolized in the gut wall (77) or other organs. Rat liver cells in culture as well as the intact rat converts MEHP to several metabolites (7,55). The -and w-l-carbon oxidation products constitute more than 85% of the metabolites (7,55,60). The ethyl side chain may also be oxidized (55). It has been suggested that oj-oxidation leads to a product which is further metabolized by p-oxidation in the peroxisomes (7,55). A non-linear dose-dependency of this metabolism in the rat has been observed; the dominating role of u>-oxidation over co-1-oxidation was increased by high doses of MEHP (55). 14 Small amounts of radiolabel derived from 2-ethyl-(l-C)-hexyl-labeled DEHP was recovered in a DNA fraction (8). However, the metabolite responsible for this radioactivity or the nature of its binding was not fully explored. There are marked animal species differences in the metabolism of DEHP. Thus the ^-oxidation seems to play a dominate role in the rat and guinea pig (8,54,55), but seems to be a minor pathway in the mouse, hamster, green monkey, cynomolgus monkey, and marmoset (8,54). In urine of DEHP treated rats, no conjugated metabolites have been detected. A minor portion is conjugated in the hamster and a major portion is conjugated in the marmoset, mouse, guinea pig, green monkey and, man (8,54). Only glucuronides have been found in these species (8). The amount of unmetabolized MEHP excreted in urine also varies considerably between species; it is low in the rat and hamster, but high in mouse, guinea pig, green monkey and man (8). Repeated oral administration of DEHP or MEHP at high doses (500 mg/kg) to rats leads to a change in the metabolic profile. There was an increase in -oxidized metabolites and a decrease in co-1-oxidized metabolites (55). Drug metabolizing enzyme activ ities have been studied after DEHP administration and in some cases changes have been observed (2,37,119). The same metabolites as those found in rat urine can be detected in human urine. One study on i.v . injected DEHP (8) and one on orally administered DEHP (90) indicated that man metabolizes DEHP by to and 0) -1-oxidation as well as by oxidation of the ethyl side chain. However, the U) -oxidation pathway seems to be a minor pathway in man. More than half of the metabolites recovered in human urine were conjugated metabolites (8,90). Time-averaged concentrations of DEHP, MEHP and phthalic acid in blood, reported for patients undergoing maintenance hemodialysis, were 1.9, 1.3 and 5.2 Mg/ml respectively (76). These patients are considered to be at risk of potential DEHP toxicity through prolonged contact periods with medical plastic products that contain DEHP. The relatively high circulating level of phthalic acid may indicate an altered metabolism of DEHP in uremic patients (76). Levels of DEHP and MEHP in plasma were studied in newborn infants receiving blood exchange transfusions. In one case the MEHP h a lf-life was the same as for DEHP (about 12 hours), indicating that the hydrolysis of DEHP was the rate limiting metabolic step. However, in other children the half-time of MEHP was longer than that of DEHP, suggesting a low oxidizing capacity in most newborns (10A). # A.4 Excretion Radioactivity from intravenously injected ^C-labeled DEHP is mainly recovered in urine and feces after 2A hours (92), indicating that urine and bile are major excretory pathways. At a low dose (0.1 mg/kg) given to rats, 50-60% of injected radioactivity was recovered in urine and feces after 2A hours, while less than 50% was recovered at a high dose of 200 mg/kg (92). Seven days after an oral dose (2.9 mg/kg) of DEHP, 42% of the radioactivity was recovered in urine and 57% in feces (27). In these experiments on rats the biliary excretion was also quantitated, and it was found that 14% of the radioactivity was recovered in bile after 4 days (27). The almost 100% recovery documented by Daniel & Bratt (27) has been confirmed by Teirlynck & Belpaire (109). Oral administration of MEHP (50-500 mg/kg) gave a higher urinary recovery than orally administered DEHP (50-500 mg/kg) as measured after 24 hours (55). Urinary excretion in man has been quantitated after oral administration of non-radioactive DEHP (0.45 mg/kg). It was found that 15-25% was excreted in urine as MEHP or oxidized metabolites within 2-3 days (90). In the rat no unmetabolized DEHP is excreted in urine, while small amounts are found in mouse or green monkey urine (8). Major amounts of MEHP are excreted in the urine by mouse, guinea pig, green monkey and man (8). However, oxidized metabolites constitutes a major portion of excretion products in urine from ra t, mouse, hamster, green monkey, and man (8). Changes in excretion pathways have been observed after prolonged administration of DEHP. In control rats the fecal excretion pathway dominated after p.o. administration, while in habituated rats (7 days feeding with DEHP) the urinary pathway dominated (27). # Retention and turnover At least two elimination phases of radioactivity, given as DEHP, have been observed in ra t blood, but these have short half-lives (4.5-9 and 22 min respectively) (92). In the liver after 7 weeks of oral administration the elimination phase was considerably slower, with a h a lf-life of 3-5 days (27). No accumulation of DEHP or MEHP was observed after dosing with 2.8 g/kg/day for 7 days (109). No accumulation was reported from a long term feeding study at doses of 1000 or 5000 ppm in the food (corresponding to a daily dose of about 50 and 250 mg/kg) for 5-7 weeks (27). Analysis of the to tal amount of urinary metabolites, measured as derivatized phthalic acid, indicated a weak positive correlation between occupational exposure to phthalate and the metabolites (56,64). In the f ir s t study (64) workers were mainly exposed to DEHP and diisodecyl phthalate. In the second study (56) workers were exposed to DEHP and phthalic anhydride. The authors concluded that phthalic anhydride influenced the urinary level more than did DEHP. # Summary DEHP is hydrolyzed in the gut. In the liver unhydrolyzed DEHP can only be found after administration of high doses. The hydrolyzed metabolite MEHP is rapidly absorbed and is further metabolized in the liver. In the rat the w -and to -1-carbon oxidation products constitute more than 85 % of the metabolites. I t has been suggested that oxidation products are further metabolized by 3-oxidation in the peroxisomes. This metabolism is dose-and frequency of administration-dependent. The metabolism is changed by repeated administration of DEHP. There are great species variations, and the 0) -oxidation pathway seems to play a minor role in man. Major excretory pathways are urine and bile. In feces and urine almost 100 % of an administered dose can be recovered. No accumulation of DEHP or MEHP has been observed. # EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS # Single Exposure Numerous LD^^ values have been reported for DEHP. The oral LD^q values in rats generally exceeded 25 g/kg and in mice, 30 g/kg (66, 125). The oral LD^q value for the rabbit is given as 33.9 g/kg (95), and for the guinea pig, 26.3 g/kg (49). After i.p . administration to rats an LD^q value of 30.7 g/kg has been reported (95). In mice the value is noted to be 37.8 g/kg (51). In other studies LD^q values in the range 14-75 g/kg have been calculated for the mouse after i.p . administration (125). LD50 values in the range 200-250 mg/kg were reported for the rat after i.v . doses of DEHP solubilized in nonionic detergent (84,91). From the information provided in the acute studies the main sign of toxicity after single oral or intraperitoneal dosing is diarrhoea, possibly due to the oily nature of the ester. An i.p. dose of 500 mg/kg in rats decreased spontaneous running activity indicating behavioural changes (85). After i.v. dosing, lung lesions characterized by oedema, haemorrhage, and in filtratio n s of polymorphonuclear leucocytes have been observed in the rat (93). The effects were evident at doses as low as 50 mg/kg. The mechanism of the aetiology of the lung lesions is unknown. I t has, however, been suggested that some changes could be due to the release of lysosomal enzymes from alveolar macrophages, which has been seen in vitro in rabbit tissues treated with DEHP (11). Treatment i.v. of rabbits with DEHP induced a fa ll in blood pressure and an increase in breathing rate at a dose of 350 mg/kg. No deaths occurred after doses up to 650 mg/kg (20). The monoester, MEHP, may be more toxic than the diester but data are very limited. In a short note (118) the oral LD^q in the rat was reported to be 1.3A g/kg (female) and 1.8 g/kg (male). # Short-Term Exposures The most obvious sign of toxicity in the rat after oral administration is a reduction in the rate of weight gain, usually evident within a few days of dosing of 0.A g/kg/day or above (A0, 65). Reduction in body weights were observed in rats given dietary levels of 12,500 and 25,000 ppm for 13 weeks. Dosages of 1600-6300 ppm resulted in either slight elevations of body weight or had no effect (62). Reductions in haemoglobin, packed cell volume and erythrocytes have been observed in rats given 1% or 2% dietary DEHP for 17 weeks but not at 0.2% for the same period (A0). Doses of more than 3 g/kg/day for periods up to 90 days were necessary to cause deaths in rats (65,95). No deaths occurred in rats after dietary dosing for 1A days at 50,000 ppm or below (62). MEHP also reduced the body weight gain when given in the diet of rats at 6,400 ppm (22). No effects on body weight occurred at dietary levels up to 625 ppm for 3 months. At 625 ppm a significant reduction in blood glucose was observed. Decreases in body weight have also been observed in mice given dietary DEHP for 14 days at levels from 6,300 ppm to 100,000, or for 13 weeks at 1000 ppm to 12,500 ppm (62). Cystic kidneys and centrilobular necrosis were noted in one strain of mice (ddY) fed 0.25 or 2.5% DEHP for 2 weeks but not in another study using a different strain (B6C3F^), higher exposure levels, and longer periods (125). DEHP administered i.v . at 25-500 mg/kg/day for 2-4 weeks to beagle dogs resulted in pulmonary haemorrhage and inflammatory response similar in appearance to the "shock-lung" effect (125). A few inhalation studies have been reported. However, due to the omission of experimental details they can not be assessed. # Biochemical effects A large amount of research work has been carried out on the hepatic effects such as cell proliferation, of DEHP in laboratory animals. A single dose of DEHP, 500 mg/kg, resulted in a six-fold increase of male rat hepatocytes in S-phase and a 15-fold increase of male mouse hepatocytes in S-phase 24 h after dosing. Three weeks of feeding DEHP at 6000 ppm in the diet increased liver/body weight ratios to approximately 140% that of controls in female rats and 170% of controls in male mice (19). However, at the end of 2 years of feeding DEHP at 0.03, 0.1 or 1.2% in the diet there was no detectable liver cell proliferation as studied by H-thymidine incorporation (78). In vitro studies also have shown that DEHP decreases the protein kinase c activity ( 100). The cell proliferation induced by DEHP forms the basis of one theory of DEHP hepatocarcinogenesis. This theory argues that the increased cellular growth induced by DEHP may result in spontaneous mutational events or promotional effects (16,19). Peroxisomes (microbodies) are small cytoplasmatic organelles. Functionally, peroxisomes have been implicated in gluconeogenesis, detoxification of and in lipid metabolism (82). Some chemical agents may cause peroxisome proliferation in mouse and rat liver. This property was f ir s t discovered for some hypolipidemic drugs, such as clofibrate and naphenopin, but has later been found to be common to a structurally diverse group of chemicals including DEHP. Peroxisome proliferators including DEHP and other phthalates are liver carcinogens, when administered in the diet (80). There seems to be a fair correlation between the ab ility of a chemical to induce peroxisome proliferation and its liver carcinogenic properties (81). According to the peroxisome proliferation hypothesis for liver carcinogene sis, DEHP and/or its metabolites reduces lipid synthesis and oxidation so that fatty acid derivatives (e.g. triglycerides) are accumulated in the hepatocyte. Genes for lipid metabolizing enzymes, including peroxisomal beta-oxidation enzymes, are then expressed. It has recently been shown that MEHP and the (j J -1-carbon oxidation products are the DEHP metabolites responsible for peroxisome proliferation in primary hepatocyte cultures (60). The increased lipid metabolism in the peroxisomes may generate increased amounts of H^O^. Since catalase, the enzyme which catalyzes the breakdown of to water, is only slightly induced by DEHP the result w ill be an increased formation of oxygen radicals which may damage membranes and/or DNA (16). If the exposure is prolonged a series of cellular insults may result in permanently altered cells which form foci and ultimately tumors. I t should, however, be clear that this hypothesis has only limited experimental support. DEHP is a moderately effective inducer of peroxisome proliferation in the rat. Chronic administration of doses of 50 mg/kg/day seems to be effective as measured by an increase in peroxisomal enzymes (61). However, doses of 25 mg/kg/day seem not to increase these enzyme activ ities in the rat liver (50). Another experiment has shown a large increase of hepatic peroxisomes in the rat after 1A days of oral DEHP administration at 2000 mg/kg/day. When the same dose was given to marmosets there was no peroxisome proliferation. Moreover, peroxisomal enzymes showed a pronounced rise in the rat but not in the marmoset (83). The difference may have been caused not only by a less efficient hydrolysis of DEHP and therefore less efficient absorption in the marmoset ( 83) but also by different intrinsic responsiveness to MEHP by the rat and marmoset hepatocytes (60). There is some experimental support for both of these explanations. Some experiments suggest that human hepatocytes may be similar to marmoset hepatocytes in their peroxisomal response to MEHP (16). Nothing is known about ra t, marmoset, or human peroxisome responses to DEHP by inhalation exposure. In vitro, rat liver microsomal cytochrome P-450 levels were not affected by DEHP (37). However, when rats were treated in vivo with DEHP by i.p. injections (119) or repeatedly given DEHP orally (2), an increase in cytochrome P-450 levels has been observed. In the liver, mitochondrial enzymes and mitochondrial morphology have been affected by DEHP administration (74, 96). The significance of the effects on mitochondria is not known as the mitochondrial functions usually appear to be normal (125). In male rats given DEHP in the diet, urinary excretion of Zn is enhanced and the testicular levels of Zn decreased (42,68). See also 6 . A number of studies has shown that DEHP given in the diet (0.5-2%) causes lowering of triglyceride and cholesterol levels in the plasma of the rat (13,14,15,24,87,127,128). DEHP inhibits the biosynthesis of cholesterol, an effect which is accompanied by phospholipidosis. The same effects are seen with MEHP (72). # Skin and eye irritatio n ; sensitization The data available indicate that DEHP is a weak irrita n t to mammalian skin on topical or intradermal exposures (20,125). In one study no irrita tio n in the rabbit eye occurred when DEHP was in stilled into the eye (51). There are no data indicating that DEHP should be a sensitizing agent. # Long-Term Exposures In a 24 month study (44) groups of 43 male and 43 female Wistar rats were fed diets containing 0, 0.1 or 0.5% DEHP, with interim k ills at 3, 6 and 12 months. Because of high mortality only two control, four low dose and seven high dose animals were alive at termination. During the f irs t year DEHP slightly reduced body weights but by the second year the weights of a ll groups were sim ilar. During the firs t six months an increase in relative liver and kidney weights were seen in DEHP treated animals but later they were sim ilar in control and treated animals. After 3 months 1/8 rats in the low dose group were found to have mild tubular atrophy in the kidney. After In another 24 month study (21) groups of 32 male and 32 female Sherman rats were given diets containing 0, 0.04, 0.13 or 0.4% DEHP. Because of reduced life-expectancy of the animals and the small numbers of animals used, the study is inadequate to assess the chronic toxicity of DEHP. In a 12 month study (65) a group of 20 male and 20 female Wistar rats were given a diet containing 0.35% DEHP. A control group received the diet only. The only gross or micropathology noted in dosed animals at necropsy was hepatomegaly. During the study, however, about 30% of the animals died due to congestion of the small intestine and loss of the gastric or intestinal mucosa, which was complicated by purulent pneumonia and endometritis. In a 2 year study (47,62) groups of F344 rats were given dietary levels of 0, 6000 or 12000 ppm DEHP. A decreased body weight in exposed groups was noted from around week 30 u ntil termination. Except for neoplastic effects (section 8 ) and testicu lar atrophy (section 6 ) a compound related hypertrophy of cells of the anterior pituitary were noted at necropsy of the high dose rats. In both of the exposed groups an increased incidence of clear cell changes in the livers was observed. In the same study (47,62) B6C3F^ mice were exposed to 3000 or 6000 ppm DEHP. A dose related decrease in dosed female mice body weights was observed. There was no increased incidence of non-neoplastic lesions except for seminiferous tubular degeneration of the testes in male mice (section 6 ). In a study with groups of male and female guinea pigs fed diets containing 0, 400 or 1300 ppm DEHP for 12 months (21), dosed animals had sta tistic a lly higher body weights than controls and a slight increase in liver weights was noted in dosed females. No other compound related lesions were found. # Summary Based on LD^q studies DEHP has a low acute toxicity. A prolonged dosing of DEHP to animals produced proliferation of liver peroxisomes, hepatomegaly and a reduction of body weight gain. DEHP is a weak irrita n t to mammalian skin but there are no data indicating that DEHP should act as a sensitizing agent. # REPRODUCTIVE, EMBRYOTOXIC, AND TERATOGENIC EFFECTS # .1 Reproductive effects The effects of DEHP on male reproductive organs have been studied extensively. The majority of the studies have been carried out using rats or mice given DEHP in the diet. Seminiferous tubular atrophy, comprising a loss of spermatids and spermatocytes, was the result when 4-week-old Wistar rats were administered 2800 mg DEHP/kg by oral intubation for 10 days (39). In sim ilarly treated 10-week-old rats about 50% of the tubules were atrophic and the remainder unaffected. No testicular damage was seen in treated 15-week-old rats. When DEHP was given in the diet (2%; approximately 1200 mg DEHP/kg) daily to 4week-old rats, the lesions produced were reversible whether treatment was stopped prior to, or continued until after the control rats had reached sexual maturity. In rats given 1 or 2% dietary DEHP the effect was dose-dependent with visible signs of atrophy after approximately 2 weeks of feeding (AO). The atrophy was accompanied by pituitary changes, namely enlargement and vacuolization of the basophils of the pars d ista lis corresponding to the formation of the so-called castration cells seen after gonadectomy (AO). Similarly, there was a concomitant reduction in testicular and prostatic zinc levels with increased urinary excretion of zinc (A2). In a rat study with orally administered DEHP (2% in the diet) the serum testosterone levels were reduced by approximately 50% but the levels in testes rose by 150% (70). Simultaneous administration of testosterone or zinc had no protective effect on the atrophy but did prevent the weightreduction of the accessory sex organs (39,73). DEHP in the diet (2%) given to 7 young Wistar rats for one week decreased the testicular weight significantly (p < 0.05) compared to controls (67). The testicu lar zinc concentration was decreased as well. In another study (68) groups of 20 male rats were given 2.0 g/kg/day by gavage for 1A days. Ten rats were then killed and the remaining 10 rats were followed for an additional A5 day period without administration of DEHP. The histopathological changes of the testes seen at day 15 were: a marked shrinkage of the seminiferous tubules; germinal epithelium consisting only of Sertoli cells; very few spermatogonia. After A5 days the percentage of spermatogenic tubules had increased from 0 (at day 15) to 12.8%, indicating a limited reversibility of the testicular atrophy. Similar degeneration of the seminiferous tubules were seen (89) when 13week-old Wistar rats were given 2 g DEHP/kg p.o. for 7 consecutive days. The changes induced in rats by DEHP may be age dependent (106). Younger animals appeared to be more susceptible to testicu lar injury and were slower to recover (39). If treatment was withdrawn before the rats were sexually mature the effects were reversible (39). Plasma levels of DEHP were similar in sexually mature and immature rats indicating no difference in absorption (107). Rats given i.p . injections of DEHP did not show any strong evidence for testicular atrophy (25). As with oral dosing, however, i.p . administration of DEHP decreased serum testosterone levels (69). Both routes have also altered the activ ities of some testicular enzymes (25,94). Some degenerated primary spermatocytes and altered Sertoli cells were observed in Sprague-Dawley rats given 3 h infusions of an emulsion at a rate of 1 ml/h corresponding to a daily dose of 500 mg DEHP/kg (103). The infusions were given every other day on six occasions. The emulsion contained DEHP, fractionated egg yolk phosphatides, glycerol, and water. No effects were observed when emulsions corresponding to 0, 5, or 50 mg DEHP/kg were given. In another study (26) groups of Swiss-Webster mice were given daily i.p. injections of 50 or 100 mg DEHP/kg for 5 days or alternate daily i.p. injections of 50 or 100 mg DEHP/kg for 20 days (10 injections). The animals were killed 24 h following the last injection. No significant alterations in testicular weight or zinc levels occurred. In Sprague-Dawley rats given similar treatment the gonadal zinc level decreased about 30%. In a NTP-sponsored study (58) with CD-I mice given 0.3% DEHP in the diet, the animals had significantly diminished te s tis and epididymis weights compared to controls. In addition, the sperm concentration in the cauda epididymis was decreased and the percent abnormal sperm in the cauda was significantly higher in the treated mice. A high oral dose (4.2 g/kg) of DEHP gave a minimal tubular atrophy in hamsters but did not produce any effects on urinary zinc excretion, testicular zinc levels or on testicular weights (42). The effects of the monoester (MEHP) has not been as well studied. An oral dose of 1 g/kg/day for 5 days to rats produced a significant decrease in testes weights and an extensive testicular atrophy (42). On the other hand, rats given i.p. doses of up to 100 mg/kg of MEHP for 5 days showed no abnormal histology (25) and i.p . doses of 50 mg/kg on alternate days for 20 days produced only a reduction in prostatic zinc levels (26). In mice fed diets containing 2% MEHP for 1 week (71) testicular zinc and testosterone levels were markedly reduced but there were no reductions in testicular weights. Hamsters given 1 g/kg/day of MEHP for 9 days showed more severe testicu lar effects than those given DEHP at levels of 4.2 g/kg/day for the same period (42). These studies indicate that the rat is the most susceptible species to DEHP-induced testicu lar atrophy. The mechanism of phthalate-induced testicu lar damage is not fully understood. The testicular zinc depletion has been suggested as a primary event (34,35). Zinc is essential for normal testicular function and its depletion is known to lead to testicular atrophy (12). Inhibition of dehydrogenase enzymes, e.g. those controlling the biosynthesis of testosterone, lead to reduced testosterone levels. DEHP administration has been shown to reduce serum testosterone in the rat (69,70) as well as in the mouse (42), although in the mouse no testicular atrophy was observed. Supplementation with testosterone or zinc did not prevent the testicular damage induced by DEHP (39,73). In vitro studies have indicated that the Sertoli cell is the target. Mixed cultures of Sertoli and germ cells prepared from rat testes were exposed to DEHP or MEHP (10 ^-10 ^M) (38,41). DEHP had no effect but MEHP caused a dose-dependent increase in the rate of germ cell detachment from Sertoli cells, accompanied by changes in Sertoli cell morphology. In another study (58) CD-I mice were given 0, 0.01, 0.1 or 0.3% DEHP in the diet during a 7 day pre-mating period and a subsequent 98-day cohabitation period. This resulted in complete suppression of fe rtility in the 0.3% group and a significant reduction in the fe rtility in the 0.1 group compared to controls. There was no effect of DEHP on fe rtility in the 0.01% treatment group. In a f e r tility study (3) groups of ICR male mice were administered DEHP subcutaneously at dose levels of 1, 2, 5 and 10 ml/kg on day 1, 5 and 10 of the study. At day 21 each male was housed with one virgin female for 7 days. There was a reduction in the incidence of pregnancies in the treated groups (3/8 at the three highest dose levels; 5/8 at the lowest dose level; 14/16 in the control group). On the other hand, repeated matings with virgin females starting on day 2 , 6 , 1 1 , 16 and 2 1 , and at weekly intervals through 8 weeks, revealed no decrease in the incidence of pregnancy. In the treated groups, examination of pregnant females on day 13 of gestation revealed an increase in the incidence of preimplantation losses and early fetal deaths. Only one study (94) has investigated the effects of phthalates on female reproductive organs. Three doses of 4.93 g DEHP/kg at 5-day intervals were given i.p . to female rats. No histopathological changes of the ovaries were seen 22 days after the firs t injection, but reductions of some enzyme activités were noted. However, i.p. injections of DEHP to male rats did not result in histopathological changes of the testes. It appears that rats and guinea pigs are sensitive to testicu lar atrophy caused by DEHP while mice are fairly and hamsters highly resistant. That at least some of the effects associated with this pathology can be produced in vitro argues against a hormonally mediated indirect effect. The earliest effects are seen in Sertoli cells and are described as vacuolation (5). # Embryotoxicity, Teratogenicity In a study (65) with female Wistar rats given 0.34 or 1.7 g DEHP/kg by gavage during the f ir s t 21 days of gestation, the only untoward effects seen were reductions in fetal body weight. Two percent (2%) DEHP in the diet of Fischer 344 rats during the firs t 20 days of gestation increased the number of resorptions (123). Intraperitoneal injections of 4.93 and 9.86 g DEHP/kg to Sprague-Dawley rats on days 5, 10, and 15 of gestation resulted in an increased number of resorptions and reduced fetal weights (101). In the highest dose group gross abnormalities, such as twisted hind legs and anopthalmia, were noted but no skeletal defects were observed. Plasma extracts of two polyvinyl chloride (PVC) plastics containing DEHP were administered intravenously to groups of pregnant Sprague-Dawley rats daily from the 6th to the 15th day of gestation (52). The animals were killed at day 20. The daily doses of DEHP were equivalent to 1.3 mg/kg (low dose) and 5.2 mg/kg (high dose). No significant teratogenic or embryotoxic effects were noted. Groups of ICR mice were given DEHP in the diet at levels of 0.05 to 1.0% for days 0-18 of gestation whereafter they were sacrificed (97,99). The food intake was about 7 g/day as an average. At 0.4 and 1.0% levels no live fetuses were found. At the 0.2% level, 40% of the fetuses had malformations including exencephaly, spina bifida and malformed ta il. A delayed ossification was seen in about 15% of the fetuses at the 0.1 and 0.2% dose levels. Dietary administration of 0.025 to 0.15% DEHP on days 0-17 of gestation to CD-I mice increased the number of resorptions at the 0.1 and 0.15% levels (124). A single p.o. administration of 0.1 ml/kg DEHP on day 7 of gestation to SPF mice decreased the number and the body weights of living fetuses (116). In another study (126) DEHP was given orally to SPF mice at day 6 , 7, 8 , 9 or 10 of gestation. When 5.0 or 10.0 ml/kg was given on day 7 there were no live fetuses. 2.5 ml/kg administered the same day produced 14% of living embryos and 1.0 ml/kg gave 40% living embryos. The percentages of live embryos when 10.0 ml/kg was given on day 8 , 9 or 10 of gestation were 18, 92 and 95% respectively. Gross and skeletal abnormalities occurred in fetuses given 2.5 and 7.5 ml/kg on day 7 or 8 . The abnormalities included exencephaly, open eyelid and club-foot. In a later study (98) groups of ICR mice were given DEHP by stomach intubation on days 7, 8 and 9 of gestation. The DEHP doses (in olive oil) were 250, 500, 1000, and 2000 mg/kg. The mice were sacrificed on day 18. In the two higher dose groups the numbers of resorptions and malformed fetuses were significantly increased. The malformations most commonly produced were anencephaly and exencephaly. When doses of up to 8000 mg/kg were given i.p. at days 7,8, and 9 of gestation no effects were noted. The monoester, MEHP, at oral doses of 225, 450 and 900 mg/kg produced significant signs of maternal toxicity when given to pregnant Wistar rats on days 6-15 of gestation (86). In the highest dose group a 73% mortality was observed in the dams. In the SPF mouse, oral dosing with 0.1 or 1.0 g/kg MEHP on day 7 of gestation led to increased incidence of early embryonic deaths but dosing on day 8 or 9 had less effect (117,126). The fetuses had reduced body weight and a higher incidence of gross abnormalities in fetuses from the high dose group on days 8 and 9 as compared to controls. The mice dosed on day 8 produced fetuses with high incidences of skeletal effects. Intravenous injections with 11.38 mg/kg MEHP to rabbits on days 6-17 of gestation gave a high incidence of resorptions (114). The incidence of fetal anomalies was similar to controls. The mechanism of teratogenicity of DEHP or MEHP is not known. Teratogenic activity could result from zinc deficiency, which is known to produce teratogenic effects (108). In a study (65) with DEHP at doses at 0.34 or 1.7 g/kg/day given to female Wistar rats by gavage for 3 months prior to mating, no effects were seen on the number of resorptions, fetal weights or incidence of skeletal anomalies. 6 .3 Summary DEHP can cause testicular damage in rats. The no-effect level is about 0.3 -0.5 % in the diet. There is evidence that DEHP and its metabolite MEHP are teratogenic and embryolethal to rodents. In rats 2 % in the diet throughout the gestation period produced an increased incidence of resorptions and in mice 0.1 % also produced fetal abnormalities. F ertility studies provided contradictory results. # MUTAGENICITY AND RELATED END-POINTS The possible genotoxic effect of DEHP has been thoroughly investigated in several different short-term tests. Effects of the major metabolites of DEHP; the monoester (MEHP) and 2-ethylhexanol, as well as phthalic acid and phthalic anhydride, have also been studied. Studies on the possible mutagenic effect of DEHP have been performed in bacteria, fungi and in cultured mammalian cells. Drosophila melanogaster has also been used and results from a few in vivo studies on mice have been published. Many laboratories have used several strains of Salmonella typhimurium and doses of DEHP up to 10,000 Mg/plate. Incubations both with and without exogenous activation systems have usually been performed. S9-mix from Aroclor 1254 induced rats is commonly used, but other species as well as other inducers have also been used to produce metabolic activation systems. With one exception (115) these test results have been negative (see e.g., 4,46,130,131) and in a IPCS study (9) a ll five laboratories reported negative results. Other bacteria than S. typhimurium have also been used. Negative results were obtained with E. coli WP2 at doses up to 2000 Mg/plate in one laboratory (130). The major metabolites of DEHP have also been tested for mutagenic activity in bacteria. Doses up to 3333 Mg/plate for MEHP and phthalic anhydride (131) and 2000 ng/plate for 2-ethylhexanol and phthalic acid (4) were used with negative results in strains of Salmonella (see also 46,130). However, one laboratory (115) reported a significant increase in revertants in TA 100 for both DEHP and MEHP, with and without S9, respectively. The same investigators (115) also detected a dose-dependent (400 and 500 Mg/plate) DNA damaging effect to B. su btilis in the Rec-assay for MEHP, while DEHP, phthalic acid and 2-ethyl-hexanol were a ll negative. In this study MEHP showed a positive response in E. coli WP2 b/r as well. Negative results were obtained when pooled urine from rats, treated with DEHP 2000 mg/kg/day for 15 days, were tested for genotoxic activity. A direct plating procedure was used with S. typhimurium strains TA-98, TA-100, TA-1535, TA-1537 and TA-1538, both with and without S9 and 3glucuronidase/aryl sulfatase as activation system. When 2-ethylhexanol was tested according to the same protocol was also negative (30). # Mutation The induction of mutations by DEHP has been studied in different species of fungi. In the IPCS collaborative study on in vitro assay systems (9) DEHP was considered to be negative in six out of seven assays. Positive results were obtained with Saccharomyces cerevisiae both with and without S9 activation at the lowest effective concentrations of 1541 Mg/ml and 3081 Mg/ml, respectively. Other laboratories using other strains of S. cerevisiae or Schizosaccharomyces pombe reported negative results at maximum tested doses of 5000 Mg/ml. Mouse lymphoma cells (L5178Y), Chinese hamster V79 cells, as well as human lymphoblasts have been used to study the mutagenic effect of DEHP in cultured mammalian cells. Several investigators have reported negative resu lts, but a few positive results can also be found in the literature. In the IPCS study ( 9) only one out of ten investigators reported a positive response. Mouse lymphoma cells were exposed to DEHP, without S9, and two doses were positive (7.5 pg/ml and 20 Mg/ml), indicating a positive response for DEHP without S9 in this te st. In a separate study (46) where MEHP and 2-ethylhexanol, as well as DEHP were tested in the mouse lymphoma cell assay, a ll three substances were found to be negative. The doses were 0.016-1.0 pl/ml -S9 and 0.067-5.0 nl/ml +S9 for DEHP and 0.013-1.0 yl/ml for MEHP and 2-ethylhexanol. DEHP has also been tested for mutagenicity in Drosophila melanogaster, using the sex-linked recessive lethal (SLRL) and different somatic recombination and mutation assays. 20 ppm of DEHP administered via injection did not induce SLRLs (129). In the IPCS study (9), however, DEHP gave a positive response in the unstable eye mosaic test in two separate experiments, but only at one dose (6.1 mg/ml), and were weakly active at 611 Mg/ml in another eye mosaic assay. No activity however, was seen in the wing spot te st at single doses of 6.1 mg/ml. I t was concluded that the DEHP test results may be interpreted to show marginal-positive responses (9). # DNA damage Different end-points, such as unscheduled DNA synthesis (UDS), and single strand breaks have been used to detect damage to DNA induced by DEHP in different mammalian test systems. In a IPCS study (9) negative results were obtained when single strand breaks were measured, either by alkaline elution in hepatocytes, up to 3907 Mg/ml or alkaline sucrose sedimentation in CHO cells, up to pg/ml. In the IPCS study UDS was also measured in either isolated hepatocytes or cultured HeLa cells by four different laboratories. One investigator detected a positive response of DEHP using isolated hepatocytes. However, since this result was only sta tistic a lly significant at one dose and not dose-related, the consensus was that DEHP was negative for UDS. In a separate study DEHP did not induce DNA-repair in primary rat hepatocytes (18). Similarly neither DEHP nor MEHP induced any DNA-repair in primary human hepatocytes, from three different subjects. In this study concentrations as high as 10 mM of DEHP and up to 0.5 mM of MEHP were used and exposure continued for 18 hours. No induction of DNA-repair or increased alkaline elution of DNA were seen in hepatocytes from either female or male F-344 rats treated with DEHP in vivo. Peroxisomal proliferation was induced in male rats treated with 500 mg/kg DEHP at 2, 12, 24 or 48 h before sacrifice, or with 150 mg/kg/day DEHP for 14 consecutive days. Female rats were treated with either 12000 ppm in the diet for 30 days, or 500 mg/kg 2 h before sacrifice, or the combination of both treatments. Similar in vivo/in vitro measurements of unscheduled DNA synthesis (UDS) in hepatocytes were reported by Kornbrust et al (48). Unscheduled DNA synthesis was not observed in primary rat hepatocytes exposed in vitro to -5 -2 10 -10 M DEHP or in vivo by a single gavage dose of 5 g/kg 2, 15 or 24 h prior to isolation of hepatocytes. Dietary concentration of 2% DEHP led to a marked proliferation of peroxisomes after 4 weeks. Neither this treatment nor the additional administration of a single gavage dose of 5 g/kg DEHP 15 h before sacrifice to animals fed the 2% diet for 8 weeks, or 4 weeks with or without pretreatment with 3-am ino-l,2,4-triazole (to inhibit endogenous catalase activity) induced any detectable DNA-repair in hepatocytes. Radioactivity from carbonyl-labeled DEHP did not associate with purified protein, RNA or DNA from rat liver in vivo. Label from 2 -eth y l-(l-^C )hexyl-labeled DEHP or MEHP did appear to associate strongly with purified 14 DNA, but label from free C-labeled 2-ethylhexanol did not. However the apparent binding of DEHP and MEHP was not further characterized (8). In a similar study (57) DEHP radiolabeled in different positions was administered orally to female F344 rats with or without pretreatment for 4 14 weeks with 1% unlabeled DEHP in the diet. Administration of Ccarboxylate-labeled DEHP resulted in no measurable DNA radioactivity while 14 radioactivity clearly was measurable after administration of DEHP, C-or 3 H-labeled in the alcohol moiety, as well as after administration of 2ethyl(l-^C )hexanol. HPLC analysis showed that the normal nucleosides had incorporated radiolabel, while fractions expected to contain carcinogenmodified nucleoside adducts did not contain any radioactivity. DNA isolated from the livers of male F344 rats administered 2000 mg/kg DEHP daily by gavage for 3 days was analyzed for possible carcinogen-DNA adducts 32 by the P-postlabeling technique (43). No adducts were detected in the -3 DNA, which also was the case when DNA from hepatocytes exposed to 10 M DEHP in vitro for 4 h was analyzed. # Chromosomal Effects Chromosomal effects of DEHP have mainly been studied in vitro, although some studies on the induction of micronuclei in peripheral blood erythrocytes of mice have been published. DEHP did not induce any increase in the level of siste r chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells, treated for 1 hour, either with or without S9, with doses up to 10 mM (32). On the other hand, MEHP has been reported to induce SCEs in V79 cells treated with 25 or 50 Mg/ml for 24 hours, and 1500 Mg/ml for 3 hours (115). MEHP also induced chromosomal aberrations in CHO cells and RL^ cells (from rat liv er), but only at cytotoxic concentrations in CHO cells (1.0 and 1.3 mM; ± S9). MEHP was less 7.3 DNA-binding toxic to RL^ cells and nontoxic concentrations between 2.0 and 6.5 mM gave a dose-related increase in aberrations (75). The induction of aneuploidy by DEHP was investigated both in mammalian cells and in fungi in the IPCS study (9). The mammalian assays, using either a fibroblast cell line or Chinese hamster primary liver cells, gave a positive response at 50 Mg/ml and at doses between 5 and 50 pg/ml, respectively. Two out of four studies using fungi were also positive and the consensus was that DEHP had the potential of inducing aneuploidy in vitro in both fungi and mammalian cells. DEHP and its major metabolites have also been tested for their potential of inducing micronuclei. DEHP (0.6, 3.0 or 6.0 g/kg/day/5 days) failed to induce micronuclei in peripheral blood erythrocytes of B^C^F^ male mice during a A week period (32). Negative results were also obtained in another mouse micronucleus test after both a single dose 5 g/kg, as well as after multiple doses of 5 g/kg/day. In this study MEHP and 2-ethylhexanol were also negative ( 10). # Cell Transformation DEHP induced cellular transformation has been studied in several different experimental systems. In a te st program (10) the BALB/3T3 cell transforma tion assay was used with and without ra t primary hepatocyte activation. DEHP (0.875-1 nl/ml) as well as the two metabolites MEHP and 2ethylhexanol were reported negative. On the other hand, the majority of transformation tests in the IPCS study (9) were positive for DEHP. Negative results were obtained with BALB/c-3T3 cells, while a study measuring the enhancement of v iral transformation of Syrian hamster embryo (SHE) cells, was considered to be inconclusive. Positive responses were obtained by four other investigators (9), using SHE cells, with doses of 1-300 |ig/ml (two different laboratories), embryonic mouse fibroblasts at 1000 ng/ml with S9 and 10 ng/ml without S9, or retrovirus-infected Fischer ra t embryo cells, at the highest dose tested, 2000 pg/ml. In a separate study (115) both DEHP (7500 mg/kg and 15000 mg/kg) and MEHP (375 mg/kg and 750 mg/kg) induced morphological transformation, as well as chromosomal aberrations, in SHE cells after transplacental administration. The induction of anchorage independence in JB6 mouse epidermal cells has been used to study tumour promoting activity in vitro. This assay gave a positive response for DEHP at concentrations of 500 to 20,000 ppm/ml culture medium (31). In another study (120) There are also a few studies on DEHP induced inhibition of metabolic cooperation, which may be indicative of the promoting potential of a substance. Metabolic cooperation in Chinese hamster V79 cells was not inhibited by DEHP at non-cytotoxic concentrations, 300 nM (0.12 Mg/ml) or below (48). In the IPCS study ( 9) one investigator reported an inhibition in V79 cells at non-cytotoxic concentrations of DEHP Mg/ml in two separate experiments and 5-25 ng/ml in another), while another investigator, using V79 cells in a microassay method, detected a slight but non-significant increased inhibition with doses between 10 and 200 nM. # Summary Numerous studies on possible genotoxic effects of DEHP have been performed using different short term tests. The results indicate that DEHP is not a direct acting genotoxic agent in vitro. With few exceptions mutagenicity studies both in bacteria and eucaryotic cells have been negative and essentially no positive response has been obtained in assays measuring DNAdamage. This is also consistent with results obtained in DNA-binding studies, which have been unable to detect any covalent binding of DEHP or its metabolites to DNA. Tests measuring chromosomal abberations and SCE have also largely been negative. However, MEHP has been found to be a clastogen in vitro but i t has been argued that this effect could be related to the surface active properties of MEHP. A few in vivo assays, measuring the induction of micronuclei, UDS or strand breaks in DNA, have also been performed with negative results. Neither could any mutagenic metabolites be detected in the urine from DEHP treated rats, using a Salmonella assay. In contradiction to these negative results, a few in vitro assays measuring aneuploidy have mainly been positive. Different cell transformation assays that have been performed have also mainly been positive. Although DEHP is not as thoroughly tested in these assays, the mainly positive results obtained indicate that DEHP can affect the cellular genome in vitro. In a carcinogenicity study (47,62) groups of 50 male and female Fischer 344 rats and male and female B6C3F^ mice were fed diets containing 6000 or 12000 (rats) or 3000 or 6000 (mice) mg DEHP/kg for 103 consecutive weeks. Concurrent controls (50 of each sex and species) were fed diet without the addition of DEHP. All of the animals were given control diet for 1-2 weeks after 103 weeks of treatment and were then killed and examined both grossly and microscopically. Food and water were supplied ad libitum. The administered concentrations of DEHP were estimated to be half maximally tolerated doses and maximally tolerated doses. Under these conditions, DEHP caused an increased incidence in female rats and male and female mice of hepatocellular carcinomas, and an increased incidence in male rats of either hepatocellular carcinomas or neoplastic nodules. (See Table I.) Twenty of the 57 hepatocellular carcinomas in the DEHP-treated mice (sexes and doses combined) had metastasized to the lung. The 9 hepatocellular carcinomas in control male mice are said to be within a normal range (62). The reported decreased incidence of tumors of the thyroid, pituitary, and te s tis could be related to an increased endocrine activity of the pituitary gland (62). The carcinogenicity of DEHP was supported by the results of another chronic study (78) even though the group sizes were small in that study. IARC (45) has made the evaluation that there is sufficient evidence for the carcinogenicity of DEHP phthalate in mice and rats, based on a significantly increased incidence of liver cell tumors in animals of both species, and an observed dose-response relationship. Two other long-term studies have been performed (21,44), but due to the small numbers of animals used, the studies are inadequate to assess the carcinogenic potential of DEHP. # SPECIAL STUDIES Since DEHP in most test systems lacks genotoxic activity it has been hypothetized that the carcinogenic effect is exerted during the promotion phase of hepatocarcinogenicity. DEHP has therefore been tested in several initiation/promotion experiments in rats and mice where the end point has been the number and/or volume of foci of altered liver cells. As expected, DEHP lacks in itiatin g activity in these experiments (78,120). DEHP is a probable promoter of such foci in the mouse liver and accordingly a possible tumor promoter in the mouse (120). In the ra t, however, DEHP does not promote altered foci during two years of feeding ( 78) and even seems to accelerate the regression or inhibit the appearance of some kinds of such foci (28,29). The reasons for this, as well as for the divergent responses in rats and mice, are unclear. Extrapolation from mouse data to humans is considered impossible since the mechanism of altered foci promotion in mice is unknown. # EFFECTS ON MAN Two adult subjects who were given 5 or 10 g of DEHP experienced no untoward effects apart from mild gastric disturbances and moderate catharsis at the 10 g dose (95). Three cases of non-specific hepatitis were described among 27 hemodialysis patients with terminal renal failure. The PVC blood tubings used released DEHP in an amount of 10-20 mg/1 perfusate. The symptoms and signs of hepatitis disappeared rapidly when the use of tubings not containing DEHP was resumed (63). There are very few data on effects on man of specific DEHP occupational exposure on man. Two studies report symptoms and signs of polyneuropathy among 47 out of 147 and 12 out of 23 workers examined in a Russian PVC-processing plant and an Italian plant for phthalate production. The workers were exposed to mixed phthalates and DEHP was a minor exposure, at least in the Russian plant. The to tal phthalate air concentrations recorded varied between 1.7 and 66 3 3 mg/m and 1 and 60 mg/m respectively (36,59). In a study from a Swedish PVC-processing factory the presence of symptoms and signs from the peripheral nervous system were examined among 54 male workers exposed mainly to DEHP, diisodecylphthalate and some butylbenzylphthalate. The workers were divided into three groups of equal size with mean phthalate exposures 0 . 1 , 0.2 and 0.7 mg/m , respectively. None of the outcome variables studied showed a significant association with exposure (64). No subject reported work related obstructive lung disease and conventional lung function tests showed no association with exposure. Several biochemical parameters showed significant associations with exposure. There was a slight decrease of the hemoglobin level with time of employment as well as exposure in the last year. Alpha-l-antitrypsin in serum increased slightly with time of employment and immunoglobulin A in serum rose with rising exposure during the last year (64). One case of occupational asthma due to DEHP has been reported in a PVCprocessing worker (17). When the patient was exposed to DEHP in an inhalation chamber an asthmatic reaction was elicited . The action was inhibited by prior administration of sodium chromoglycate. A study of blood lipids, serum activ ities of liver enzymes and routine hematological tests was carried out among workers in a German plant for DEHP production. The study was negative and uninformative due to lack of a 3 control group and very low exposures, below 0.16 mg/m (112). Thiess & Flieg (110) investigated the frequency of chromosome aberrations in 10 workers engaged in DEHP production in the same plant from 10-30 years. There was no increase in chromosome aberrations compared to control groups but a ir exposure levels were very low, 0.09-0.16 mg/m . A mortality study of 221 workers exposed to DEHP in the same plant was also conducted in which there were only 8 deaths. The study is uninformative due to small cohort size, short follow-up and low exposures (111). IARC (45) concluded that no adequate data were available to assess the carcinogenicity of DEHP to humans. Dose dependent kinetics of DEHP or its metabolites have been indicated in several studies as well as marked animal species differences in metabolism. Induction phenomena have also been described. These facts complicate extrapolation from animal studies to man and also extrapolations from high doses to low doses. Data on effects of DEHP on humans are scarce and do not permit any conclusions on dose-effect or dose-response relationships. There are no data on health effects from DEHP exposure outside the occupational environment. A few studies of workers exposed to phthalate mixtures have been published. However, no consistent findings are reported. One case-report suggests that DEHP could cause asthma. In animals few inhalation studies have been performed. The oral and intraperitoneal LD^q values exceed 25 g/kg, which indicate that DEHP has low acute toxicity. Prolonged dosing of DEHP produces hepatomegaly and proliferation of peroxisomes. In the rat the no-effect level for feeding studies appears to be about 0.01% in the diet. The no-effect level in the rat for testicular atrophy fed DEHP is about 0.3-0.5% in the diet, and is more pronounced in young animals. Hamsters and mice appears to be more resistant to the testicu lar effects of DEHP. In rats 2% DEHP in the diet throughout gestation produced an increased incidence of resorptions but not of malformations. In the mouse, however, 0 . 1% throughout pregnancy increased the incidence of embryolethality and abnormalities. Days 7-9 of gestation were most sensitive. The dose, 0.05 g/kg, to mice which induced fetotoxicity, is not expected to induce maternal toxicity. Contradictory results are obtained in fe rtility studies with DEHP. Results from several different genotoxicity tests indicate that DEHP and its major metabolites do not exhibit any direct genotoxic effect in either bacteria, fungi or mammalian cells in vitro. This has also been confirmed in binding studies with DEHP, which indicated that DEHP and its metabolites do not interact covalently with DNA. However, it has been established that DEHP has the potential of inducing aneuploidi in fungi, as well as in mammalian cells in vitro. These results, together with several positive results obtained in different cell transformation assays, indicate that DEHP can effect the cellular genome in vitro. DEHP acts as a tumor promoter in mouse liver but not in rat liver in established in vivo test systems. High doses (12000 mg/kg in rats; 6000 mg/kg in mice) of DEHP in a feeding study resulted in increased incidences of hepatocellular carcinoma. Based on animal data i t can be concluded that DEHP is carcinogenic and teratogenic. Due to a lack of human data the degree of risk to humans can not be evaluated, but DEHP should be considered as potentially carcinogenic and teratogenic to humans.

In 2010, the Advisory Committee on Immunization Practices (ACIP) first recommended annual influenza vaccination for all persons aged ≥6 months in the United States (1). Annual influenza vaccination of all persons aged ≥6 months continues to be recommended. This document 1) describes influenza vaccine virus strains included in the U.S. seasonal influenza vaccine for 2012-13; 2) provides guidance for the use of influenza vaccines during the 2012-13 season, including an updated vaccination schedule for children aged 6 months through 8 years and a description of available vaccine products and indications; 3) discusses febrile seizures associated with administration of influenza and 13-valent pneumococcal conjugate (PCV-13) vaccines; 4) provides vaccination recommendations for persons with a history of egg allergy; and 5) discusses the development of quadrivalent influenza vaccines for use in future influenza seasons. Information regarding issues related to influenza vaccination that are not addressed in this update is available in CDC's Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010 and associated updates (1,2). Methodology for the formulation of the ACIP annual vaccine recommendations has been described previously (1). The ACIP Influenza Work Group meets every 2-4 weeks throughout the year. Work Group membership includes several voting members of ACIP and representatives of ACIP Liaison Organizations. Meetings are held by teleconference and include discussion of influenza-related issues, such as influenza surveillance, vaccine effectiveness and safety, coverage in groups recommended for vaccination, program feasibility, cost-effectiveness, and anticipated vaccine supply. Presentations are requested from invited experts, and published and unpublished data are discussed. CDC's Influenza Division provides data on influenza surveillance, antiviral resistance, and vaccine effectiveness. CDC's Immunization Safety Office provides information on vaccine safety, and CDC's Immunization Services Division provides information on vaccine distribution and coverage. # Vaccine Strains for the 2012-13 Influenza Season U.S. influenza vaccines for 2012-13 will contain A/California/7/2009 (H1N1)-like, A/Victoria/361/2011 (H3N2)-like, and B/Wisconsin/1/2010-like (Yamagata lineage) antigens. The influenza A(H3N2) and B antigens differ from the respective 2010-11 and 2011-12 seasonal vaccine antigens (3). The influenza A(H1N1) vaccine virus strain is derived from an influenza A(H1N1)pdm09 (2009) virus and was included in the 2009(H1N1) monovalent pandemic vaccine as well as the 2010-11 and 2011-12 seasonal vaccines. # Recommendations for Vaccination Routine annual influenza vaccination is recommended for all persons aged ≥6 months. To permit time for production of protective antibody levels (4,5), vaccination optimally should occur before onset of influenza activity in the community. Therefore, vaccination providers should offer vaccination as soon as vaccine is available. Vaccination should be offered throughout the influenza season (i.e., as long as influenza viruses are circulating in the community). # Vaccine Dose Considerations for Children Aged 6 Months Through 8 Years Children aged 6 months through 8 years require 2 doses of influenza vaccine (administered a minimum of 4 weeks apart) during their first season of vaccination to optimize immune response. In a study of children aged 5 through 8 years receiving trivalent inactivated influenza vaccine (TIV) for the first time, # Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) -United States, 2012-13 Influenza Season Recommendations for routine use of vaccines in children and adolescents are issued by CDC and are harmonized to the greatest extent possible with recommendations made by the American Academy of Pediatrics, the American Academy of Family Physicians (AAFP), and the American College of Obstetrics and Gynecology (ACOG). CDC recommendations for routine use of vaccines in adults are harmonized to the greatest extent possible with recommendations made by AAFP, ACOG, and the American College of Physicians. The Advisory Committee on Immunization Practices (ACIP) is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of CDC on use of vaccines in the civilian population of the United States. ACIP members are named by the Secretary of the U.S. Department of Health and Human Services. ACIP recommendations become CDC policy once approved by the Director of CDC, on the date published by MMWR. the proportion of children with protective antibody responses was significantly higher after 2 doses compared with a single dose (6). Several studies have indicated that the time interval between two initial doses (from 4 weeks up to 1 year) of the same antigen might not be critical (7)(8)(9). However, because of the antigenic novelty of the 2009(H1N1) pandemic virus, which is anticipated to continue circulating during 2012-13, exposure history to this antigen also must be considered. Children who last received seasonal (trivalent) influenza vaccine before the 2010-11 season but did not receive a vaccine containing 2009(H1N1) antigen (either seasonal vaccine since July 2010 or monovalent 2009 vaccine) will not have received this antigen. These children are recommended to receive 2 doses this season, even if 2 doses of seasonal influenza vaccine were received before the 2010-11 season. This is illustrated in two approaches for determining the number of doses required for children aged 6 months through 8 years, both of which are acceptable (Figure 1). 1. The first approach takes into consideration only doses of seasonal influenza vaccine received since July 1, 2010. This recommendation is harmonized with that of the American Academy of Pediatrics (10). This approach has the advantage of simplicity, particularly in settings in which ascertaining vaccination history before the 2010-11 season is difficult. Using this approach, children aged 6 months through 8 years need only 1 dose of vaccine in 2012-13 if they received a total of 2 or more doses of seasonal vaccine since July 1, 2010. Children who did not receive a total of 2 or more doses of seasonal vaccine since July 1, 2010, require 2 doses in 2012-13. 2. In settings where adequate vaccination history from before the 2010-11 season is available, the second approach may be used. By this approach, if a child aged 6 months through 8 years is known to have received at least 2 seasonal influenza vaccines during any previous season, and at least 1 dose of a 2009(H1N1)-containing vaccine (i.e., either 2010-11 or 2011-12 seasonal vaccine or the monovalent 2009 vaccine), then the child needs only 1 dose for 2012-13. Using this approach, children aged 6 months through 8 years need only 1 dose of vaccine in 2012-13 if they have received any of the following: -2 or more doses of seasonal influenza vaccine since July 1, 2010; or -2 or more doses of seasonal influenza vaccine before July 1, 2010, and 1 or more doses of monovalent 2009(H1N1) vaccine; or -1 or more doses of seasonal influenza vaccine before July 1, 2010, and 1 or more doses of seasonal influenza vaccine since July 1, 2010. Children for whom one of these conditions is not met require 2 doses in 2012-13. # Available Vaccine Products and Indications Multiple influenza vaccines (with the same antigenic composition) are expected to be available during the 2012-13 season (Table ). Current package inserts should be consulted for updated information and description of additional components of various vaccine formulations, indications, contraindications, and precautions. TIV preparations, with the exception of Fluzone Intradermal (Sanofi Pasteur), should be administered intramuscularly. For adults and older children, the deltoid is the preferred site. Infants and younger children should be vaccinated in the anterolateral thigh. Specific guidance regarding site and needle length for intramuscular administration can be found in ACIP's General Recommendations on Immunization (11). For intramuscular TIV preparations, children aged 6 through 35 months receive 0.25 mL per dose; persons aged ≥36 months receive 0.5 mL per dose (Table ). Fluzone Intradermal is administered intradermally via a single-dose, prefilled microinjection syringe. The preferred site for administration is over the deltoid muscle. Age indications for the various TIV products differ. All TIV preparations contain the same quantity of hemagglutinin (15 µg per vaccine virus strain per 0.5 mL dose; 45 µg total), except Fluzone Intradermal and Fluzone High-Dose (Sanofi Pasteur). Fluzone Intradermal is indicated for persons aged 18 through 64 years and contains 9 µg of hemagglutinin per vaccine virus strain (27 µg total) in a 0.1 mL dose. Fluzone High-Dose is indicated for persons aged ≥65 years and contains 60 µg of hemagglutinin per vaccine virus strain (180 µg total) in a 0.5 mL dose. Within specified age indications, ACIP expresses no preference for any given TIV formulation over another. The intranasally administered live-attenuated influenza vaccine (LAIV), FluMist (MedImmune), is indicated for healthy, nonpregnant persons aged 2 through 49 years. No preference is indicated for LAIV versus TIV in this age group - Vaccination providers should consult Food and Drug Administration-approved prescribing information for 2012-13 influenza vaccines for the most updated information, including indications, contraindications, and precautions. † Data on maximum ovalbumin content is supplied in package inserts of certain vaccines. Persons with a history of mild allergy to egg (specifically, those who experience only hives) should receive TIV with additional precautions (Figure 2). § Information is not included in package insert but is available upon request from the manufacturer, Sanofi Pasteur, by contacting 1-800-822-2463 or mis.emails@ sanofipasteur.com. ¶ Figure 1 describes two approaches for determining the number of doses needed for children aged 6 months through 8 years. For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. † † Age indication per package insert is ≥5 years; however, the Advisory Committee on Immunization Practices recommends that Afluria not be used in children aged 6 months through 8 years because of increased risk for febrile reactions noted in this age group with CSL's 2010 Southern Hemisphere TIV. If no other age-appropriate, licensed inactivated seasonal influenza vaccine is available for a child aged 5 through 8 years who has a medical condition that increases the child's risk for influenza complications, Afluria can be used; however, vaccination providers should discuss with the parents or caregivers the benefits and risks of influenza vaccination with Afluria before administering this vaccine. Afluria may be used in persons aged ≥9 years. § § A 0.5-mL dose contains 60 µg of each vaccine antigen (180 µg total). ¶ ¶ A 0.1-mL dose contains 9 µg of each vaccine antigen (27 µg total). * A new quadrivalent formulation of FluMist was approved by the Food and Drug Administration in February 2012. It is anticipated that this formulation will replace the currently available seasonal trivalent LAIV formulation for the 2013-14 season. FluMist is shipped refrigerated and stored in the refrigerator at 35°F-46°F (2°C-8°C) after arrival in the vaccination clinic. The dose is 0.2 mL divided equally between each nostril. Health-care providers should consult the medical record, when available, to identify children aged 2 through 4 years with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2 through 4 years should be asked, "In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?" Children whose parents or caregivers answer "yes" to this question and children who have asthma or who had a wheezing episode noted in the medical record within the past 12 months should not receive FluMist. † † † Insufficient data available for use of LAIV in egg-allergic persons. § § § Flumist is indicated for healthy, nonpregnant persons aged 2 through 49 years. Persons who care for severely immunosuppressed persons who require a protective environment should not receive FluMist given the theoretical risk for transmission of the live-attenuated vaccine virus. (1). Persons with a history of egg allergy should receive TIV rather than LAIV. Persons who care for severely immunosuppressed persons who require a protective environment should not receive LAIV given the theoretical risk for transmission of the live-attenuated vaccine virus. # Febrile Seizures Associated with TIV and PCV13 Febrile seizures are common in young children. At least one febrile seizure is experienced by 2%-5% of children, and nearly all children who have a febrile seizure recover quickly and are healthy afterwards (12). Before the 2010-11 influenza season, an increased risk for febrile seizures after TIV administration had not been observed in the United States (13,14). During the 2010-11 influenza season, CDC and the Food and Drug Administration (FDA) conducted enhanced monitoring for febrile seizures after influenza vaccination because of reports of an increased risk for fever and febrile seizures in young children in Australia associated with a 2010 Southern Hemisphere vaccine produced by CSL Biotherapies (up to nine febrile seizures per 1,000 doses) (15). Because of the findings in Australia, ACIP does not recommend the U.S.-licensed CSL Biotherapies' TIV, Afluria, for children aged <9 years (2,16) (Table ). Surveillance for U.S.-licensed influenza vaccines during the 2010-11 season subsequently detected safety signals for febrile seizures in young children after TIV administration (17,18). Further assessment determined that the increased risk was in children aged 6 months through 4 years on the day of vaccination to the day after (the 0-1 day risk window). The risk was higher when children received concomitant PCV13 (i.e., when the two vaccines are administered at the same healthcare visit) and peaked at approximately age 16 months (18). No increased risk was observed in children aged ≥5 years after TIV or in children of any age after LAIV. The magnitude of the increased risk for febrile seizures in young children in the United States (<1 per 1,000 children vaccinated) was substantially lower than the risk observed in Australia in 2010 (15). After evaluating the data on febrile seizures from the 2010-11 influenza season and taking into consideration benefits and risks of vaccination, no policy change was recommended for use of TIV or PCV13 for the 2011-12 season (16,19,20). Surveillance data on febrile seizures in young children after administration of influenza vaccine for the 2011-12 influenza season (same vaccine formulation as 2010-11) were consistent with those from the 2010-11 influenza season (CDC, unpublished data, 2012). No changes in the use of TIV or PCV13 are recommended for the 2012-13 influenza season. As stated previously, ACIP does not recommend the U.S.-licensed CSL Biotherapies' TIV, Afluria, for children aged <9 years (2,16) (Table ). # Influenza Vaccination of Persons with a History of Egg Allergy Severe allergic and anaphylactic reactions can occur in response to a number of influenza vaccine components, but such reactions are rare. All currently available influenza vaccines are prepared by means of inoculation of virus into chicken eggs. The use of influenza vaccines for persons with a history of egg allergy has been reviewed recently by ACIP (16). For the 2011-12 influenza season, ACIP recommended that persons with egg allergy who report only hives after egg exposure should receive TIV, with several additional safety measures, as described in this document. Recent examination of VAERS data indicated no disproportionate reporting of allergy or anaphylaxis after influenza vaccination during the 2011-12 season (21). For the 2012-13 influenza season, ACIP recommends the following: 1. Persons with a history of egg allergy who have experienced only hives after exposure to egg should receive influenza vaccine, with the following additional safety measures (Figure 2): a) Because studies published to date involved use of TIV, TIV rather than LAIV should be used ( 22); b) Vaccine should be administered by a health-care provider who is familiar with the potential manifestations of egg allergy; and c) Vaccine recipients should be observed for at least 30 minutes for signs of a reaction after administration of each vaccine dose (22). Other measures, such as dividing and administering the vaccine by a two-step approach and skin testing with vaccine, are not necessary (22). 2. Persons who report having had reactions to egg involving such symptoms as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or another emergency medical intervention, particularly those that occurred immediately or within a short time (minutes to hours) after egg exposure, are more likely to have a serious systemic or anaphylactic reaction upon reexposure to egg proteins. Before receipt of vaccine, such persons should be referred to a physician with expertise in the management of allergic conditions for further risk assessment (Figure 2). 3. All vaccines should be administered in settings in which personnel and equipment for rapid recognition and treatment of anaphylaxis are available. ACIP recommends that all vaccination providers should be familiar with the office emergency plan (11). 4. Some persons who report allergy to egg might not be eggallergic. Those who are able to eat lightly cooked egg (e.g., scrambled egg) without reaction are unlikely to be allergic. Egg-allergic persons might tolerate egg in baked products (e.g., bread or cake). Tolerance to egg-containing foods does not exclude the possibility of egg allergy (23). Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs and egg-containing foods, plus skin and/ or blood testing for immunoglobulin E antibodies to egg proteins. 5. A previous severe allergic reaction to influenza vaccine, regardless of the component suspected to be responsible for the reaction, is a contraindication to future receipt of the vaccine. # Quadrivalent Influenza Vaccines All currently available influenza vaccines are trivalent and contain A(H1N1), A(H3N2), and B viral antigens. There are two antigenically distinct lineages of influenza B viruses referred to as Victoria and Yamagata lineages (24). Immunization against B virus strains of one lineage provides limited cross-protection against strains in the other lineage (25). Because of this and the difficulty of predicting which B virus lineage will predominate during a given season, inclusion of a second influenza B vaccine virus strain in seasonal influenza vaccines has been proposed. A recent analysis indicates that the impact of such a quadrivalent vaccine could result in a modest reduction in influenza-associated outcomes, depending upon adequate vaccine supply, coverage, effectiveness, and incidence of influenza associated with the two B lineages (26). In February 2012, FDA approved a new seasonal quadrivalent LAIV, FluMist Quadrivalent (MedImmune). This vaccine currently is not anticipated to be available until the 2013-14 influenza season, at which time it is expected to replace the currently available seasonal trivalent FluMist formulation (Table ). Inactivated quadrivalent influenza vaccines currently are in development. These vaccines will be addressed in the ACIP influenza statement as they are approved and become available commercially. - Respiratory distress (e.g., wheezing)? - Gastrointestinal (e.g., nausea/vomiting)? - Reaction requiring epinephrine? - Reaction requiring emergency medical attention? ? # Reported by Lisa Grohskopf

# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR INORGANIC LEAD recommends that employee exposure to inorganic lead in the workplace be controlled by adherence to the following sections. The standard is designed to protect the health and safety of workers for an 8-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of lead on the health and safety of workers. The standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. Sufficient technology exists to permit compliance with the recommended standard. The criteria and standard will be subject to review and revision as necessary. "Inorganic lead" means lead oxides, metallic lead, and lead salts (Including organic salts such as lead soaps but excluding lead arsenate). "Exposure to Inorganic lead" is defined as exposure above half the recommended workroom environmental standard. Exposures at lower environmental concentrations will not require adherence to the following sections, except for Section 7(a). # Section 1 -Environmental (workplace air) (a) Concentration Occupational exposure to Inorganic lead shall be controlled so that workers shall not be exposed to inorganic lead at a concentration greater that 0.15 mg Pb/m^ determined as a time-weighted average (TWA) exposure for an 8-hour workday. (b) Sampling, Collection, and Analysis Procedures for collection of environmental samples shall be as provided in Appendix I, or by an equivalent method. Analysis of samples shall be as provided in Appendix II, or by any method shown to be equivalent in precision and accuracy to the method specified in Appendix II. # Section 2 -Medical Medical monitoring (biologic monitoring and medical examinations) shall be made available to workers as outlined below. (a) Biologic monitoring Biologic monitoring shall be made available to all workers subject to "exposure to inorganic lead." It consists of sampling and analysis of whole blood, or alternatively, of urine for lead content. Such monitoring shall be performed to ensure that no worker absorbs an unacceptable amount of lead. Unacceptable absorption of lead posing a risk of lead poisoning is demonstrated at levels of 0.080 mg Pb/100 g of whole blood or greater, or at levels of 0.20 mg Pb/liter of urine (with urine specific gravity corrected to 1.024) or greater. Procedures for sampling and analysis of blood or urine for lead shall be as described in Appendix II, or by any method shown to be equivalent in precision and accuracy. In the case of urine, "spot" urine specimens of about 100 ml shall be collected during a workday, and urine specimens with a specific gravity less than 1.010 shall be discarded and another sample obtained. Half of all workers subject to "exposure to inorganic lead" shall be offered biologic monitoring every 6 months, so that each worker 1-2 shall have blood sampling and analysis made available to him yearly. If urine sampling and analysis are chosen instead of blood lead sampling and analysis to satisfy the biologic monitoring requirement, every worker shall have urine sampling and analysis made available to him at 6 month intervals. The schedule of biologic monitoring, above, may be altered if indicated by a professional industrial hygiene survey. If environmental sampling and analysis show that environmental levels are at or greater than the environmental limit, the interval of biologic monitoring shall be halved, i.e. blood analysis shall be conducted quarterly, with each worker sampled semi annually, or urinalysis shall be conducted quarterly on every worker. This increased frequency shall be continued for at least 6 months after the high environmental level has been shown. If a worker's urine lead level is found to be 0.20 mg/liter or greater, calculated to a specific gravity of 1.024, a blood sample shall be obtained and analyzed within two weeks. If a blood lead level of 0.080 mg Pb/100 g or greater is found, and confirmed by a second sample to be taken within two weeks, steps to reduce his absorption of lead shall be taken as soon as the high levels are confirmed. Steps to be considered should include improvement of environmental controls, of personal protection or personal hygiene, and use of administrative controls. A medical examination for possible lead poisoning shall be made available, and the OSHA area industrial hyglenist shall be informed of the results of the biologic 1-3 sampling of those workers with confirmed, high biologic levels of lead. Biologic monitoring shall also be made available where the OSHA area Industrial hygienlst has reason to believe operations produce unusual exposure excursions or that environmental samples do not adequately describe worker exposure. (b) Medical examination Medical examinations shall be available when a variance has been granted permitting administrative controls or use of respiratory protection, for workers with unacceptable absorption of lead as judged by biologic monitoring, or when environmental levels are at or above the environmental standard. These examinations should be made available prior to employee placement and annually thereafter. They should include a physical examination, complete blood counts, blood lead determinations, routine urinalysis (specific gravity, sugar and protein determinations, and microscopic examination), and should record any signs or symptoms of plumbism, if present. Where urine is selected instead of blood for biologic monitoring, the preplacement examination should also include a urinary lead determination. Each employee who absorbs unacceptable amounts of lead as indicated by biologic monitoring shall be examined as soon as practicable after such absorption is demonstrated and confirmed, and at least every 3 months thereafter until his blood or urine lead levels have returned to normal, i.e. below 0.080 mg/100 g of blood or 0.20 mg/liter of urine. If clinical evidence of plumbism 1-4 is developed from these medical examinations, the worker shall be kept under a physician's care, in accordance with applicable Workman's Compensation provisions, until the worker has completely recovered or maximal improvement has occurred. Medical records shall include information on all biologic determinations and on all required medical examinations. These records shall be available to the medical representatives of the employer, of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, and, at the employee's request, to the employee's physician. These records shall be kept for at least five years after the last occupational exposure to inorganic lead. # Section 3 -Labeling (Posting) Areas where exposure to lead at levels over one-half the workroom air standard is likely to occur shall be posted with a sign reading: LEAD (Pb) DANGER! High concentrations of fume or dust may be hazardous to health. Provide adequate ventilation. If environmental levels are at or greater than the environmental limit, or if a variance permitting use of respiratory controls has been granted, add information to the label or placard describing the location of the respirators. Engineering controls shall be used wherever feasible to maintain lead dust and fume concentrations below the prescribed limits. Appropriate respirators shall be provided and used when a variance has been granted to allow respirators as a means of control of exposure to routine operations and while the application is pending. Administrative controls should also be used to reduce exposure. Respirators shall also be provided and used for nonroutine operations (occasional brief exposures above the TWA of 0.15 mg/n? and for emergencies); however, for these instances a variance is not required but the requirements set forth below continue to apply. Appropriate respirators as described in Table 1-1 shall only be used pursuant to the following requirements: (1) For the purpose of determining the class of respirator to be used, the employer shall measure the atmospheric concentration of inorganic lead in the workplace when the initial application for variance Is made and thereafter whenever process, worksite, climate or control changes occur which are likely to affect the lead concentration. The employer shall test for respirator fit and/or make lead measurements within the respiratory inlet covering to ensure that no worker is being exposed to inorganic lead in excess of the standard either because of improper respirator selection or fit, (4) The employer shall provide respirators in accordance with the Table below and shall assure that the employee uses the respirator provided. (5) If both fume and dust are present, the recommended usage is that for fume. (6) Respiratory protective devices described in the following (2) Work clothing should be vacuumed before removal. Clothes shall not be cleaned by blowing or shaking. (3) Work clothing should be changed at least twice a week and more frequent changes, especially in high exposure areas, are suggested. (4) Adequate shower facilities should be available and used. (5) When in the judgment of the OSHA area industrial hygienist contamination of clothing or exposed body surfaces can produce significant secondary exposures, items (1), ( 2), (3), and (4) above shall be mandatory. (2) Respirators shall be available for wearing during evacuation procedures if long distances need to be traversed; supplied air respirators shall be available for employee use where equipment or operations cannot be abandoned. # (b) Exhaust Systems Where a local exhaust ventilation and collection system is used, it shall be designed and maintained to prevent the accumulation of lead dust and fume. (1) Hazardous types of exposure should not be scattered throughout a plant but, rather, concentrated in a single area where special control procedures can be utilized. (2) Air from the exhaust ventilation systems shall not be recirculated into the workroom, and should not be discharged outside the plant so as to create an air pollution problem. (c) General Housekeeping (1) Vacuuming shall be used wherever practicable and no dry sweeping or blowing shall be performed. (2) Emphasis shall be placed upon cleanup of spills, periodic repair of equipment and leaks, proper storage of material«, and collection of lead-containing dust. Records of these surveys, including the basis for concluding th?f f,,r levels are below half the environmental standard, shall be k®pt. # T--7 2 Requirements set forth below apply to inorganic lead exposures, (a) Employers shall monitor environmental levels of lead at least every 6 months, except as otherwise indicated by a professional industrial hygiene survey. If environmental levels are at or above the standard, environmental levels shall be monitored every 3 months. This increased frequency of monitoring shall be continued at least 6 months (i.e. two more quarterly monitoring periods) after the last sampling that demonstrated levels at or above the environmental limit. Periodic environmental sampling shall be performed to coincide with periodic biologic sampling, i.e. shall be performed within 2 weeks of biologic sampling. Metal products and miscellaneous categories account for the bulk of lead consumption. The refining and processing necessary to form these products include heating, grinding, and volatilization and therefore produce potentially hazardous industrial atmospheres. The impression should not be left that all workers in these industries are jeopardized, but rather that such uses of lead places them at risk of lead absorption. # Historical Lead has been used for thousands of years because of its availability and desirable properties. Its low melting point (327 C), ductility, malleability, and weathering resistance enabled its use without the need for the more complex equipment that, in modern times, has enabled the use of other metals such as steel that have more desirable properties for many applications. In the 1800's, there was an increasing recognition of hazards to health associated with lead. It was found that lead could be absorbed by inhalation and ingestion, and that lead absorption was responsible for loss of movement in printers' fingers exposed to heated lead type and for "dry grippes" in pottery and glass workers. In 1839, Tanquerel des Planches^ published a treatise on lead diseases, to which Dana later added notes on the effects of using lead pipes. Progress in recognizing signs of lead absorption was made during the 19th Century also. Burton,^ described in 1840 the "Burtonian Line", a blue line on the gums, as a sign of lead absorption, and chemical methods for detection of lead in blood or urine were developed. The prevalence of lead poisoning in ancient times is speculated upon, and it has been suggested that Rome fell because of the prevalence of lead III-2 poisoning (plumbism) in its citizens. It seems likely that, with the ignorance that existed on the hazards of lead and on methods of limiting exposure, there was a significant incidence of plumbism until its recognition in recent times generated preventive procedures. # Effects on Humans A description of effects of lead absorption can be graphic if based 8 on effects seen in industries earlier in this century. Thus, Mayers can describe effects of lead poisoning, from studies of many years ago, such as loss of appetite, metallic taste in the mouth, constipation and obstipation, anemia, pallor, malaise, weakness, insomnia, headache, nervous irritability, muscle and joint pains, fine tremors, encephalopathy, and colic. In lead colic, there may be severe abdominal pain, such that abdominal surgery has occasionally been performed. In workers, as pointed 8 out by Mayers, who have had repeated attacks of lead colic over many years, there is a tendency towards the occurrence of weakness of extensor muscle groups. This weakness may progress to palsy, often observed as a characteristic "wrist drop" or "foot drop." The important routes of absorption of lead by man and animals are ingestion and inhalation. Eating of lead-bearing paint by children and drinking of lead-contaminated, illicitly distilled whiskey are important sources of non-industrial poisoning. Other sources include exposure to buring battery casings, drinking of liquids from improperly fired, leadglazed containers, and high levels of airborne lead. But man absorbs lead in small amounts not normally leading to poisoning from his food and water, and from the air. These sources lead to the "normal" body burden III-3 of lead. Thus, the lead absorbed in the course of occupational exposure Is superimposed on lead abosrbed from other means. Descriptions of lead poisoning appear in many texts and reviews, for example Airborne Lead in Perspective, a report of the National Epidemiologic Studies L a n e^ examined the causes of death of storage battery workers, including retired workers, and compared data from this group with data from all English and Welsh males of similar ages during the same period of time. Among the retirees who had been exposed to lead, there were found to be greater numbers of deaths than would have been expected, for their ages, from data on the population as a whole. Most of this excess in expected mortality was accounted for by vascular lesions in the central nervous system. Lead workers who died during employment also showed an excess of deaths from this cause. Another study of electric storage battery workers was conducted by the Public Health Service over 30 years a g o .^ In this study, the incidence of various disease states was studied in relation to lead exposure of 766 workers, most of whom (75%) had worked in storage battery plants for more than five years and some of whom (12%) had worked there for twenty years or more. The incidence of disease (other than plumbism) in men exposed at 3 levels of 0.15 mg/m and higher (high exposure group) was compared to the 3 incidence in men exposed below 0.15 mg/m (low exposure group). Special attention was given to cardiovascular disease because of the common belief that chronic plumbism results in arteriosclerosis; however, the data developed by the PHS team did not show that more severe exposure to lead is associated with a significantly higher incidence of vascular disease. The incidence of arteriosclerotic-hypertensive disease was not significantly different in the high and low exposure groups. The responses to a standard III-6 exercise, in terms of return to pre-exercise pulse rates and to systolic and diastolic blood pressure, were also compared, and again the two groups were found not to be significantly different from each other. These lead workers were also found not to be significantly different from other, non-lead, workers in terms of blood pressure. From this, it was concluded that exposure to lead in the storage battery industry does not cause cardiovascular effects. A contrary conclusion was reached by Dingwall-Fordyce and Lane ^ in a study of British battery workers. A significant excess of deaths from cerebro vascular accidents was found in pensioners who had had exposure to lead of sufficient degree to have caused mean urinary lead levels of 0.25 mg/liter during many years of lead work. They compared three groups of workers-those with no occupational lead exposure, those with negligible exposure, and those occupationally exposed to leadwith the general population of English and Welsh males of similar ages. They found a significant excess of death, over that predictable from the population at large, among retirees in the highest exposure group, and this was largely attributable to cerebrovascular accidents. They also examined records of deaths due to cancer in lead workers, both employed and retired, and concluded that there was no association between malignant disease and lead absorption. While they found an excess of deaths from cancer in the negligible exposure group (in the last decade of the 35-year figures only), there was *Urinary lead levels in this group averaged between 0.10 and 0.25 mg/liter for a 20-year period. III-7 a slight decrease in deaths, from that expected from statistics on the whole population, among workers absorbing more than negligible amounts of lead, hence their conclusion that malignant disease is not related to lead absorption. As improved working conditions decreased lead exposure, the excess of cerebrovascular deaths diminished. 13 Malcolm recently conducted similar investigations of past and present employees exposed to lead. Since 1927, airborne lead to which these men 3 had been exposed had been limited to 0.15 mg/m , according to Malcolm. He divided the workers into three groups: (A) no exposure, (B) mild exposure, 'ft and (C) severe exposure. Average blood lead in group (C) workers, since 1961, has been 0.065 mg/100 g, from which it may be inferred that the 3 0.15 mg/m air concentration was sometimes exceeded. Urinary leads in subgroups averaged 0.09 to 0.180 mg/liter, and averaged 0.119 mg/liter for the entire group of workers. Based on comparison of blood pressures of the two exposed groups (B and C) with the control group (A), it was concluded that there was no occupationally induced hypertension (although there might have been leadinduced hypertension before improved hygienic measures were instituted). There was a non-significant increase in chest disease among older retired workers, attributed to other causes, since most of these pensioners lived in an urban area with a higher rate of death from chest disease than that in the country as a whole. "Concentrations of lead in blood are expressed as weight units (such as mg) per 100 ml or 100 g of whole blood. European workers more commonly express blood lead as weight units per 100 ml of blood, while American workers more commonly express blood lead as weight units per 100 g of blood. This document will follow the American custom except in referring to studies reporting blood lead in weight units per 100 ml. The difference between the two expressions is small, about 5% or less. Thus, a blood lead concentration of 0.080 mg/100 g would be equivalent to about 0.084 mg/100 ml. III-8 Unlike the findings of earlier investigators (Dingwall-Fordyce and Lane, and Lane ^ Malcolm found no evidence of increased frequency of cerebrovascular death in his study, which included deaths occurring between 1963 and 1967, while data from the two earlier reports included deaths from 1926 to 1960. Thus, if all three reports are correct in their conclusions, it would seem that improving hygiene has diminished leadinduced cerebrovascular disease. For years, chronic nephritis was thought to be a consequence of plumbism, and an analysis of death rates in the U.K. in 1921 ^a n d in 13 1931 shows a considerable excess in plumbers and painters due to nephritis and to cerebrovascular disease. The question of nephropathy 14 from lead has also been raised by Henderson and Inglis, who showed a relationship between chronic nephritis and excessive lead absorption as indicated by elevated lead levels in bone. L a n e^ described 9 deaths from renal failure in lead workers, men 3 who had been exposed for long periods at lead concentrations around 0.5 mg/m . Terminally, they all had evidence of chronic azotemic nephritis. These men, all of whom worked in storage battery industries for over 20 years, died between the ages of 42 and 52 (average age at death was 48.4). Other than two episodes of colic, there had been no previous history of lead intoxication. In the United States, there have been few reports of renal disease in 13 lead workers, though the PHS survey of storage battery workers discovered an increased incidence of albuminuria in affected workers. # III-9 Animal Toxicity Unlike toxicologic studies of many industrial substances, experimental animal studies of either inorganic or organic lead have contributed far less to an understanding of the toxicology of lead and its compounds than studies on man, and hence have directly contributed very little to the criteria for the standard for lead. The reason is that until recently, much of the investigative effort was directed to the effects of lead on the red blood cell, its urinary intermediates and lead content of blood and urine, all readily investigated in man. Moreover, many of the studies in man or animals relate to detecting changes in biologic constituents of the blood and urine, and hence are relevant more to criteria for biologic standards than to air standards. Thus, the experimental studies discussed herein will be confined to those that confirm or extend the findings in man in these areas and which are related, even if only indirectly, to the criteria for the air standard. In recent years, research investigations have broadened to include biologic systems other than the erythropoietic, and in this way may ultimately provide new criteria for standards. Lead intoxication has been studied for its effects on the rat thyroid, comparative changes in kidneys of rat and man, and the effect of certain trace metal deficiencies on the toxicity of lead. But only a beginning has been made in our understanding of the action of lead on the nervous system; behavioral effects have been A distinct relationship has been found between lead poisoning and the metabolism of nicotinic acid^®; animals poisoned by lead showed a marked decrease in the nicotinic acid content of blood (and urine), indicating an increased utilization of this constituent by lead, and suggesting that lead exerts serious effects on the pyridine nucleotides, either by blocking *This is not to detract from the major recommendation of the PHS conference on lead ° to search for ever-more sensitive indicators of response, because much of value on the mechanism of lead in the biosynthesis of heme has resulted, but it does clearly point out 1) that ultra-sensitive methods may not always have practical utility in estimating and controlling workers exposure, and 2) that, inasmuch as highly sensitive methods are used as the criteria for many, if not most, of the air standards in the U.S.S.R., these standards must be carefully reexamined in the light of their appropriate' ness and suitability. their synthesis or by accelerating the degradation of nicotinic acid. These changes have been suggested as a means of assessing the severity of lead poisoning. In line with the general opinion that toxic substances adversely affect the body's resistance to disease by interfering with natural 31 immunologic processes, Fonzi et al. showed that lead-treated and actively immunized animals developed lesser amounts of gamma globulin than did immunized controls. Similarly, lysozyme, another part of the defense mechanisms of the body, was progressively reduced in the blood serum of 32 dogs administered lead salts for a prolonged period. Although shifts in the body's inorganic elements (copper, calcium 33 phosphorus, sodium and potassium ) from lead poisoning have been 34 reported, their significance in over-all body metabolism is yet to be clearly demonstrated. e. Endocrine Changes. The effects of lead exposure on some aspects of endocrine function have been studied in animals, as well as in man. The excretion of steroids was studied in the urine under different conditions of lead exposure in the hope of finding some evidence of their relation to lead absorption. Adrenal steroids were reported at first to decrease, then to 35 increase considerably during advanced stages of lead intoxication. Vitamin C content of the adrenal gland was decreased in the guinea pig following exposure to l e a d .R elatively little use has been made of animals in the study of other 37 endocrine functions, these functions being readily studied in man. Sandstead has, however, reported that lead, like other heavy metals, impairs the uptake of iodine by the thyroid, and that the conversion of iodine to proteinbound iodine is retarded; females were more affected than males. f. Renal Changes, Goyer has recently reviewed the current state of knowledge of the effects of lead on the kidney; his review is based in large part on his investigations and those of his associates. Prominent among their findings of acute lead poisoning in animals were 1) formation of intranuclear inclusion bodies, 2) mitochondrial swelling with impairment of oxidative and phosphorylative processes, and 3) ami noaciduria (apart from the long-recognized delta-aminolevulinic aciduria); the intranuclear inclusion bodies were a lead-protein complex that may have adaptive function in excessive lead exposure. The acute renal changes progress to a diffuse nephropathy with tubular atrophy and dilation. Rats developed hyperuricemia and in chronic lead poisoning, renal adenocarcinoma. In all but the last, the findings made in rats paralleled those seen in man. g. Trace Metal Interactions. In recognition that lead poisoning is often associated with an iron-deficiency anemia, the interaction of lead on 39 iron deficiency was studied in the rat. An enhancement of lead retention and toxicity was found in the iron-deficient animals as measured by elevated ALA excretion. To control urinary coproporphyrin to normal levels (below 50 pg/liter), 3 they recommended a TLV of about 0.12 mg/m for daily 8-to 10-hour exposures. However, the workers studied by these investigators worked 48 to 60 hours a week. With the increased lead absorption from these working hours, a lower standard than that suitable for a 40-hour week would be indicated. If other criteria were chosen on which to base an air limit, other limits O would have been selected; 0.10 mg/m would have been recommended to keep q urinary lead levels below 0.15 mg/liter, 0.14 mg/m to keep basophilic 3 stippling at 0.3 per thousand, and 0.14 to 0.15 mg/m to prevent anemia. They did not use blood lead as a criterion of effect. The study of Williams, King, and Walford was based on observations of storage battery workers who worked a 40-hour week, and were stable in their exposure. They had worked without job change for a year, there was no recent absence for sickness or vacation, and no change in overtime or productivity for 6 months. Workers in the plastics department were exposed to airborne lead levels of about 0.01 mg/m , while workers in lead handling departments were exposed q to higher levels, up to about 0.3 mg/m . Specific gravities of urine samples averaged 1.020 in the morning and 1.022 at lunch time. They concluded that air levels of 0.20 or 0.15 would result in the blood and urinary lead levels given in Table X-5 (urinary lead levels were corrected for a specific gravity of 1.024; it should be noted that a urinary level of 0.20 mg/liter corrected to a specific gravity of 1.024 would be 0.133 mg/liter corrected to 1.016). These investigators also showed a very low correlation (r = 0.09) between airborne lead and blood hemoglobin levels. Selander and Cramer compared blood lead, urinary lead, and urinary ALA in lead workers. They found several workers with high urinary lead and ALA values in relation to blood lead and attributed this to a metabolic influence of lead; ALA excretion in these workers had seldom fallen to normal values. They recommended that workers removed from lead overexposure not be allowed to return until ALA excretion was normal. Blood lead: 0.08 mg/100 ml Urinary lead: 0.15 mg/liter Urinary coproporphyrin: 0.50 mg/liter Urinary ALA: 20 mg/liter They point out that these values may not be applicable when there are low hemoglobin levels or where chelating agents have been used. Stankovic^ reported on blood and urine lead concentrations, urinary coproporphyrin, and urinary ALA in workmen exposed to lead at various « 1 concentrations of lead in air. In workmen exposed to 0.15 mg/m-and below, the highest Individual blood lead found was 0.06 mg/100 g, the highest urine lead 0.12 mg/liter, the highest urinary coproporphyrin 0.186 mg/liter, and the highest urinary ALA 11.85 mg/liter. There were 48 workers exposed to air lead levels of 0.025 to 0.15 mg/m , whose mean blood lead level was 0.05 mg/100 g (range of 0.03 to 0.06). However, the number of workers exposed to or near 0.15 mg/m was not stated. Zielhuis^ has reviewed and analyzed the data of several other investi gators of human absorption of lead, In terms of the. relationships between, blood lead, ALA, and copToporphyrin. He concluded from analysis of these data that a combination of blood lead greater than 0.08 mg/100 g with values of urinary lead greater than 0.15 mg/liter or urinary ALA greater than 20 mg/llter or urinary coproporphyrin greater than 0.80 mg/liter is evidence of an unacceptable degree of occupational exposure to lead. He did not review the relationships between airborne lead and the several Indices of biological effect of absorbed lead. The selection of 0.08 mg Pb/100 g of whole blood has been described by 52 # Kehoe as the critical concentration of lead in blood below which no case of even olid poisoning has been induced by lead. The higher the concentration of blood lead above 0.08f the greater the likelihood of lead poisoning, though higher concentrations did not mean lead poisoning in all Individuals. The scientific consensus supports the view of Kehoe as it applies to adults. However, even in the hands of the best analyst, there may be a 10% error in a specific lead determination. Thus, an analysis showing a blood level of 0.08 mg/100 g may have a true value of almost 0.09. This may account for the recommendation of some authorities^® that blood lead levels be kept below 0.07 mg/100 g. IV. ENVIRONMENTAL DATA Information presented in this section was selected to satisfy two purposes: (1) link measured environmental and biological levels to specific lead using industries, and (2) to link exposure levels to clinical lead intoxication. Table X- Leaded steel production sometimes generates hazardous occupational exposures to lead. Ruhf^® reported that the highest atmospheric lead concentra tions prevailed during the steel pouring operation in which the lead is added. Other elevated exposures were measured in processes such as the rolling mills. However, because of the intermittent nature of the operations the time weighted average exposure was below the then current limit of 0.20 mg/m^. Ruhf further described control measures and manufacturing techniques whereby lead exposure can be minimized. # IV-4 V. DEVELOPMENT OF STANDARD # Basis for Previous Standards The American Conference of Governmental Industrial Hygienists (ACGIH) ^ has reviewed previous standards for lead in the work environment, and has commented that there are few meaningful data relating to the threshold limit value, probably because most authorities rely primarily on other tests for estimating lead hazards, such as urinary and blood leads, urinary coproporphyrin and ALA, as well as examination of the blood for stippled cells. Nevertheless, attempts were made to control occupational lead poisoning by establishing acceptable air levels to guide engineering control measures. Although the point is not documented, it seems that 3 at one time an air limit value of 0. This ANSI standard provided no basis for its recommendation. # Basis for Recommended Environmental Standard and Biologic Monitoring Earlier in this century, efforts to reduce occupational lead poisoning were based on adherence to hygienic workroom air guides. As more knowledge developed, increasing attention was given to blood and urinary lead levels as guides to reduction of occupational poisoning. Concomitantly, there was increasing attention to better lead analyses. There was also an increasing knowledge of the relationship between levels and rates of absorption and excretion, blood lead levels, and health status. The PHS study by Dreessen et al.^was undertaken during the period q that the workroom air guide of 0.15 mg/m was accepted, but failure to achieve eontrol of airborne lead to this level was common, so findings of slight effects among workers in lead-using industries by Dreessen and co-workers did not invalidate the guide. Though not documented, it appears that many industries have rotated their workers to various jobs to keep blood lead levels below 0.08 mg/100 g; thus, exposure to unsafe workplace air levels did not result in adverse effects on health. # V-2 Consequently, there is a little definitive information from experience in the United States and other countries on the suitability of 0.15 or O 0.20 mg/m as an air-lead level to which workers can be safely exposed over a working lifetime. However, much experience has accrued to show that absorption of lead in amounts resulting in blood lead concentrations of 0.08 mg/100 g or less will not lead to adverse effects on health, and there is information from studies in other countries relating airborne lead levels to blood lead. # It was previously concluded (III. Biologic Effects of Exposure; Correlation of Exposure and Effect) that a blood lead level of 0.08 mg/100 g is useful for delineating acceptable from nonacceptable lead absorption. While levels below 0.08 mg/100 g are indicative of acceptable occupational lead absorption and, if also representative of past absorption of lead by an individual person, also indicative of insignificant risk of lead poisoning, it should not be concluded that lead poisoning will occur if blood lead levels exceed 0.08 mg/100 g. However, there is an increasing risk of poisoning as levels increase above 0.08 mg/100 g, so absorption of lead should be held to amounts that will result in blood lead levels less than 0.08 mg/100 g. As K e h o e^ has stated, "...lead poisoning occurs in man only when certain well-defined conditions have been fulfilled" and that this is quantitatively applied by "...the relationship between the current rate and the extent of the absorption of the inorganic compounds of lead, and the concentration of lead in an accessible tissue of the living body, namely, the blood." Thus, a biologic standard of 0.08 mg of lead per 100 g of whole blood is recommended; it provides a margin of safety in adults, but probably not in children. The extent of this margin of safety is not known, but it seems likely that there will be few, if any, cases of lead poisoning below 0.09 mg/100 g. Kehoe^"- also pointed out the usefulness of urinary lead as an index of current absorption of lead, but added that it was a quantitatively less certain index than blood lead. It may be consistent with this view that 47 Williams, King, and Walford found that the best correlation between air borne lead and biochemical index of effect was with blood lead (r = 0.90) and less correlation with urinary lead (r = 0.82). The study of Williams and # co-workers Indicates that blood levels of 0.08 mg/100 ml is associated (Urinary lead levels of 0.20 mg/liter, adjusted to a specific gravity of 1.024, would be 0.133 mg/liter if the specific gravity were calculated to 1.016.) Thus, the conclusion of Zielhuis"^ that urinary lead greater than 0.15 mg/liter, uncorrected for specific gravity, represents unacceptable absorption of lead is consistent with the selection of a biologic standard for urinary lead of 0.20 mg/liter, so long as the specific gravity correction is used. ALA and coproporphyrin assays, and blood examinations for hemoglobin, reticulocytes, and stippled cells are useful in the assessment of worker health, but are less useful than blood lead as a single criterion for week. The study most directly relevant to the development of a recommended 47 workplace air standard is the study of Williams, King, and Walford. Their data (Table X-5), from studies of storage battery workers stable in their employment (40-hour work week, no job change in the past year, no recent absence or sickness, no change in overtime or productivity), showed that 3 exposure at 0.15 mg/m resulted in a mean blood lead of 0.060 mg/100 ml. Were mean blood lead the criterion of effect, an air standard much higher 3 than 0.15 mg/m could be recommended, but in order to keep most or all workers' blood lead below 0.084 mg/100 ml (0.080 mg/100 g), it is believed that a mean of about 0.060 mg/100 ml should be achieved. The data of 47 Williams and associates does not provide a basis for interpreting the 3 percentage of workers exposed at 0.15 mg/m that will have blood levels above 0.084 mg/100 ml. However, it is believed that a small percentage will have blood lead levels at or above 0.084 mg/100 ml or 0.080 mg/100 g, so it Is recommended that workers be monitored biologically, by periodic assays of blood lead, or of blood and urinary lead. # V-6 Stankovic^ also compared airborne lead with blood and urinary lead, 3 and in workmen exposed to lead at 0.15 mg/m and below, the highest individual blood lead found was 0.06 mg/100 g, and the highest urinary lead 0.12 mg/liter. However, the number of workers exposed at or near 0.15 mg/m was not stated, so his finding of 0.06 mg/100 g as the highest individual blood lead is not believed to contradict the previously stated inference that some workers The recommended method of sampling air involves collection of 100 liters of air or more, use of breathing zone samplers with sampling at a rate of 2 liters/min., and collection on 0.45y cellulose membrane filters. Other sampling rates and other collection media (filter paper, nitric acid impinger, electrostatic precipitation) are capable of giving equivalent results. The recommended procedure is described in Appendix I. For analysis of lead in blood, atomic absorption spectrophotometry^ 7 2 7â nd dithizone colorimetry - were considered. Appreciable consonance can be demonstrated between results obtained with atomic absorption and dithizone methods. Both methods have been used for analysis of air samples, and both are concluded to be capable of giving accurate results. After a review of the several procedures involving atomic absorption spectrophotometry, it was concluded that no one of these procedures has been sufficiently standardized. Individual laboratories get excellent results with a specific procedure, but these procedures have not been compared in a number of laboratories. Dithizone colorimetry, on the other hand, has been used for a long time and has been thoroughly studied. The procedures, interferences, sensitivity, and replicability have been studied and are described by Keenan, Byers, Saltzman, and Hyslop.^ The recommended procedure is described in Appendix II. Dithizone colorimetry is a wet chemical method requiring equipment found in most chemical laboratories, but requires meticulous attention to detail and to the prevention of loss and the exclusion of contamination. V-8 Results of lead analysis by this method obtained by well trained technicians are often superior to results obtained by other methods of analysis. # Basis for Biologic Analytical Method Blood lead was selected as the best method, and urinary lead as an accept able method, for judging lead absorption, for reasons discussed in earlier sections (see "Basis for Recommended Environmental Standard and Biologic Monitoring"). Specific details for collection of biologic specimens for lead have described some of the results, from which it is apparent that lead analysis is subject to significant error unless a very high degree of care is used. Methods for the collection of blood and urine are described by Additional methods, such as cell stippling, porphobilinogen determinations, and examination of intranuclear Inclusion bodies have received less acceptance. These biochemical indices are not recommended at this time. They can be sensitive, perhaps too sensitive, but they are not specific for lead, and are judged to be less useful than blood and urinary lead deter minations for estimating the absorption of lead. However, future develop ments may resolve some of the present objections to the routine use of these indices of alterations of heme synthesis in the assessment of lead absorption. The dithizone procedure is recommended for analysis of lead in blood and urine. As discussed in the previous section (Basis for Environmental Sampling Method), the method is capable of good results if meticulous attention is given to details, including sources of contamination and loss. Additional information on the reproducibility and accuracy of the method is given in other portions of the report. # REAGENTS Analytical grade reagents are used. Purification is essential when analyzing biological tissues and fluids because of the very low levels of lead in these materials; purification of reagents may not be required for air samples containing quantities of lead sufficiently greater than that present in the reagent blank. A reagent blank sample is carried through the entire procedure with each set of unknown samples (air, biological, or other type) and its analyzed lead content is subtracted from each analytical result to calculate the net quantity of lead in each unknown sample. A boiling rod is used to prevent bumping in the flasks when distilling reagents. This is prepared by cutting 3 or A mm O.D. glass tubing to a length which is one cm greater than the height of the flask. The tubing is sealed at a spot about one cm above the bottom end which is fire- Use an electric heating jacket on the boiling flask to minimize danger of its breakage, and a boiling rod to prevent bumping, which otherwise would be severe. Discard the first 50 ml of distillate; this may be combined with the acid allowed to remain in the flask at the end of the distillation and used for washing glassware. The reagent is conveniently dispensed from a small automatic burette. No grease should be used on the stopcock. Nitric Acid, 1:99 -Dilute 10 ml of the redistilled, concentrated acid to one liter with doubled-distilled water. Ammonium Hydroxide, Concentrated -Distill in an all borosilicateglass still 3 liters of the ACS reagent grade, 28.0% minimum specific gravity 0.8957 at 60 F, into 1.5 liters of double-distilled water, VIII-2 contained in a 2-liter reagent bottle which is chilled in an ice bath. Continue the distillation until the bottle is filled up to the pre viously marked 2-liter level. Submerge the condenser tube deeply in the water in the receiver, but withdraw it before discontinuing the heat to avoid siphoning back of distillate. This reagent may be pre pared more conveniently from tank ammonia, using a small wash bottle to scrub the gas and a sintered glass delivery tube which extends to the bottom of the reagent bottle. The ammonia gas is absorbed in double-distilled water until the solution reaches the desired specific gravity. Chloroform -Use a brand with a statement on the label that the chloroform passes the American Chemical Society test for suitability for use in dithizone procedures. In addition, each batch of chloroform should be purchased in glass containers only and should be tested as follows in the laboratory to make sure that it is satisfactory for preparing the dithizone solutions: add a minute quantity of dithizone to a portion of the chloroform in a test tube, shake gently, then stopper with a cork. The faint green color should be stable for one day. Our experience has indicated that the procedures for reclaiming Store in a brown bottle in the refrigerator but allow to warm to room temperature before using. Age for at least one day, then standardize as described in the procedure. Restandardize every few months. Sodium Citrate -Dissolve 125 g of the 2 Na^C^H^-O^-11 H2O salt in sufficient distilled water to provide a solution nearly 500 ml in volume. Adjust the pH to 9-10, using a very small quantity of phenol red indi cator solution (strong red color) and fresh, pHydrion test paper to check the pH. Extract in a large separatory funnel with a 100 mg per liter solution of dithizone and finally with the extraction dithizone reagent until a green extract is obtained with the latter reagent. Add a small volume of lead-free citric acid until an orange color (pH 7) appears. Extract the excess dithizone repeatedly with chloroform until a colorless extract is obtained. Remove the last traces of chloroform. Hydroxylamine Hydrochloride -Dissolve 20 g of the salt in distilled water to provide a volume of 65 ml. Add a few drops of m-cresol purple indicator, then add ammonia until the indicator turns yellow (pH 3). Add a sufficient quantity of a 4% solution of sodium diethyldithiocarbamate to combine with metallic impurities, then mix. After a few minutes extract repeatedly with chloroform until the excess carbamate reagent has been removed, as indicated by the absence of a yellow color in the final chloroform extract tested with a dilute copper solution. # VITT-4 To the aqueous solution of the hydroxylamine hydrochloride add redistilled, 6N hydrochloric acid until the indicator turns pink, and adjust the volume to 100 ml with double-distilled water. Potassium Cyanide -(Danger! Highly poisonous!I) To 50 g of potassi um cyanide in a beaker, add sufficient distilled water to make a sludge. Transfer the sludge to a separatory funnel previously marked to Bhow 100-ml volume. Add a small amount of distilled water to the beaker and warm. (Potassium cyanide cools the solution as it dissolves, thus retarding the solution process.) Add this warm water to the separatory funnel but do not permit contents to exceed the 100-ml mark. Shake, then let stand until the contents come to room temperature. A practically saturated solution results. Extract the lead by shaking repeatedly with portions of the extrac tion dithizone solution until the lead has been removed. Part of the dithizone dissolves in the aqueous phase but enough remains in the chloroform to color it. A green extract indicates that all the lead has been completely extracted. Most of the dithizone in the aqueous phase is then removed by repeated extractions with pure chloroform. Dilute the concentrated solution of potassium cyanide with double-distilled water to 500 ml. It should not be necessary to filter the solution, if the directions are followed precisely. Extraction is carried out before dilution because the higher pH of the dilute solution is less favorable. V I I I -5 (NOTE: A colorless solution usually results if above directions are followed. Occasionally aging results in a brown color or precipitate due to polymerization of hydrogen cyanide. This does not interfere with use of the reagent if it is carefully decanted. Old potassium cyanide reagent may lose enough strength to cause insufficient complexing of large amounts of zinc.) Ammonia-cyanide Mixture -Mix 200 ml of the purified 10% potassium cyanide reagent with 150 ml of distilled ammonium hydroxide (specific gravity 0.9, corresponding to 28.4% NH^) and dilute to one liter with double-distilled water. If the measured specific gravity of the ammonia is not 0.9, use the equivalent volume as calculated from a table of specific gravity vs. percentage ammonia. Standard Lead Solution -Dissolve 1.5984 g of pure lead nitrate in one liter of 1:99 nitric acid to provide a strong stock solution containing one mg Pb per ml. Pipet exactly 20 ml into a 500-ml volumetric flask and make to mark with 1:99 nitric acid to give a dilute stock solution containing 40 y g Pb per ml. (A standard lead solution, 10 yg Pb/ml, was stable in 1:99 nitric acid for three years.) Prepare a working solution, containing 2 y g Pb per ml, just before it is needed by pipetting 5 ml of the dilute stock solution into a 100-ml volumetric flask and making to mark with 1:99 nitric acid. Phenol Red -0.1% aqueous solution. Ashing Aid Acid -Dissolve 25 g potassium sulfate in sufficient redistilled concentrated nitric acid to make 100 ml. # VIII-6 White Petrolatum -Supplied in a glass jar, for greasing stopcocks. To check on the purity, put a pinch of this petrolatum in a beaker, add a few milliliters of the standard dithizone and swirl. If the dithizone is no longer green after a few minutes, the material is unsatisfactory for greasing stopcocks. (This wash nitric acid may be used repeatedly until it loses its strength.) # APPARATUS Then rinse successively with three or four portions each of tap water, distilled and double-distilled water. Set the beakers upright on the bench and cover with a clean dust-case or a large piece of filter paper (or otherwise protect from dust). Under no circumstances is glassware turned upside down to drain on a towel or cheesecloth placed on a laboratory bench. Use an oven operating at 105 C if dry glassware is required. # VIII-8 Separatory funnels are rinsed with tap water immediately after use. If a high lead sample was present or if a visible precipitate remains on the inside, it is rinsed with a small portion of 1 : 1 wash nitric acid (which is discarded), followed by tap water. The stoppered funnels are stored in double-deck racks. Immediately before use, stopcocks are regreased if necessary.. Then the funnels are rinsed with wash acid, four times with tap water, and four times with dis tilled water. Each rinse is accomplished by shaking with the stopper, then draining through the stopcock with two or three turns. Spectrophotometer tubes are rinsed four times each with tap and distilled water immediately after use. They are placed upright in a large beaker and dried in an oven at 105 C, then stored under a dust-cover. Occasionally they are cleaned with dichromate-sulfuric acid and nitric acid as described above. (NOTE: With this method of cleaning glassware we have never encountered cross-contamination from chromium, lead, or from any other trace element being determined routinely in this laboratory.) ANALYTICAL PROCEDURE 1. Warm the sample ash (prepared as described in the following sections) with 2 ml of concentrated nitric acid for a few minutes, then add 25 ml of distilled water, heating on the hotplate until a clear solution is obtained. 2. Cool to room temperature. Add to the solution in the beaker one ml of hydroxylamine hydrochloride, 4 ml of sodium citrate (10 ml is required for a urine sample), one drop of phenol red indicator, and titrate to a strong red color with concentrated ammonia reagent. Add a few drops excess of ammonia to make sure that the pH is between 9 and 10, using fresh pHydrion test paper to check the pH. (NOTE: Phenol red has a weak orange-red color in strong acid, yellow in weak acid, and a red color in alkaline solution. Do not mistake the VIII-9 first color for that produced in alkaline medium!) 3. Transfer the sample quantitatively with double-distilled water rinsings to a 125-ml Squibb separatory funnel containing 5 ml of the potassium cyanide reagent. 4. Add 5 ml of the extraction dithizone and shake two minutes, after releasing the initial pressure by momentarily opening the stopcock of the inverted separatory funnel. Allow the chloroform layer to settle. 5. Draw off most of the extraction dithizone into a second funnel containing exactly 30 ml of 1:99 nitric acid. 11. Set the spectrophotometer at a wavelength of 510 nm. 12. Set the instrument at zero absorbance using the zero lead standard solution. 13. Read the absorbances of the samples and of the reagent blank. Finally, the residue will remain pale yellow or light brown (due to iron con tent) after heating for 5-10 minutes at the high temperature. Avoid excess baking at this stage as the ash will become decomposed to a difficultly soluble form. It is now ready for solution and analysis. Report results as milligrams of lead per 100 grams of whole blood. # COLLECTING AND ASHING URINE SAMPLES Use lead-free, narrow-mouthed, reagent-type, borosilicate, 250-ml bottles provided with standard taper glass stoppers to collect grab samples of VIII-14 urine. Add 2.0 ml of a 37% formalin solution as a preservative, shaking the bottle 10-12 times after the contribution of the urine to mix the specimen with the formalin thoroughly. Alternatively, urine specimens may be collected in 125-ml polyethylene bottles containing as a preservative 100-200 mg of EDTA (acid form) per bottle. This is convenient and economical for shipping samples considerable distances. If the urine sample is clear and only one or two days old, measure a 50 ml portion into a graduated cylinder. However, if the sample is older, much of the lead may be in a sediment or on the walls of the bottle and must be dissolved before aliquoting. Transfer the entire specimen to a glassstoppered graduated cylinder, record the volume, rinse the sample bottle with three small portions of concentrated nitric acid and add these rinsings to the cylinder. Mix thoroughly (Caution! Old samples may foam over.) Note the total volume and remove an aliquot equivalent to 50 ml of urine for analysis. Transfer the aliquot portion to a lead-free, 250-ml borosilicate Phillips beaker and add 5 ml of redistilled concentrated nitric acid. Evaporate just to dryness on a hotplate operating at about 130 C. Cool, add sufficient nitric acid to moisten the residue and cover the beaker with a lead-free watchglass. Heat on the 130 C hotplate and then alternately bake for a few minutes and digest with minimal amounts of nitric acid (as des cribed in the ashing method for blood) until a white residue remains after the final heating for 5-10 minutes at the high temperature. The sample is now ready for solution and analysis. Report results as milligrams of lead per liter of urine. # VIII-15 PROCEDURE FOR AIR SAMPLES It is convenient to wash out samples in electrostatic precipitator tubes with redistilled ethanol, using a special policeman made with a rubber disc cut to fit the tube like a piston, and transferring the sample through a short stem funnel into a 250-ml Phillips beaker; gently evaporate just to dryness. (Ethanol is helpful in removing greasy deposits on the walls of the precipitator tube. Some chemists may prefer hot 1 to 5% nitric acid to transfer the sample.) Transfer impinger samples or membraine filter samples to Phillips beakers. If little ash is expected (usually for impinger or membrane filter samples), add 2 ml of ashing aid acid reagent. (The presence of this salt will prevent loss of lead by glazing onto the surface of the beaker during ashing.) Otherwise add 1-2 ml nitric acid. Evaporate to dryness. Continue ashing with nitric acid at a moderate heat until organics are destroyed. Dissolve the ash in 2 ml of concentrated nitric acid and distilled water and then transfer quantitatively to a 100-ml volumetric flask and make to mark. Pipet a suitable aliquot into a separatory funnel, contain ing about 5 ml of double-distilled water, add sufficient additional double-distilled water to make the total volume about 25 ml, and apply the Analytical Procedure, starting with step 2. In step 3, as the sample is already in a separatory funnel, merely add the cyanide. The amount of lead present in the aliquot may be estimated as described in step 6. If it is less than a few micrograms, an additional aliquot may be added to the same funnel, and the pH readjusted with ammonia. The extraction is then continued, and extracts combined with those collected previously in the second funnel. If the estimated amount of lead exceeds the range of the method (25 micrograms), take an aliquot as described in Note 2, step 8. When calculating the results, make allowance for the total number of aliquots. If convenient, aliquot the reagent blank in the same manner so that the correction represents the same amounts of ashing and extraction reagents as are present in the sample. However, the blank correction is usually small for air samples. Report results as milligrams of lead per cubic meter of air. This may be indicated as a range of maximum amount, i.e., 10-20% V; 10% max. W. From reference SB V

This manual introduces the reader to the principles and practical tools of crisis and emergency risk communication (CERC). Principles in this manual adapt (1) writings of classical rhetoricians; (2) a wealth of modern crisis, issues management, communication theory, and psychological theory; and (3) lessons learned from the real and often painful world of experience, old-fashioned trial and error. CERC addresses a number of topics critical to successful public, partner, and stakeholder communication during crises and emergencies. This is not intended to be an in-depth manual on risk communication, issues management, crisis communication, or disaster communication. It is an amalgamation of all of these, incorporated from theory and practical applications. CERC draws on the work of many experts including Drs. Peter Sandman and Vincent Covello; therefore, no single chapter is a complete source for a specific discipline. The chapters are meant to help those who are charged with these responsibilities, but who may not be steeped in these subjects, to manage the task of planning and implementing CERC activities. When possible, we have provided resource sites that offer more in-depth materials on a particular subject. CERC is the attempt by public health professionals to provide information that allows individuals, stakeholders, and entire communities to make the best possible decisions for their well-being during a crisis or emergency. CERC includes communicating to these groups regarding decisions made by response organizations within nearly impossible time constraints. CERC principles teach us to accept the imperfect nature of choices as the situation evolves.Communication in a Crisis is Different 29 1. We simplify messages. 29 2. We hold on to current beliefs. 29 3. We look for additional information and opinions. 30 4. We believe the first message.The Perception of Risk 32 1. Accept and involve the public as a legitimate partner. 33 3. Be honest, frank, and open. 33 4. Coordinate and collaborate with other credible sources. 34 5. Meet the needs of the media. 35 6. Speak clearly and with compassion. 35 7. Plan carefully and evaluate performance. CERC in Action 36 1. Don't Dismiss Outrage. 36 2. Be careful with risk comparisons. 37 3. Don't over-reassure. 37 4. Put the good news in secondary clauses. 37 5. Acknowledge uncertainty. 38 6. Give people meaningful things to do.# Dear Reader, In 2002, the Centers for Disease Control and Prevention (CDC) decided to fill a critical training gap and resource need and developed the Crisis and Emergency Risk Communication manual. When it was written, the central role of crisis communication in public health responses to crises was beginning to be recognized. Since that time, thousands, perhaps tens of thousands, of health, emergency management, and government professionals have been trained using the original CERC Manual and associated materials in the United States, Canada, Europe, and many other locations. While CERC principles are timeless, new information has been developed, new examples have emerged, and new understandings have been created. Crisis communication is by definition a very dynamic field, and for any work to maintain its state-of-the art relevance, revisions and updates are required. Risk Communication 7 # Table of Contents Issues Management Communication 7 Crisis and Emergency Risk Communication 8 Emergencies, Disasters, and Crises The Communication Lifecycle 10The Pre-crisis Phase 11 The Initial Phase 12 The Maintenance Phase 13 The Resolution Phase 14 The Evaluation Phase 14 The Role of CERC Tables Table 1-1 "CERC is a way to talk to people, a set of principles that allow us, in the heat of a crisis when the unthinkable happens, to be able to get a message through to people in a way that they can actually understand it and act on it." Dr. Barbara Reynolds, Centers for Disease Control and Prevention "We will always be giving people the best information we have and the best recommendation based on what we know the best information is right now. That's one of the ways you can be first and be credible, because it sets the expectation that things will change and we are working to learn more. That's always a challenge, but I think it is our best practice." # Dr. Marsha Vanderford, Centers for Disease Control and Prevention Throughout this book, six principles 1 of effective crisis and risk communication are emphasized: 1. Be First: Crises are time-sensitive. Communicating information quickly is almost always important. For members of the public, the first source of information often becomes the preferred source. 2. Be Right: Accuracy establishes credibility. Information can include what is known, what is not known, and what is being done to fill in the gaps. 3. Be Credible: Honesty and truthfulness should not be compromised during crises. 4. Express Empathy: Crises create harm, and the suffering should be acknowledged in words. Addressing what people are feeling, and the challenges they face, builds trust and rapport. 5. Promote Action: Giving people meaningful things to do calms anxiety, helps restore order, and promotes a restored sense of control. 6. Show Respect: Respectful communication is particularly important when people feel vulnerable. Respectful communication promotes cooperation and rapport. Well-planned and well-executed CERC, fully integrated into every stage of the crisis response, helps ensure that limited resources are managed well and can do the most good. # Types of Disasters The most common disasters 2 are natural disasters, but the line between natural and manmade often blurs, as it did with Hurricane Katrina. Based on the disaster, both CDC and the Federal Emergency Management Agency (FEMA) have grouped them by type (see lists of specific types extracted from publications by both agencies in Table 1-1 and Table 1-2 at the end of this chapter). While there are many types of disasters, most planners try to take an all-hazards approach. Most planners create general plans that are designed such that they can be adapted to specific situations, rather than trying to plan separately for every possible type of disaster. In addition, all disasters are managed locally until local resources are overwhelmed, at which point state, regional, national, and international resources are deployed. While an all-hazards approach works in operational response, there will be important distinctions in the way communication is executed by type of disaster and these differences require consideration during planning. 3 # A Changing World Disasters test emergency response capabilities. The ability to deal effectively with disasters is becoming more relevant, because the factors that tend to increase risks are also increasing. Infectious diseases remain a danger to all people, no matter their age, gender, lifestyle, ethnic background, or economic status. They remain among the most common causes of suffering and death. These infections impose a huge cost to society. Since it is never certain when or where new diseases will arise, we must always be prepared. # Emerging Infectious Diseases and Antibiotic Resistance In the years following World War II, it was widely believed that humans were winning the war against infections. We learned antibiotics could treat life-threatening bacterial diseases. Dreaded childhood diseases, such as polio, could be prevented through vaccinations. However, this hopefulness was premature. Listed are just a few events over the last 60 years that demonstrate that infections are here to stay: As early as the 1950s, penicillin began losing its ability to cure Staphylococcus aureus infections, also known as staph. 12 In the 1970s, there was a resurgence of sexually transmitted diseases. 12 Also during the 1970s, new diseases were identified, such as Legionnaires' disease, toxic shock syndrome, and Ebola. 12 At the same time, antibiotic-resistant bacteria became more common in hospitals, spreading to patients and into communities. 12,13 In 1981, AIDS was first reported by CDC. 14 Flu season remains a yearly threat. Experts say it is possible that a new pandemic strain might emerge that could span the globe and reduce the world's population. 15 In 1997, the avian influenza, H5N1, scare in Hong Kong raised the specter of a possible global pandemic and jolted the world. 16 The emergence of H1N1 in 2009 was yet another sign that a deadly pandemic is possible. 16 # Increased International Travel International travel and trade play a role in the rapid spread of disease and the resistance to antibiotics. A microbe originating in Africa or Southeast Asia can arrive on North American shores within 24 hours. In the U.S., published reports show that the majority of multidrug-resistant typhoid cases originated in six developing countries. The exact number varies, depending on population criteria and how city limits are defined, but according to one source, 17 as of January 2012, 26 cities worldwide had populations above 10 million. While there are many heavily populated cities in developed countries, experts suggest that future growth in urban areas will occur mainly in developing countries. These are where we are likely to see the following problems: # Poverty Population density # Lack of sanitation Bacteria and viruses growing and rapidly spreading The threat from terrorism is real, ongoing, and evolving. State-sponsored terrorism appears to have declined recently, but transnational groups are emerging. They tend to have dispersed networks and decentralized leadership that is harder to disrupt. Increasingly, terrorists' acts are initiated and executed at lower levels and decentralized units. # Increased Terrorism 18 Terrorists are increasingly adept and technically savvy in their ability to defeat counter-terrorism measures. As security around government and military facilities improves, terrorists are seeking out vulnerable targets for mass casualties. They do this according to well-conceived plans, such as: Employing advanced tools, such as improvised explosive devices Using strategies such as simultaneous attacks, which kill or injure many people at once An act of biological or chemical terrorism may range from the dissemination of anthrax spores to intentional food product contamination. Accurately predicting when and how such an attack may occur is impossible. The probability of biological or chemical terrorism cannot be ignored. The possibility of mass causalities plus widespread social and economic disruption means threats must be taken seriously. study and practice can fulfill a basic need for public health professionals as they react to a public health emergency. This book reflects the special combination of "crisis and emergency risk communication." Together, they help us create effective strategies. # Crisis Communication The term "crisis communication" is generally used in two ways: 1. It describes the communication activities of an organization or agency facing a crisis. They need to communicate about that crisis to their organization, various partners, and the public. Typically, a crisis: y Occurs unexpectedly y May not be in the organization's control y Requires an immediate response y May cause harm to the organization's reputation, image, or viability As an example, the 1984 Bhopal gas leak in India 19 was a crisis confronted by an organization that faced blame for the situation. The company faced legal challenges and negative public reactions for many years after the crisis. This organization faced some legal or ethical responsibility for the crisis (unlike a disaster, where, for example, a tornado does the damage). The public and many stakeholders judged the organization based on their actions throughout the response. For example, leaders might need to evacuate a community in advance of a hurricane. In this definition, the organization is not facing a threat to its reputation or image. The effort to inform and warn the public is universally recognized as important. Many public alert systems, like the old Emergency Broadcast System and the new Commercial Mobile Alert System are based on this form of crisis communication. The underlying thread in both forms of crisis communication is that an unexpected and threatening event requires an immediate response. The content, form, and timing of the communication can help reduce and contain the harm or make the situation worse. Crisis may also imply lack of control by the involved organizations based on the timing of the incident. # Risk Communication The field of environmental health elevated the prominence of risk communication. Through risk communication, the communicator hopes to provide the audience with information about the expected type (good or bad) and magnitude (weak or strong) of an outcome from a behavior or exposure. Typically, risk communication involves a discussion about adverse outcomes, including the probabilities of those outcomes occurring. In some instances, risk communication has been used to help an individual make a decision in response to many questions, including the following: Should I undergo a medical treatment? What are the risks of living next to a nuclear power plant? Do I elect to vaccinate a healthy baby against whooping cough? In some cases, risk communication is used to help individuals adjust to something that has already occurred, such as exposure to harmful carcinogens, possibly putting them at greater risk for cancer. Risk communication would prepare people for that possibility. If warranted, the communication would offer steps to take to lower their chance of dying from cancer, such as screenings. # Issues Management Communication Issues management communication can be similar to crisis communication. An issue is a public question that has generated some interest by stakeholders. Questions about vaccine safety, for example, have generated concern among some groups. Their worry has sparked a great deal of public debate. Issues management involves using communication to influence how the organization responds to the issue and how it is potentially resolved. In some cases, an issue can become a crisis. Issues managers have forewarning that an issue is developing. Issues may develop more slowly and continue over extended periods. Managers typically have more time to respond to issues than they would to a crisis. Again, the organization or agency is central to the event. # Crisis and Emergency Risk Communication CERC combines the elements of crisis communication and risk communication as they are used during an emergency response. CERC involves experts who provide information allowing individuals or an entire community to make the best possible decisions about their well-being. Communicators must also help people accept the imperfect nature of choices during the crisis. CERC also differs from pure risk communication in that a decision must be made within a narrow time constraint. The decision may be irreversible, the outcome of the decision may be uncertain, and the decision may need to be made with imperfect or incomplete information. Communicators must inform and persuade the public in the hope that they will plan for and respond appropriately to risks and threats. The work presented here shows that your organization should follow CERC principles when responding to a crisis. If you fail to use CERC, you may fail to effectively communicate key information that could save lives. # Emergencies, Disasters, and Crises What do emergencies, disasters, and crises have in common? Simply that something bad has happened or is happening, that it is surprising on some level, and that an immediate response is required. When something bad or unexpected happens, it may be called an emergency, a disaster, or a crisis depending on who is involved, the magnitude, and the current phase of the event. A crisis involves many players and, depending on the location and the nature of the event, different agencies and groups take different roles. Government agencies that may be involved in the response at some level include the following: # Businesses It is important to remember that at the center of any crisis are those individuals, groups, and communities most directly affected. All disasters are local. The community is the first and most important responder. The role of government agencies is outlined by a set of federal guidelines called the National Incident Management System (NIMS). 20 NIMS is a national standard for organizing agencies and improving coordination of incident management operations. Communication is a key part of NIMS. It applies to creating systems where agencies can communicate with each other, what is called interoperability. It also ensures that good communication occurs with the public. "Numerous after-action reports from major incidents throughout the history of emergency management in our nation have cited communications difficulties among the many responding agencies as a major failing and challenge to policymakers." The National Emergency Communications Plan The Communication Lifecycle Understanding the pattern of a crisis can help communicators anticipate problems and appropriately respond. For communicators, it's vital to know that every emergency, disaster, or crisis evolves in phases. The communication, too, must evolve through these changes. By dividing the crisis into the following phases, the communicator can anticipate the information needs of the media, agencies, organizations, and the general public. For each of these phases, specific types of information need to be created and delivered to your audience. # Figure 1-1. Crisis and Emergency Risk Communication (CERC) Lifecycle Be prepared. Foster alliances. # Develop consensus recommendations. Test messages.

depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# acute renal failure, acute respiratory distress syndrome, and disseminated intravascular coagulation. He required hemodialysis and mechanical ventilation and underwent bilateral foot amputations subsequently because of ischemia. After a 6-week ICU stay, he recovered and was discharged to a long-term-care rehabilitation facility. Case 2. On November 3, the wife, aged 47 years, of patient 1 also became ill. On November 5, she sought medical care for fever, fatigue, myalgias, and unilateral inguinal swelling. A physical examination noted tender right inguinal and femoral adenopathy with overlying erythema and induration. Her temperature was 102.2 º F (39.0 º C), blood pressure was 120/72 mm Hg, and oxygen saturation was 98% on room air. WBC was 9,500/µL, and platelet count was 189,000/µL. Aspiration of the inguinal lymph nodes did not yield any material. The patient received a presumptive diagnosis of bubonic plague because of her clinical signs and symptoms and the recovery of Y. pestis from her husband's blood culture. She was hospitalized and treated with gentamicin, doxycycline, and ticarcillin-clavulanic acid, followed by a 14-day course of oral Epidemiology - Plague is usually transmitted to humans by the bite of an infected rodent flea. - Incubation period is 1-7 days for bubonic plague and 1-4 days for pneumonic plague. - Case-fatality rate for untreated bubonic plague is >50%. - Domestic pets (i.e., cats and dogs) can carry plagueinfected fleas. - Risks include hunting, trapping, cat ownership, and rural residence in areas where plague is endemic. - Person-to-person transmission can occur after contact with a suppurating lesion (bubonic plague) or via respiratory droplets (pneumonic plague). - Naturally acquired plague typically begins as bubonic plague; intentional release (i.e., terrorism) would manifest chiefly as pneumonic plague. Clinical findings - Signs and symptoms include fever, chills, malaise, sore throat, and headache. - A lymphadenitis (bubo) commonly develops; inguinal lymph nodes are affected in 90% of cases. - Infection can progress to shock (septicemic plague) and pneumonia (pneumonic plague). Laboratory testing - Bipolar staining, "safety pin" ovoid, gram-negative organisms are suggestive of plague infection. - Direct fluorescent antibody testing or antigen capture enzyme-linked immunosorbent assay are specific tests. - Confirmatory testing includes culture or a fourfold or greater change in antibody titer. Recommended treatment - Primary therapy: streptomycin; alternatively use gentamicin, tetracyclines, or chloramphenicol. - Mortality from bubonic plague is reduced markedly by appropriate therapy. - Patients with primary pneumonic plague are not likely to survive if they do not receive adequate therapy within 18 hours after onset of respiratory symptoms. Prevention and reporting - Educate the public about plague symptoms, mode of transmission, and prevention methods. - Use insect repellents. - Rodent-proof buildings. - Avoid handling rodents or camping near rodent burrows. - Treat dogs and cats in rural areas where plague is endemic with insecticides. - Report plague cases and sick or dead animals to health authorities. 80% of these exposures occurred in peridomestic environments, particularly those that provided abundant food and harborage for flea-infested, plague-susceptible rodents. Travelers can acquire plague in one area and become ill in another area where plague is not endemic (i.e., peripatetic plague) (3)(4)(5)(6)(7). Although rare, peripatetic plague is more likely to result in fatal outcomes because of delays in seeking treatment or misdiagnosis in areas where health-care providers might be less familiar with the disease (3)(4)(5)(6)(7). In the current state of heightened awareness of possible terrorism, peripatetic cases also might be confused with those arising from an intentional release of plague bacteria. The two cases described in this report did not cause such confusion because the initial history provided a plausible exposure. In addition, both patients had inguinal adenopathy, indicating that transmission was from bites of infectious fleas rather than inhalation of airborne materials, the route considered more likely for terrorism (8). However, intentional release should be considered as a cause of cases occurring outside an area where plague is endemic, particularly for patients with primary pneumonic or primary septicemic plague. Plague prevention depends on the timely implementation of preventive measures, including public education, applying insecticides to kill fleas, using various personal protective measures (e.g., common insect repellents), and avoidance of sick or dead animals (2) (Box). A vaccine is not available in the United States. The rapid identification of peripatetic cases depends on public health surveillance systems that include the availability of laboratory expertise and facilities to provide rapid presumptive evidence and laboratory confirmation of Y. pestis infection. Because NMDOH had identified plague previously on the patients' property, the patients were able to alert clinicians of their potential plague exposure, which enabled early diagnosis and prompt treatment. NYCPHL, which had received training and reagents for diagnosis of Y. pestis as part of a nationwide effort to enhance terrorism response capabilities (9), also performed DFA and PCR analyses that presumptively identified Y. pestis as the bacterium cultured from patient 1. This was later confirmed by phage-lysis and other analyses. Genotyping at CDC indicated that the isolate was indistinguishable from (by PFGE) or highly similar to (by MLVA) an isolate obtained earlier in the year from wood rat fleas collected on the patients' property (10). The findings in this report highlight how clinical, epidemiologic, and laboratory programs can act in a coordinated manner to diagnose peripatetic plague cases rapidly and identify probable exposure sites and sources of infection. Communication between public health and law enforcement agencies remains paramount in the effective diagnosis, treatment, and investigation of infections with potential terrorism agents. These capabilities have been enhanced, particularly in areas such as NYC, where plague is not endemic by a series of efforts undertaken by local, state, and federal agencies to prepare for the possibility of terrorist attacks. for 2002 † , which indicate a marked nationwide increase in coverage with >1 dose of varicella vaccine (VAR), substantial uptake for >3 doses of pneumococcal conjugate vaccine (PCV), generally steady coverage levels for other vaccines nationwide, and continued wide variability in coverage among the states and selected urban areas. To collect vaccination data for all age-eligible children, NIS uses a quarterly random-digit-dialing sample of telephone numbers for each of the 78 survey areas. NIS methodology, including how the responses are weighted to represent the population of children aged 19-35 months, has been described previously (1,2). During 2002, health-care provider vaccination records were obtained for 21,317 children. The overall response rate for eligible households in 2002 was 62.3%. National vaccination coverage with >1 dose of VAR increased from 76.3% (95% confidence interval = ±0.8%) in 2001 to 80.6% (95% CI = ±0.9%) in 2002. Coverage for >3 doses of PCV, reported for the first time, was 40.9% (95% CI = ±1.1%). For all other vaccines, coverage levels remained steady during . For all combined vaccine series reported previously, coverage remained steady (Table 1). In 2002, coverage was reported for the 4:3:1:3:3:1 § series, which includes >1 dose of VAR. Coverage in 2002 for the 4:3:1:3:3:1 series was 65.5% (95% CI = ±1.1%), compared with 2000 and 2001, when coverage for this series was 54.1% (95% CI = ±1.0%) and 61.3% (95% CI = ±1.0%), respectively (Table 1). In 2002, substantial differences remained in estimated vaccination coverage among the states. The estimated coverage with the 4:3:1:3:3 ¶ series ranged from 86.2% in Massachusetts to 62.7% in Colorado (Table 2). Variability among the 28 selected urban areas was slightly less than that among the states. Among the 28 selected urban areas, the highest estimated coverage for the 4:3:1:3:3 series ranged from 81.1% in Santa Clara County, California, to 57.5% in Newark, New Jersey (Table 2). Changes in national level coverage from 2001 to 2002 with all vaccines other than VAR and PCV were so small that they are unlikely to have a major public health impact. Although coverage with recommended vaccines for each new birth cohort remains high, vigilance is needed to maintain these high levels. Eliminating the coverage disparity between states and urban areas with the highest and lowest coverage remains a priority. If vaccine-preventable disease is introduced in an area with low coverage, groups of susceptible children might serve as a reservoir to transmit disease. Because coverage with >1 dose of VAR attained a level approximately equal to that of >4 doses of DTaP, coverage for the 4:3:1:3:3:1 series, which includes VAR, was assessed and presented for the first time in this report. From 2000 to 2002, steady increases were observed. The 2002 NIS cohort was the first entire NIS birth cohort to be eligible for PCV. Coverage with >3 doses of PCV (40.9%) was similar to coverage for VAR in 1998 (43.2%), the first year for which the entire NIS birth cohort was eligible for that vaccine. Uptake for >3 doses of PCV showed steady quarterly increases (Q1 = 24.5%; Q2 = 35.3%; Q3 = 48.8%; Q4 = 56.3%), with a similar trend for >4 doses. The findings in this report are subject to at least three limitations. First, NIS is a telephone survey; although statistical weights adjust for nonresponse and households without telephones, some bias might remain. Second, although NIS relies on provider-verified vaccination histories, incomplete records and reporting could result in underestimates of coverage. The estimation procedure assumes that coverage among children whose providers do not respond is similar to that among children whose providers respond. Finally, although national level estimates are precise, estimates for states and urban areas should be interpreted with caution (3); CIs are wider for state and selected urban areas compared with national estimates. During the time that children in the 2002 cohort were to be vaccinated, vaccines in short supply included DTaP; measles, mumps, and rubella (MMR); VAR; and PCV (4-7). When DTaP was in short supply, approximately 86% of the NIS cohort needed >1 dose of the vaccine to stay on schedule. For MMR, VAR, and PCV, the percentages were approximately 6%, 21%, and 37%, respectively. NIS has sufficient power to detect a moderate (e.g., 15%) decrease in coverage even among the 6% of children due to receive a dose of MMR during the period it was in short supply; no effect on coverage was noted for any vaccine or series. These shortages affected children, their parents, and health-care providers; however, many aspects of vaccine delivery are not reflected by coverage attained among children aged 19-35 months. For example, if vaccine was unavailable at a health-care provider visit, another visit could have been made at a later time when vaccine was † For the January-December 2002 reporting period, NIS included children born during February 1999-June 2001. § Comprises >4 doses of diphtheria and tetanus toxoids and pertussis vaccine, diphtheria and tetanus toxoids, and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTP/DT/DTaP); >3 doses of poliovirus vaccine; >1 dose of measles-containing vaccine (MCV); >3 doses of Haemophilus influenzae type b vaccine (Hib); >3 doses of hepatitis B vaccine (hep B); and >1 dose of VAR vaccine. ¶ Comprises >4 doses of DTP vaccine, >3 doses of poliovirus vaccine, >1 dose of MCV, >3 doses of Hib vaccine, and >3 doses of hepB vaccine. # Vaccination Services in Postwar Iraq, May 2003 In the aftermath of the war in Iraq, widespread looting and intentional damage to government facilities resulted in the interruption of public services and utilities. Basic communications were disrupted nationally. Public health headquarters, clinics, and laboratories were damaged, records were ruined, and equipment was stolen. Because travel often was difficult and dangerous, Coalition forces received numerous requests from hospital directors for armed security, and many healthcare workers reportedly feared either to commute to their worksites or to remain after dark (D. Simpson, M.D., Coalition Provisional Authority 's Ministry of Health Team, personal correspondence, 2003). Public health employees who were able to continue their work went unpaid for several weeks. As a result, throughout Iraq, core public health services (e.g., vaccination services, vectorborne disease control, and the Tuberculosis Directly Observed Therapy program) were disrupted. In addition, severe health hazards caused by damaged water and sanitation systems were added to an already compromised and deteriorating health-care system (1,2). This report assesses the cumulative impact of these conditions on vaccination services in postwar Iraq, including the subsequent loss of staff, facilities, and equipment. Because vaccinations in Iraq are available only through the national system of primary health-care centers (PHCCs), this assessment can help address comparable problems experienced by other programs offered through Iraq's PHCCs, guide subsequent emergency responses to vaccine shortages, and provide a preliminary gauge of the status of preventive health-care infrastructure and services to children in Iraq. By late March 2003, public health officials thought that routine childhood vaccinations were unavailable at the majority of public health clinics. In mid-May, with assistance from CPA and the United Nations Children's Fund (UNICEF), the Iraqi Ministry of Health (IMoH) sent teams to assess the damage that hampered the efforts of the Expanded Program on Immunization (EPI). During May 17-22, six teams traveled to all of Iraq's 18 governorates and visited major vaccine-storage sites and some primary health-care centers. Each team visited three to four governorates and used a standard form to collect information on clinic staff availability, remaining vaccine supplies at the major storage sites, and the status of cold-chain equipment. Karkh and Rusafa, the two districts comprising the governorate of Baghdad, were assessed separately because of the size of their populations and the number of public health facilities (Table ). At the time of the survey, 893 (61%) PHCCs in Iraq had equipment and staff sufficient to provide vaccinations daily. On the basis of the amount of equipment known to have existed immediately before the war, the assessment found that 532 (33%) of the 1,628 refrigerators, 18 (46%) of the 39 cold rooms, and 81 (13%) of the 642 generators needed to provide electricity to some equipment were damaged. Four of the 18 governorates maintained >80% of their prewar cold- chain equipment. The overall loss for the entire Baghdad governorate was 24%, with the Karkh district losing substantially less equipment (12%) than Rusafa (40%). Total vaccine stocks- were assessed at the major storage sites but not at the clinic level. Only Sulaimaniyah had BCG vaccine, and stocks of HBV were low in all governorates except Najaf. However, tens of thousands of doses of both OPV and DTP vaccine were counted in all but five governorates. Although rabies is endemic in Iraq, stocks of rabies immunoglobulin were reported in only three governorates. Nine (50%) of the governorates had stocks of hepatitis B immunoglobulin. The presence of working cold-chain equipment was recorded, but levels of vaccine maintained constantly under proper environmental conditions at the surveyed sites were not determined. Editorial Note: This assessment found that the Iraqi vaccination program had lost necessary cold-chain equipment throughout the country and that the supply of properly maintained vaccine and immunoglobulin had been disrupted. Despite the brief duration of the war in Iraq and the intent to spare hospitals and clinics from direct attack, resulting disruptions in civil order and public services affected public health programs severely. Of urgent concern to public health officials were the temporary disruption of routine childhood vaccination activities and the lack of potable water. Vaccination services were especially susceptible to disruption because the effectiveness of the vaccination program depended on continuous provision of services in all parts of the country, easy accessibility by vulnerable women and children, and working cold-chain equipment. Before the war, EPI typically provided approximately 750,000 doses of routine vaccines † monthly to children aged 12 months (IMoH, unpublished data, 2003). Results of this survey are being used to revise distribution methods until damaged or looted cold-chain equipment can be replaced. Vaccines at central sites are being packaged into cold boxes and transported to clinics without refrigerators so vaccines will be available at least a few times each week in each PHCC. However, the provision of vaccines, medicines, supplies, and equipment is not alone sufficient to restore public health services interrupted in the aftermath of the war. A safe and secure work environment, a fair and reliable salary for public health staff, and accessible transportation also should be re-established. CPA and IMoH, with the assistance of the Coalition forces, UNICEF, the World Health Organization, and many nongovernment organizations, are working to ensure security, rehabilitate clinics and laboratories, and restore public health programs. Early results of these combined efforts include 1) an increasing number of adequately chlorinated public water supplies, 2) a rapid assessment of the nutritional status of young children in Baghdad, and 3) the distribution of routine childhood vaccines throughout Iraq by the third week of June. Despite these gains and the re-establishment of many services, substantial work remains for the Iraqi public health system to prevent resurgence of endemic diseases (e.g., visceral leishmaniasis, typhoid fever, and cholera) and the emergence of drug-resistant TB and malaria. The efforts of public health workers and the continued support of partner organizations will be critical to meeting these concerns in the coming months. # Update: Adverse Event Data and Revised American Thoracic Society/CDC Recommendations Against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection-United States, 2003 CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month- regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring (1-4). To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI (Table ). Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease (5). For surveillance purposes, a case of severe liver injury was defined as one leading to the hospitalization or death of a patient being treated for LTBI with RZ (2). During October 2000-June 2003, CDC received reports of 48 patients who had confirmed cases; 33 (69%) cases occurred in the second month of treatment. A total of 11 (23%) patients died † , including two persons known to be infected with human immunodeficiency virus (HIV). † Of the 11 deaths, eight were reported previously (1-3). # TABLE. Revised drug regimens for treatment of latent tuberculosis infection (LTBI) in adults- Rating § (Evidence) ¶ HIV-HIV-Drug Interval and duration Comments † negative infected A. Both strong evidence of efficacy and substantial clinical benefit support recommendation for use. Should always be offered. B. Moderate evidence for efficacy or strong evidence for efficacy but only limited clinical benefit supports recommendation for use. Should generally be offered. C. Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (e.g., drug toxicity, drug interactions) or cost of the treatment or alternative approaches. Optional. D. Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered. E. Good evidence for lack of efficacy or for adverse outcome support a recommendation against use. Should never be offered. ¶ Quality of evidence supporting the recommendation: I. Evidence from at least one properly randomized controlled trial. II. Evidence from at least one well-designed clinical trial without randomization from cohort or case-controlled analytic studies (preferably from more than one center), from multiple time-series studies, or from dramatic results from uncontrolled experiments. III. Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. Recommended regimen for persons aged <18 years. † † Recommended regimens for pregnant women. § § The substitution of rifapentine for rifampin is not recommended because rifapentine's safety and effectiveness have not been established for patients with LTBI. # Isoniazid In HIV-infected persons, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Directly observed therapy (DOT) must be used with twice-weekly dosing. Not indicated for HIV-infected persons, those with fibrotic lesions on chest radiographs, or children. DOT must be used with twice-weekly dosing. Used for persons who are contacts of patients with isoniazid-resistant, rifampin-susceptible TB. In HIV-infected persons, most protease inhibitors or delavirdine should not be administered concurrently with rifampin. Rifabutin with appropriate dose adjustments can be used with protease inhibitors (saquinavir should be augmented with ritonavir) and NNRTIs (except delavirdine). Clinicians should consult web-based updates for the latest specific recommendations. RZ generally should not be offered for treatment of LTBI for HIVinfected or HIV-negative persons. A two-phase retrospective survey was conducted to estimate the incidence of severe liver injury among persons receiving RZ for treatment of LTBI. In December 2001 (phase I), CDC sent a questionnaire by e-mail to TB-control programs in 12 large cities and all 50 states, asking them to identify programs and health-care providers prescribing RZ for treatment of LTBI. All controllers responded, and in February 2002, CDC staff called the programs and health-care providers identified as prescribing RZ for LTBI to confirm its use. In September 2002 (phase II), CDC mailed a second questionnaire to the 150 health-care providers identified during the first phase, requesting aggregate cohort data for January 2000-June 2002; 109 (78%) health-care providers responded by June 6, 2003. Of 7,737 patients who were reported to have started RZ for treatment of LTBI during the survey period, 5,980 (77%) received daily doses, and 1,757 (23%) received twice-weekly doses. A total of 204 patients discontinued using RZ because of aspartate aminotransferase (AST) concentrations greater than five times the upper limit of normal (rate: 26.4 per 1,000 treatment initiations; 95% confidence interval (CI) = 22.8-30.0). An additional 146 patients discontinued using RZ because of symptoms of hepatitis (rate: 18.9 per 1,000 treatment initiations; 95% CI = 17.4-20.4). Of the 48 cases of severe liver injury reported to CDC through passive surveillance, 30 also were detected in the second phase of the survey. Of the 18 patients whose cases were not detected, six patients had liver injuries outside the survey period, five patients' health-care providers did not respond to the questionnaire, and seven (six of whom were in private practice) were not identified in the first phase of the survey. Of the 30 patients whose cases were detected, 23 (77%) recovered, and seven (23%) died. On the basis of these 30 cases, the estimated rates of hospitalization and death during the survey period were 3.0 (95% CI = 1.8-4.2) and 0.9 (95% CI = 0.2-1.6) per 1,000 treatment initiations, respectively. # Reported by: State and territorial health depts. Div of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC. Editorial Note: The CDC cohort analysis found that the rates of severe liver injury and death related to the use of RZ are higher than the rates for isoniazid (INH)-associated liver injury in the treatment of LTBI. Although initial studies attributed hospitalization rates as high as 5.0 per 1,000 treatment initiations and mortality rates as high as 1.0 per 1,000 to INH (6,7), studies conducted since 1991 involving more than one million persons treated with INH have reported hospitalization rates of 0.1-0.2 (median: 0.15) and mortality rates of 0-0.3 per 1,000 (median: 0.04) (4,8,9). This decrease from earlier studies might reflect careful selection of patients and active monitoring for early signs of adverse events. In addi-tion to the survey on the use of RZ described in this report, recent studies have reported episodes of liver injury and hospitalization associated with RZ for treatment of LTBI (10,11), including the need for transplantation in one patient (12). Among first-line agents in the treatment of active TB disease, pyrazinamide (PZA) might be the most hepatotoxic (13). These data and other recent studies (4,10,11,14-16) were reviewed by TB experts § at a meeting held during the 99th International ATS Conference in Seattle, Washington, on May 12, 2003, to discuss proposed revisions to guidelines for the treatment of LTBI. ATS and CDC now recommend that this regimen should generally not be offered to persons with LTBI for either HIV-negative or HIV-infected persons. On the basis of the investigation of potential cofactors in the 48 patients with serious liver injury, this regimen should never be offered to patients who 1) are concurrently taking other medications associated with liver injury; 2) drink excessive amounts of alcohol, even if alcohol use is discontinued during treatment; 3) have underlying liver disease; or 4) have a history of INH-associated liver injury. If the potential benefits of this regimen outweigh the risk for severe liver injury and death associated with it, use of RZ might be considered in carefully selected patients, but only if 1) the preferred or alternative regimens (i.e., 9 months of daily or biweekly INH, 6 months of daily or biweekly INH, or 4 months of daily rifampin) are judged not likely to be completed and 2) oversight by a clinician with expertise in the treatment of LTBI can be provided. A TB/LTBI expert should be consulted before RZ is offered. In addition, patients should be asked whether they have had liver disease or adverse effects from taking INH or other drugs, informed of potential hepatotoxicity of the RZ regimen, and advised against the concurrent use of potentially hepatotoxic drugs, including over-the-counter drugs such as acetaminophen. To instruct the patient to stop taking RZ immediately and seek medical consultation if abdominal pain, emesis, jaundice, or other symptoms of hepatitis develop. Provider continuity is recommended for optimal monitoring. For persons taking this regimen, serum aminotransaminases (AT) and bilirubin should be measured at baseline and at 2, 4, 6, and 8 ¶ weeks of treatment. Because the majority of these patients had onset of symptoms of liver injury after the fourth week of therapy (Figure ), patients should be monitored throughout the entire course of treatment. Use of RZ should be discontinued immediately and not resumed for any of the following findings: 1) AT greater than five times the upper limit of normal range in an asymptomatic person, 2) AT greater than normal range when accompanied by symptoms of hepatitis, or 3) a serum bilirubin concentration greater than the normal range, whether or not symptoms are present. The risk for progression from LTBI to active TB is increased substantially in persons with HIV infection (4). Therefore, as recommended previously for the treatment of all persons in whom LTBI is diagnosed, voluntary HIV counseling and testing should be offered routinely. For progression to TB disease to be prevented, persons with LTBI should be identified in contact investigations and targeted screening programs and should complete treatment with safe and effective regimens. The successful treatment of LTBI is an essential component of the TB elimination strategy in the United States (4). In addition to this report, CDC and its partners are sending a letter to TB-control programs in 12 large cities and all 50 states and organizations active in TB control (e.g., the National Coalition to Eliminate Tuberculosis). To reach clinicians who are treating patients with LTBI, primary care medical associations (e.g., the American Medical Association and the American College of Physicians) are distributing this report to their members. This report and the letter are available at . The letter is being added to the April 2000 CDC Targeted Tuberculin Testing and Treatment of Latent TB Infection Guidelines, and existing provider educational materials are being revised. The recommendations against the use of RZ for treatment of LTBI described in this report do not apply to the appropriate use of rifampin and PZA in multidrug regimens for the treatment of persons with active TB disease. In these circumstances, the risk for morbidity and mortality from TB disease is substantially greater than with LTBI. Rifampin and PZA are essential components of recommended ATS/CDC/IDSA regimens that render patients noninfectious rapidly and are effective in curing patients with drug-susceptible M. tuberculosis strains within 6 months (5). CDC continues to collect reports of severe liver injury leading to hospital admission or death in persons receiving any treatment for LTBI. Health-care providers are encouraged to report such events to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442. Details of the RZ survey analysis and the case series will be described in a separate publication. # Pneumococcal Vaccination for Cochlear Implant Candidates and Recipients: Updated Recommendations of the Advisory Committee on Immunization Practices On July 31, this report was posted on the MMWR website (). In October 2002, CDC recommended that all persons with cochlear implants receive age-appropriate pneumococcal vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) (Prevnar ® ), 23-valent pneumococcal polysaccharide vaccine (PPV23) (Pneumovax ® ), or both according to the Advisory Committee on Immunization Practices (ACIP) schedules for persons at high risk (1). CDC issued these recommendations on the basis of preliminary data suggesting an increased risk for pneumococcal meningitis in persons with cochlear implants. Findings of a recent investigation by CDC, the Food and Drug Administration (FDA), and state health departments support this recommendation. Children aged <6 years with a cochlear implant had a substantially greater risk for having pneumococcal meningitis, compared with children in the general U.S. population of the same age (2). Some children who are candidates for cochlear implants have preexisting anatomic factors that might contribute to an increased risk for meningitis; however, the recent study was not designed to assess this association (2). August 8, 2003 Because the rate for pneumococcal meningitis is higher in children with cochlear implants and Streptococcus pneumoniae is the most common pathogen causing bacterial meningitis in cochlear implant recipients of all ages with meningitis of known etiology (2,3) During the reporting week of July 31-August 6, a total of 109 human cases of WNV infection were reported from 13 states (Colorado, Iowa, Kansas, Kentucky, Louisiana, Minnesota, Mississippi, Nebraska, New Mexico, North Dakota, Ohio, South Dakota, and Texas), including four fatal cases from three states (Alabama, Colorado, and Texas). During the same period, WNV infections were reported in 622 dead birds, 191 horses, one dog, four unidentified animal species, and 359 mosquito pools. During 2003, a total of 153 human cases of WNV infection have been reported from Colorado (n = 72), Texas (n = 19), Louisiana (n = 15), South Dakota (n = eight), Ohio (n = seven), Alabama (n = six), Nebraska (n= six), Florida (n = four), Minnesota (n = four), Mississippi (n = four), Iowa (n = two), New Mexico (n = two), Kansas (n = one), Kentucky (n = one), North Dakota (n = one), and South Carolina (n = one) (Figure ). Among 150 (98%) cases for which demographic data were available, 81 (54%) occurred among men; the median age was 45 years (range: 17 months-87 years). Of the 153 cases, four fatal cases were reported from Alabama (n = one), Colorado (n = one), and Texas (n = two). In addition, 1,770 dead birds with WNV infection were reported from 36 states and New York City; 282 WNV infections in horses have been reported from 22 states (Alabama, Arkansas, Colorado, Florida, Georgia, Kansas, Kentucky, Minnesota, -- MOUNTAIN - - - - - 2 Mont. - - - - - - Idaho - - - - - - W y o . - - - - - - - Colo. N N - - - - - N . M e x . - - - - - - - A r i z . - - - - - 2 Utah - - - - - - - N e v . - - - - - - - PACIFIC 1 - - - - - - Wash. - - - - - - - Oreg. - - - - - - - Calif. 1 - - - - - - Alaska - - - - - - - H a w a i i - - - - - - - Guam - - - - - - - P.R. N N - - - - - V . I . - - - - - - - Amer. Somoa - - - - - - - C.N. - - - - 184 W y o . - - 1 8 - 5 - - 1 0 7 Colo. - 1 59 - 2 - - 607 N . M e x .131 - 125 - - 1,074 La. - - - - - 1 - 792 Okla. - N 126 - 111 - - 527 Tex. N 6 1,038 - 13 2 - 2,325 MOUNTAIN 1 5 311 - 15 - - 2,558 Mont. - - 19 - 1 - - 91 Idaho - 2 38

# I. RECOMMENDATIONS FOR A STANDARD FOR WORK IN HOT ENVIRONMENTS The National Institute for Occupational Safety and Health (NIOSH) recommends that employee exposure to heat in the workplace be controlled by requiring compliance with the work practice standard set forth in the following sections. Adherence to the precautionary procedures prescribed will prevent acute or chronic heat disorders and illnesses and heat induced unsafe acts, and will reduce the risk of harmful effects due to the interactions between excessive heat and toxic chemicals and physical agents. The standard is amenable to techniques that are valid, reproducible, and presently available. It will be reviewed and revised as necessary. Section 1 -Definitions (a) Acclimatization to heat means a series of physiological and psychological adjustments that occur in an individual during his first week of exposure to a hot environment so that thereafter the individual is capable of working in a hot environment without excessive strain. (b) Unimpaired mental performance means the ability of an employee to cope with conditions where safety and health depend on constant alertness because he has to make critical decisions, fine discriminations, or fast and skillful actions. (c) Intermittent heat exposure means exposure to hot environmental 1-1 conditions which continues no longer than fifteen minutes without an interrupting interval spent either spontaneously or according to a prescribed schedule in a cooler environment. (d) Continuous heat exposure means any exposure to hot environ mental conditions which is not an intermittent exposure. (e) Hot environmental condition means any combination of air temperature, humidity, radiation and wind speed that exceeds a Wet Bulb Globe Temperature (WBGT) of 79°F. # Section 2 -Applicability The provisions of this standard are applicable to all places of employment, indoors and outdoors, and to all employees except those who are required to wear impermeable protective clothing. (c) When exposure of an employee is continuous for one hour or intermittent for a period of two hours and the time-weighted average WBGT exceeds 79°F for men or 76°F for women, then any one or combination of the following practices shall be initiated to insure that the employee's body care temperature does not exceed 100.4°F: 1-2 FIGURE 1 -1 . # UPPER LIMITS OF EXPOSURE FOR UNIMPAIRED MENTAL PERFORMANCE (i) Acclimatization (1) Unacclimatized employees shall be acclimatized over a period of 6 days. The acclimatization schedule shall begin with 50 percent of the anticipated total work load and time exposure on the first day, followed by daily 10 percent increments building up 100 percent total exposure on the sixth day. (2) Regular acclimatized employees who return from nine or more consecutive calendar days of leave, shall undergo a four day acclimatization period. The acclimatization schedule shall begin with 50 percent of the anticipated total exposure on the first day, followed by daily 20 percent increments building up to 100 percent total exposure on the fourth day. (3) Regular acclimatized employees who return from four consecutive days of illness should have medical permission to return to the job, and should undergo a four day re-acclimatization period as defined in (2) above. (ii) A work and rest regimen shall be implemented to reduce the peaks of physiological strain and to improve recovery during rest periods. (iii) The total work load shall be evenly distributed over the entire work day when possible. # (iv) When possible hot jobs shall be scheduled for the coolest part of the work shift. # 1-3 (v) Regular breaks, consisting as a minimum of one every hour, shall be prescribed for employees to get water and replacement salt. The employer shall provide a minimum of 8 quarts of cool potable 0.1 percent salted drinking water or a minimum of 8 quarts of cool potable water and salt tablets per man per shift. The water supply shall be located as near as possible to the position where the employee is regularly engaged in work, but never further than 200 feet- therefrom. (vi) Appropriate protective clothing and equipment shall be provided and used. (vii) Engineering controls to reduce the environmental heat load shall be utilized. (i) Where exposure to environmental conditions is continuous for several hours or the entire work day, the WBGT shall be calculated as an hourly time-weighted-average. (ii) Where exposure is intermittent, the WBGT shall be calculated as a two-hour time-weighted average. Section 5 -Medical (a) All employees who are 45 years of age and older and who have not had previous occupational exposure to heat shall not be assigned to jobs where the environmental conditions equal or exceed 79°F WBGT for men and 76°F WBGT for women, until they are acclimatized. (b) All personnel who are to be assigned to hot jobs for the first time shall be evaluated by a physician prior to assignment to assure that the individual can cope with the hot environment. In the examination special emphasis should be on the cardiovascular, renal, hepatic, endocrine, and respiratory system and the skin. The examination should 1-5 also include a complete medical history of the worker with specific emphasis on previous heat-related disorders or illnesses. (c) All employees exposed to hot environmental conditions should be given a periodic physical examination every 2 years for employees under age 45, and every year for employees 45 years of age or older, that should include all components of the preplacement examination. (a) Information as to water intake for replacement purposes. (b) Information as to salt replacement. (c) Importance of weighing each day before and after the day's work. (d) Instruction on how to recognize the symptoms of heat disorders and illnesses, including dehydration, exhaustion, heat syncope, heat cramps, salt deficiency exhaustion, prickly heat, and heat stroke. (e) Information as to special caution that shall be exercised in situations where employees are exposed to toxic agents and/or other stressful physical agents which may be present in addition to and simultaneously with heat. (f) Information concerning heat acclimatization. The information shall be kept on file and readily accessible to the worker at all places of employment where he may be exposed to excessive heat. # Section 7 -Warning Sign The following warning sign shall be appropriately located at one or more places to be noticed by any one entering an area where environmental conditions are 86°F WBGT or above. (ii) Records of acclimatization as required by Section 3(c)(i). (iii) Records of the WBGT for each work area as specified in Section 8. (b) Records required by provisions (i) and (ii) above shall be maintained for a period of the employee's employment and for one year thereafter. (c) Records of the WBGT as specified in (iii) above shall be maintained for a period determined by the Secretary of Labor with consultation with the Secretary of Health, Education, and Welfare. The pertinent results of these field studies are summarized below. The workers in hot jobs are a highly select population. Workers who feel that they cannot cope with the prevailing heat stress change their job for a less demanding one. As a result of this natural selection process, the majority of the workers in hot jobs have high levels of physical performance and capacity and are highly adaptable to work in heat. Heat disorders are more likely to occur at times when the workers are unacclimatized as during the first hot spell in the summer or when physical fitness is diminished as on Mondays after a leisurely weekend or the first day after a vacation, or return to work after an illness. Because jobs in hot environments may be better paid than other jobs, it often happens that workers try to stay with the hot job even after their health or fitness becomes inadequate for the job. Since there is no obligatory standard for physical fitness for these jobs and since periodic III-l medical examinations have been haphazardly done in many industries, if done at all, these workers stay on the job and run a high health risk. Oral temperatures in excess of 99.6°F (corresponding to a deep body temperature of 100.4°F) or first-minute recovery heart rates in excess of 110 have been very seldom observed. They occurred mainly in jobs where the environmental conditions exceeded the upper limit prescriptive zone (ULPZ), (see part V) particularly if the workers worked overtime or worked two shifts in sequence. There are many work practices in industry which are unofficial and are aimed at ameliorating the workers heat strain on excessively hot days. # Such practices are: 1. Only the unavoidable operations are performed. Other less important jobs are postponed. 2. Workers involved in auxiliary jobs are reassigned to help out those who work in the hot areas. 3. The younger and more fit take over some of the work from the older and less fit. These practices, if not recognized, may give the wrong impression that the old and less fit worker tolerates the work in heat as well as the younger and more fit. Most workers in hot jobs drink less water than they lose by sweating. According to many laboratory and field studies, this affects physical fitness adversely, particularly if the water loss is more than 1.5% of total body weight.6 Such dehydration could be prevented by: Making drinking water of good quality easily accessible to the worker. III-2 2. Providing a 0.1 percent salt solution as drinking water, available from drinking fountains which cool the water. 3. Providing salt tablets for salt supplementation to the workers. Advising the worker about the significance of drinking water often in small installments and using much salt on food when he is exposed to hot working conditions. In many jobs the workers' heat exposure could be substantially reduced by relatively simple measures, such as wearing certain protective clothing, turning on all available fans and opening all windows, distribu ting the job more evenly during the workday and breaking up the work cycles into shorter work-rest cycles. Unfortunately, either because of ignorance or carelessness, the workers often expose themselves to greater heat stress than would be necessary. Often with little expense the climatic conditions could be ameliorated or the work load diminished. # Early Historical Reports Nearly 70 years ago concern for the health of the Cornish Tin Miners lead to one of the first studies of the effects of heat on the health of workers and stimulated the search for a method of expressing in simple terms the impact of a hot working environment. Except for the studies of Bedford,^ on the effects of atmospheric conditions on the indus trial worker, little progress was made until shortly before and during During the past 25 years much effort has centered around the problem of expressing in relatively simple terms the total impact of the hot working environment upon the worker. Several attempts have been made to < formulate a predictive scheme which would translate the heat load into biologically meaningful values. These predictive schemes can be roughly grouped into: (a) those that sought a device which would respond to the major environmental factors in a manner similar to man's, (b) those based upon measured human responses which could be used to evaluate combinations of environmental conditions, and (c) those based on calculations to determine whether it is possible to maintain thermal balance under any combinations of the climatic factors and work intensity and if so, how much physiological strain is involved. Each approach has its logic as well as its failings. A detailed discussion of the more important of the indices for estimating the biologic impact of a hot environment is presented later in the text. # 111-4 Epidemiological Studies Neither prospective nor retrospective epidemiological studies have been made in which the health experiences of workers have been correlated with the length and intensity of heat exposure at the work site during the working life of the individuals. Health data for retrospective studies could probably be found in the health and medical records of some insurance companies and larger industries. Particularly lacking in most of the morbidity and mortality reports, however, are measurements of the level of heat exposure and the time spent on the hot jobs. Health experience statistics for some hot industries have been reported over the past 50 years.1^»1^»1®>19, 20,21,22 in a study of 23,000 coal miners,!® lost time due to sickness was 63 percent higher in miners working at temperatures above 80°F. than in those working at temperatures of 70°F. or less. Death rate increase of about 35 percent was reported in 193720fOr miners working hotter mines. In another study, Britten and Thompson,21 found organic heart defects were more frequent in foundry workers. Enlarged hearts and arteriosclerosis were found more often among steel and glass workers. The frequency of industrial accidents increases in higher temperatures but the increase is mostly in minor accidents. It is not possible to generalize these reports of heat experience in chronic heat exposure in industry several decades ago to present-day industry. However, personal communications and experiences of medical and scientific personnel suggest that chronic exposure in hot working environments can have serious health and safety consequences. # III-5 The acute effects of heat on health and safety have been documented by literally hundreds of carefully controlled laboratory and field studies. The incidence of heat illness in young men in industry and military service who were not acclimatized to heat has been reported in several studies to be between 1.5 and 3. Mechanically, the heat may tend to promote accidents due to slipperyness of sweaty palms or interfering with vision through fogging of safety glasses. Beyond these obvious effects, accidents have been documented 18 to increase in hot jobs (e.g., Vernon et al. ). A striking demon stration of environmental effect on accident rates was compiled from records of a steel mill over a four-year period (Figure 1). ^ There is a definite parallelism between weather and accident frequency. The accident peaks, however, exhibit a downward trend over the years, most likely reflecting the efforts of intensive safety programs. Belding et al. have suggested the weather effect may be due to reduced general tonus of bodily activities and alertness related to high environmental temperatures. Again, increased bodily temperature and discomfort III-9 increase irritation, anger, and other emotional states which may induce 42 workers to commit rash acts or divert attention from hazardous tasks. In extreme heat, emotions may spill over into fights^ or other manifesta-43 tions of emotional crises, e.g. At lesser stresses, more subtle disturbances in emotional state, e.g., depression, may be evident. Extensive folklore has been generated around the deleterious effects of the "Foehn" of Europe, the "Sharav" 44 of Israel, and other warm "ill winds". While the correlation between these climatic changes and illness seems real, the aetiology remains 45 controversial. Intuitively, disturbed emotional states should reduce 46 alertness on the job, setting the stage for accidents. Effects of stresses in the occupational environment have been the subject of many quantitative studies. From these, threshold limit values (TLV) were derived, values which have served well as guides to reduce occupational exposures. In general, the TLV's were established from experiments with single stress exposures. Often, however, more than one stress will occur and, in fact, it will be the rare case where only one stress obtains. There has been an increasing awareness of the alteration in physiological response to a stress where other stresses are present. Because of the ubiquitous nature of heat stress, it has received attention as a potentiator or mediator of response to other physical and toxic agents; and it certainly influences the course of diseases. In combination, heat (85°F, ET) and carbon monoxide (100 ppm) have been shown to have a greater deleterious effect than either stress 47 alone. It is difficult to quantitate the effect; manifestations included 111-10 inability to complete the four-hour exposure, irritability, and, occasionally, syncope. The effects were more pronounced in women than in men. The subjects reported persistent headaches, anorexia, irritability, depression, and general malaise. These postexposure symptoms were markedly more severe after exposure to heat and CO than after exposure to either alone. It is interesting to note that these were physiological disturbances and that the more Renshaw "^investigated the effects of noise (41, 80, 90, and 100 dBA) and heat (72,78,84, and 90°F ET) on performance on a 5-Choice Serial Reaction Task. The effect of heat on "gaps" was statistically significant. Subjects committed 18 percent more gaps at 90°ET than at 72°ET at the same noise level. # III-ll It has been a common observation that mortality increases during 51 prolonged hot spells, e.g., St. Louis, 1966. Similarly, the frequency of illinesses seems to be dependent on the heat load. There are numerous instances cited in the literature where increases in dispensary visits, etc., accompany hot weather, even as do accidents (as noted above). While somewhat afield from the problem under review here, the implications are that there are many subtle little understood physiological adjustments to heat stress whose role in rendering a worker on hot jobs more or less resistant to bacterial invasion is unknown. # Correlation of Exposure and Effects The physiological and medical consequences of exposure to heat are not directly proportional to the intensity throughout the entire range of heat stress. Over a rather large range of temperatures, physiological functions are independent of the temperature. In the environment driven zone (EDZ See Part V) the physiological strain increases exponentially so that at high levels of heat stress a small incremental increase in stress 111-12 results in a large increase in strain. The safety factor becomes progressively smaller as the total heat-work stress is increased. Consequently, as the heat stress becomes higher, more care and precaution must be exercised to insure the health and safety of the worker. Many factors, which can exist in limitless combinations, interact to determine relationships between exposure and effects. The more important of these factors include the Environmental Factors, the Human Factors, and the Task Factors (Table I). The impact of some of these factors on performance and heat tolerance has recently been 33 reviewed. It is emphasized that for any specific environment-worker-job situation the total stress and health and safety consequences can be brought to acceptable and desirable levels by adequate control of one or more of the factors. One of the most dramatic and successful physiological mechanisms possessed by man is his ability to increase his tolerance to work in heat. The physiological and psychological processes involved in acclimatization to heat have been described in many technical papers and several comprehensive reviews»^ »^^»54 Acclimatization to heat is a series of physiological adjustments that occur when one who is accustomed to working in a temperate environment is suddenly placed in a hot environment. These physiological adjustments which occur over a period of one to two weeks reduce the strain experienced on the initial exposure to heat. The physiological changes during acclimatization which are most easily observed are the responses of the body temperature and pulse rate, both of which increase during the first day of heat exposure and then progressively decrease with each In four groupings of cases surviving long enough to be admitted to a hospital for treatment and reported in the medical literature, the mortality rate increased in direct ratio with the increased temperature on admission (Minard and Copman, 1963 if hyperthermia is prolonged. By the same token, survival with complete recovery is possible at extreme hyperthermia; e. g., 108 or above, if cooling is prompt and effective. Malamud, Haymaker, and Custer who described a wide range of premortem brain disorders in 125 fatal cases of heat stroke occurring in military trainees in World War II, state that "damage to the central nervous system was manifest from the onset and persisted to the end. In cases of longer duration, dementia, asphasia, or hemiplegia indicated that the effect on the central nervous system was probably lasting and irreversible. A direct relationship between the nervous manifestations and the degree and duration of hyperthermia was always evident." trainees, the primary underlying factor in heat stroke is lack of accli matization often associated with poor physical fitness and/or obesity. Precipitating factors are prolonged exertion under heat stress with inadequate time allowances for rest and recovery. Recent alcoholic overindulgence in otherwise seasoned workers has been identified as a probable factor in some cases.In elderly individuals living in poorly ventilated housing, the risk of heat stroke during prolonged heat waves in northern cities is greates in those with a history of chronic cardio-51 vascular or cardiorespiratory disease. In such cases impaired circulatory capacity to transport heat from body core to the skin is the underlying cause of hyperthermia and thermoregulatory failure rather than elevated metabolic heat production during work. The underlying disorder in heat exhaustion is depletion of body water due either to restricted water intake, or to deficient salt intake, or more often to both. In the water restriction type, urine is highly concentrated and small in volume; thirst is a prominent symptom. In the salt deficiency type, circulatory insufficiency is more extreme, urine is more dilute, larger in volume, but chlorides are absent « 1 gm/liter). Thirst is less evident. Blood electrolytes may be slightly elevated with hemoconcentration in the water restriction type and somewhat below normal in the salt defi ciency type. Laboratory facilities are often not available to differentiate the two types. Results of blood analysis, however, are not essential in making a diagnosis of heat exhaustion as this can be determined on the basis of the clinical signs and symptoms noted above. is the best method for supplementing salt intake. Also, lack of accli matization in men losing up to several liters of sweat per day often leads to voluntary dehydration, a term indicating that the thirst mechanism fails to provide an adequate stimulus to drink water in sufficient quantities to balance the losses in sweat. Workers should be instructed to drink more than necessary to satisfy thirst. Failure of supervisors to provide ready access to water, or to provide breaks at frequent intervals, may lead to degrees of dehydration which cannot readily be compensated because the volume of water necessary to be ingested causes gastric distention and distress. The objectives of a preventive program are to prevent clinical disorders from heat stress and also to prevent aggravation of existing impairments by heat and to maintain optimum health and work efficiency. The objectives can be accomplished through the following procedures: pre-placement and periodic medical examination, acclimatization of workers to heat, and monitoring of oral temperature and heart rate. The approach toward control may involve modification of one or more of these determinants of heat stress. The challenge is to select specific methods for attack which will be both feasible and effective. Serious errors can result from resorting to some single pet engineering solution. IV-2 Consider the consequences of ducting outside air to the task site. This air usually is blown at the worker at a temperature as warm as the upper reaches of the shed where the ducts have been installed. This will enhance cooling by evaporation of sweat, but if the air is warmer than the skin (35°C, 95°F), it will increase the convective heat load. Consideration of the trade off between needed heat loss and increased heat gain is essential. The same goal might be achieved less expensively with portable fans. In some situations the real mistake may be the failure to recognize that the heat problem derives from radiant load from a furnace which is not decreased by air movement. This mistake has been made less frequently in recent years, but elaborate ducting across the ceilings of older plants exist as testimony to use in the part of this inappropriate action. Effectiveness of means used to control the five listed determinants of heat stress can be compared. First to be discussed is decreasing the physical work of the task. Metabolic heat, M, can comprise a large fraction of the total heat load. However, the amount by which this factor may be reduced by control often is quite limited. This is because an average sized man who is simply standing quietly while pushing buttons will produce heat at a rate of 100 Kcal/hr whereas one who is manually transferring fairly heavy materials at a steady pace will seldom have a metabolic rate higher than 300 Kcal/hr and usually not more than 250 K c a l / h r . Obviously, control measures, such as partial mechanization, can only reduce the M component of these steady types of work by 100 to 200 Kcal/hr; nevertheless, mechanization can also IV-3 help by making it possible for the worker to be more isolated from the heat source, perhaps in an air conditioned booth. Tasks such as shovelling which involve metabolic heat production at rates as high as 500 or 600 Kcal/hr require that rest be taken one-half to two-thirds of the time simply because of the physical demands of the labor. Thus, the hourly contribution of M to heat load will seldom exceed 300 Kcal/hr. It is obvious that mechanization of such work can increase worker productivity by making possible a decrease in the time needed for rest. The second modifier warranting discussion is modifying the number and duration of exposures. When the task in a hot environment involves work that is a regularly scheduled part of the job, the combined experience of workers and management will have resulted in an arrangement which makes the work tolerable most of the time for most of the workers. For example, the relief schedule for a task which involves manual transfer of hot materials may involve two workers only; because of the heat and depending on the duress, these two workers alternate at intervals from five minutes up to an hour, which have been determined empirically. Under such conditions overall strain for the individual will be less if the cycles are short.66 Where there is a standardized quota of hot work for each man, it is some times lumped at the beginning of the shift. This arrangement may be pre ferred by workers in cooler weather; however, there is evidence that the strain of such an arrangement may become excessive on hot days. The total strain will be less, evidenced by fewer heart beats, if the work is spread out. Significantly large variations in work site temperature usually occur during the work day. A typical continuous recording is shown in Figure 4. # IV-4 The stress of hot jobs is also dependent on vagaries of weather. A hot spell or an unusual rise in humidity may create overly stressful condi tions for a few hours or days in the summer. Non-essential tasks should be postponed during such emergency periods, in accordance with a prearranged plan. Also, assignment of an extra helper can importantly reduce heat exposure of members of a working team. However, there is danger in this practice when novices are utilized. Many of the critically hot exposures to heat faced by employees in industry are incurred irregularly, as in furnace repair or emergencies, where levels of heat stress and physical effort are high and largely unpredictable, and values for the components of the stress are not readily assessable. Usually such exposures will force progressive rise in body temperature. Ideally, such physiologic measurements as body temperature and heart rate would be monitored and used as criteria for limiting such exposures on an ad hoc basis. Practically, however, the tolerance limits have been based on experience of the worker as well as of his supervisor. Fortunately, for most workers, perception of fatigue, faintness, or breath lessness may be relied upon most of the time for bringing individual ex posures to a safe ending. The highly motivated individual, particularly the novice who desires acceptance, is at greater risk. In the same spirit, foremen should respect the opinion of an employee when he reports that he does not feel up to work in the heat at a particular time. Non-job personal factors such as low grade infection, a sleepless night, or diarrhea (dehydration affects sweating) which would not affect performance on most jobs, may adversely affect heat tolearance. # IV-5 Perhaps the best advice that can be offered for control of irregular exposures is (a) that formal training and indoctrination on effects of heat be provided both supervisors and workers, and (b) that these include directions to the effect that each exposure should be terminated before physical distress is manifest. There is abundant evidence that the physiological strain of an exposure which raises body temperature above 38°C is such as to contraindicate further exposures during the same day; it may take hours for complete recovery. More work can be achieved during several shorter exposures and with less overall strain. The third modification to be discussed is modifying the thermal environment. The environmental engineer will usually identify important sources of heat stress in a qualitative sense, without resort to elaborate measurements. Thus, his experience will suggest that when air is static and the clothes of the workers become wet with sweat, it will help to provide a fan. Nevertheless, we reiterate the advantages in making a quantitative analysis of the heat stress (and where possible the resulting strains) on workers. The effects of various approaches to control can be predicted, and improvements in thermal conditions at the workplace can be documented for higher levels of management based on measurements made before and after action has been taken. We cite concrete examples to illustrate how the quantitative analytic approach may be used. Case I. A case which is encountered frequently under ordinary conditions of hot weather. # IV-6 Let us assume a laundry where the humidity is high (Pa = 30 mm Hg) despite the operation of a small exhaust fan on the wall. There is no high level heat source so the temperature of the solid surround (reflected in Tg) is about the same as that of the air. In the simplest situation we take Ta and Tg equal to the temperature of the skin, which may be assumed to be 35°C (95°F A more effective permanent approach would be to replace the small exhaust fan with exhaust hoods opening over the moisture source. Adequate make-up air would have to be provided. If outside high humidity rather than a large inside source of hot water were creating inside conditions similar to those of this case, the obvious solution would be installation of mechanical air conditioning. This would be an expensive solution for Case I. It is obvious from the deficiency of evaporation and the enormous load that the workers, despite full clothing and a face shield, were able to perform this task only for a few minutes at a time. Heat exhaustion was not uncommon (and might partly be attributable to the difficult hot conditions prevailing in the nearby rest area). Engineers undertook control of this heat exposure by interposing finished aluminum sheeting between the heat source and the worker. Infra red reflecting glass at face level permitted seeing the task and space was left for access of the arms in using the ladle. As a result of these measures it was recorded that both Tg and Ta were reduced to 43°C (110°F). The same air speed was present as before and if we assume the same Pa By this action to reduce R, the heat load was brought to a level that is reasonable for prolonged work, but did not completely eliminate the heat stress. The predicted requirement for sweating to maintain heat balance was reduced to about 0.7 liter/hr from the previously impossible-to-sustain level of 2.1 liters/hr. (The before and after average levels actually observed for two workers were not far from these predictions, namely 1.1 and 2.1 liters/hr. The same two subjects also showed a marked reduction in heart rate, as a result of the changes, from an average of 146 to 108 bears/min.) The percent reduction of the radiant load can be taken as a measure of the effectiveness of the reflective shielding, and in this instance approximates 85%. Large errors in the stimate of R are possible at extremely high globe temperatures, but in this case it appears that the IV-11 maximum relief that could be expected from shielding was achieved. Haines and Hatch reported smaller reductions in R of 51 to 74% from interposing a sheet of aluminum at eleven different work sites in a glass factory. Others have shown reduction of 90% or more under ideal conditions not likely to prevail on the plant floor. While in Case III we have dealt with some aspects of control of R by shielding, the two other classical approaches of industrial hygiene engineering, namely, control at the source and control at the man, offer possibilities which must be considered. Application of insulation on a furnace wall can reduce its surface temperature and thereby the level of R. A by-product of such treatment is a saving in fuel needed to maintain internal furnace temperatures. Application of a polished metallic surface to a furnace wall will also reduce R. However, a polished metallic surface will not maintain its low emissivity if it is allowed to become dirty. A layer of grease or oil one molecule thick can change the emissivity of a polished surface from 0.1 to 0.9. And the emissivity of aluminum or gold paints for infrared is not necessarily indicated by their sheen. If the particles are smaller than about one micron they emit almost like a black body. (The same is true for fabrics coated with very fine metallic particles.) Equal or even more effective reduction of R is achievable with nonreflective barriers through which cool water is circulated. The engineer is frequently baffled in shielding by the fact that access to the heat source is required for performance of the task. We have seen various solutions to this problem. One is a curtain of metal chains which can be parted as required and which otherwise reduces IV-12 emission like a fireplace screen. Another is a mechanically activated door which is opened only during ejection or manipulation of the product. And finally, remotely operated tongs may be provided, taking advantage of the fact that radiant heating from an open portal is limited to line of sight and falls off as the reciprocal of the square of the distance from the source. The fourth modification to be discussed is that of thermal conditions of the rest area. Brouha66 states "it is undeniable that the possibility of rest in cool surroundings reduces considerably the total cost of work in the heat." There is no solid information on the optimum thermal conditions for such areas but there are laboratory data which support setting the temperature near 25°C (77°F). This feels chilly upon first entry from the heat, but adaptation is rapid. The placement of these areas is of some importance. The farther they are from the workplace, the more likely that they will be used infrequently or that individual work periods will be lengthened in favor of prolonged rest periods. Incidentally, the same principle applies for positioning of water fountains. When they are remote from the worker, substantial dehydration is more apt to occur. The proper temperature for drinks under hot conditions is often asked. There is no scientific answer, but most men will not willingly drink fluids that are close to body temperature. They welcome chilled water and recognize that frequent small drinks are better than large draughts. # IV-13 The final modification to be discussed is clothing. Heat stress usually may be altered substantially through selective wearing of clothing. In the heat, as in the cold, the thermal function of clothing is to reduce heat transfer between the individual and his environment.14 Clothing may reduce transfer by radiation, by convection, and by evaporation of sweat. Whether clothing will represent an advantage depends not only on its design but on the characteristics of the particular thermal environment in which the work is being performed. # Conventional work clothing: We first examine what is known about the effects of ordinary work clothing consisting of work shirt and trousers. These will be of flame retardant material if fire or sparks are in the working area. Other items normally will include cotton underwear, socks (which in hot weather are better if of medium to heavy weight), perhaps gloves, and perhaps a hard hat. The wearing of long underwear, woolen or cotton, represents a special case which is dealt with later. The effect of such clothing in interfering with heat loss by R+C is substantial and can be illustrated. For a man doing moderately hard physical work (1200 Btu/hr) and wearing only shorts, comfort temperature would be about 70°F. In work clothing comfort temperature might well be 55°F. If the environmental temperature actually was 70°F, the cost of wearing clothing, in terms of heat stress, would be equivalent to an added sweat rate of at least one-half pint per hour. Laboratory studies clearly indicate that ordinary work clothing will reduce radiant heat transfer by 30 to 40 percent.70 Theory yields a similar reduction for transfer by convection. And recent studies demonstrate that this clothing will reduce the potential for evaporating sweat by about 40 percent. There are two important implications of these findings. Only the first is common experience. In warm environments, below skin temperature, wearing of clothing decreases heat loss and comfort. This is particularly true when humidity is high or the air is static. This disadvantage may become an advantage when air temperature and/or radiant temperature exceeds skin temperature. Then clothing reduces heat gain to the body. For example, on a 95°F day the radiation from the sun under a clear sky can represent the equivalent of a 20°F increase in air temperature for the seminude body.14 This load can be reduced to the equivalent of 8°F by conventional work clothing (to even less with near-white clothes). Heavier clothing would reduce R even more, but this advantage is nulified at the point such clothing interferes with evaporation of sweat. In arid climates adequate evaporation seldom is a problem, particularly with good air movement, but in an industrial plant with the high radiant heat from a furnace the limits on evaporation may preclude heavy clothing for prolonged tasks. The implication of the above is that radiant heat which was tolerable for a worker wearing shirt and trousers would be excessive for a man in shorts. This has been demonstrated in the laboratory.70 A mean radiant temperature of 205°F was used in simulation of a task involving fourminute exposures interspersed with two-minute relief periods. This was tolerable when clothes, but intolerable when nude. The radiant load became just tolerable when reduced in intensity by about 30 percent. As mentioned in the preceding section, the color of skin or of clothing is immaterial in these exposures; they are black to infrared heat. The highest local skin temperatures readily tolerable under such conditions depends on the amount of body surface area affected. For large areas such as the back it is about 105°F; for smaller areas such as a hand it may be 110°F. As an average for the whole body of an individual at work for prolonged periods, 95°F is about the limit; with higher average skin temperatures, a rise in internal body temperature may be expected. Additional information on time-tolerance relationships appears.71 Long winter-weight underwear has been adopted by many workers who move in and out of very hot environments. This makes sense to the extent that the extra layer provides a substantial buffer against extremes of heat gain (and loss, which is a factor in open sheds in wintertime). In humid slimmer weather the practice is less justified, unless there is ready access to air conditioned areas for recovery, because the underwear interferes with evaporation of sweat from the skin. The ounce-by-ounce efficiency of evaporation of sweat from clothing is considerably less than from the skin, more sweat must be produced to maintain heat balance and little or no more can be evaporated. # IV-16 It is obvious that ordinary work clothing itself moderates extremes of transient heat exposures, but this is to a lesser extent than when long underwear is worn. # Special Clothing: This may take various forms. For example, the wearing of infra red reflecting face shields may be indicated when radiant heat is high. In frequent handling of hot materials, it is good practice to provide several pairs of oversize insulative gloves, these having wide gauntlets for easy entry without using both hands. For very hot exposures, as in relining furnaces, thick insulative clothing is appropriate. This acts as a heat "sponge." This sponge may be more effective if made of high density materials (asbestos in the recent past) because of the higher heat capacity, but insulation with minimum weight is best imparted by a thickness of trapped, still air. It is obvious that for relatively longer intervals of exposure, high density and highest feasible thickness should be sought. The protective value of such clothing is enhanced by aluminizing its surface and sometimes interlining foil between insulative layers. # Aluminized Reflecting Clothing: When shielding against radiant heat loads cannot be accomplished by fixed barriers, aluminized clothing components may often be used to advantage. The aluminum is vacuum deposited on the surface of the fabric. Interposition of such coated fabrics between a 600° to 1100°F source and a black globe has resulted in reflection of 90% of incident energy.60 # IV-17 However, in a study using reflective clothing items while working in the 205°F radiant heat mentioned above, efficiency was found to be much less. Ordinary work clothing yielded 40 percent protection, an aluminized apron about 50 percent and a full aluminized suit about 60 percent. In inter mittent work at high humidities the full suit proved a handicap because of its interference with evaporation of sweat. The use of full reflective clothing can sometimes be avoided. For example, fixed shielding to waist level may make possible use of only an aluminized jacket. Or a worker who faces the heat source may resort to a long metallic apron. When the coverage with reflective clothing is only partial, there is much more opportunity for evaporation of sweat. It is obvious that an aluminum finish, as on the palmar surface of an insulative glove, will be of little use in handling materials. # Thermally Conditioned Clothing: Numerous ideas have been incorporated in special clothing for maintaining comfort in extreme heat (or cold). Some systems supply appropriately cool air from a mechanical refrigerator to points under a jacket or coveralls. When air from a remote source is used, there are two problems. One is the gain of heat through the walls of the supply tubing. This problem has been solved in some cases by using porous tubing which will leak an appropriate amount of supply air to keep the walls suitably cool. The other problem is distribution of the air through the suit. With a simple, single orifice it is difficult to cool a sufficient area of skin and the area cooled may be too cold. Provision of several orifices, though better, will create bulk and restrict mobility. # IV-18 In fact, the restriction of movement resulting from tethering the worker to a supply line will often contraindicate this type of system. When such a line is used, there should always be a simple quick disconnect for use in emergency. The vortex tube source of cool air has been used successfully in some situations. 62 The device is carried on the belt. Air introduced tangentially at high velocity is forced into a vortex, which results in two separable streams of air, one cold which is distributed under the suit, the other hot which is discarded. Compressed air requirements to operate the vortex system are large. Self-contained sources of conditioned air which can be backpacked have also been developed. One involves a liquid refrigerant which is sealed into a finned container. After being cooled in a deep freeze, the container is placed in the pack. A small battery-driven fan circulates air across the fins and into the suit. A single charging of this device may extend tolerance for relining furnace walls from several minutes to 30 or 60 minutes. More sophisticated devices employ a closed system with liquid as the coolant and a fairly elaborate network of small tubes for distribution. The nuisance factor must be considered for all such devices. Men will not go to the trouble of donning them unless they recognize more than a marginal advantage. On the other hand, with such devices, it has sometimes been possible to change hot tasks which required long rest pauses and multiple workers into single worker, continuous duty operations. IV-19 All of these indices include the four climatic factors: air temperature, humidity, radiant heat, and wind velocity. However, the work load is not included in the ET and WBGT. This fact weighs in favor of HSI and P4SR. On the other hand, the calculation of these latter two indices is much more complicated than that of ET and WGBT, even when the available monograms are used. Between ET and WBGT, the latter one wins out in simplicity of calculation. Another aspect which makes WBGT more desirable is that while wind velocity must be measured for the other three indices, for WBGT this is not required. This is a very important consideration in view of the difficulty NIOSH has experienced in field studies^" in establishing an hourly time-weighted average value for this factor. One important reason for this is that as man moves around while performing his job, he is exposed to wind velocities which vary con siderably and often suddenly. As far as the fourth criterion is concerned, all four indices have some shortcomings, as pointed out in the previous section. Thus, from this point of view, none of the four indices has an advantage over the other. The HSI has many advantages from the point of view of the fifth criterion, the greatest one being that it makes it possible to calculate the allowable exposure time as well as the minimum recovery time for a QO given heat stress condition. # V-5 The studies performed by Lind on the prescriptive zone (PZ) were used as a basis for the determination of the environmental conditions (including different combinations of climatic and work load), which can be tolerated by 95% of the worker population with body temperatures not in excess of 38° C. The essence of this principle is shown in Figure 5. Each point on the graph represents the result of an experiment lasting until the rectal temperature of the observed subject reached a steady state. This took about 30-to-60 minutes depending on the intensity of the combined heatwork exposure. It becomes apparent from the graph that up to a certain level of effective temperature (ET) the equilibrium rectal temperatures follow a straight horizontal line, i.e., they do not increase, no matter how much the ET is increased in the heat chamber. However, the rectal temperature is higher when the work rate is higher. Thus, in this range of environmental heat the rectal temperature is determined only by the work intensity. This range is called the prescriptive zone (PZ). Over a certain level of environmental heat each of the three curves in the graph show a sudden turn upward, indicating that over this level the equilibrium rectal temperatures increased each time the climatic conditions became hotter. Thus, in this range of environmental heat the deep body temperature becomes sensitive to changes in climatic conditions and man can easily lose his ability to maintain an equilibrium temperature, thus leading to heat disorders. This range of climatic conditions is called the environment driven zone (E D Z ). The environmental temperatures at the border between the PZ and EDZ are called the upper limit of prescriptive zone (U LPZ). # V-6 The value of the ULPZ varies for different individuals. It is higher for men who are acclimatized to heat, by approximately 4.0°F ET, and is lower the more clothing an individual wears. To make sure that 95% of a heat acclimatized population wearing worker uniforms will not have a rectal temperature in excess of 38°C, it must be established at what level of environmental heat will the 5 percentile man reach his ULPZ, and this value has to be corrected for the level of acclimatization and clothing. This ULPZ was found in a paper of Lind and Liddell®^ in which they tested the ULPZ of a group of 128 men of average physical fitness. Figure 6 shows that about 95% of the men could reach an equilibrium deep body temperature in the 3-hour exercise test if the climatic conditions did not exceed 80.5°F. Thus, at a work load of 300 Kcal/hr the 5 percentile man's ULPZ lies about 1.0°C lower than that of the subjects' observed by Lind in his first study of the PZ.®® This result was adopted as a guideline to correct the ULPZ values orginally recommended by Lind as shown in Figure 7. As can be seen, it was assumed that a larger correction is required at higher levels of work load when the rectal temperature in the PZ is already very close to 38°C and no correction was applied at the lowest level of work load where the rectal temperature in the PZ is much lower than 38°C. Another justification for applying this upward adjustment for heavy work and downward adjustment for light work comes from the study of Kraning et al.®^ this study evidence was presented that the heat generated by work metabolism causes about twice as much strain on the cardiovascular system as the same amount of heat taken up from the environment. Studies performed by NIOSH V-7 have confirmed these findings. Corrections would also be needed for clothing because Lind's subjects were tested wearing shorts and sneakers only whereas the workers in hot industries wear underwear and work uniforms as well as boots. This would require a lowering of the ULPZ value. However, an increase would be permitted because it is assumed that the workers in hot jobs will be acclimatized. These two factors then cancel out each other. The ULPZ values read from the abscissa in Figure 7 are expressed in 86 terms of basic ET. They were converted by using Minard's graph showing the correlation between ET and WBGT. In this graph, however, the normal ET is stated for semi-nude men. Thus the ULPZ values read from Figure 7 were first converted to normal ET values, then to WBGT values. Justification for using time-weighted average hourly work-load 87 values for intermittent work comes from another study by Lind. The results showed that from the point of view of the ULPZ it does not matter whether a certain hourly amount of work is performed at a lower rate continuously or at a higher rate but interrupted with rest periods. The permissible exposure limits for heat stress cannot be based on 8-hour average values because if excessive exposure persists for longer than 1 hour, the worker may accumulate enough heat in his body to cause him to suffer an acute heat disorder or heat illness; thus in continuous heat exposure, hourly averages are necessary. However, if the exposure is intermittent the accumulation of heat will be slowed down; thus, it is permissible to average the exposure every 2 hours. V-8 The ULPZ was found to be the same for men of different ages, 88 thus no correction for age is required according to Lind et al. However, when older men are exposed to strenuous heat load an increased caution is advisable because of their lowered physiological capacities and increased susceptibility to diseases. A sex difference in the pattern and magnitude of physiological responses to work in heat has been demonstrated. Whether the observed differences in the responses reflect real differences in heat tolerance or in work performance is not fully proven (see references 33, 43, and 89 thru 96). In resting-in-heat studies the young female subjects had a higher body temperature and a lower sweat production than did the young males 89 for the same heat exposure. The onset of sweating occurred at a higher body temperature in the females, which resulted in a time delay in the onset of sweating during both severe and mild heat stress. Actual tolerance time in the severe heat was shorter in the females even though the maximum endurable body temperature was the same in both sexes. The symptoms present when an individual collasped from the heat stress were comparable even though the females found the stress intolerable sooner with work-in-stress. Women started to sweat at a higher skin temperature and had a lower sweat production for any specific heat load. Calculated skin temperatures at the onset of sweating were about 4°F higher in female than male subjects and for equal sweat rates the skin temperature was 1.8°F lower in the males. # V-9 In spite of the greater strain in women, they are capable of effective heat acclimatization. However, even after acclimatization the sweat rate is lower in the females, and they may have more subjective distress. Resistance to naturally occurring heat waves seems to be lower in women. Apparently there is no real difference in the degree of acclimatization that can be reached in men and women, but they may achieve equal acclimatization in different ways using different configurations of components of the regulating process. The question arises whether the lower sweat production in females may be due to fewer active sweat glands during the heat exposure. Both the total number of sweat glands and the number per unit area of skin surface are greater in females. In lean females one hundred sweat glands per square centimeter of skin were counted while fifty-nine per square centimeter were found in males. In obese females there were seventy-five per square centimeter and in obese males, forty-seven per square centimeter. A recent WHO report questions this difference in sweat QAq rates after acclimatization. Differences in pulse rate responses to a standard work-in-heat test between both young and old men and women have been found.^ At the lower levels of work the women had pulse rates ten to twelve beats per minute higher than the men. For the high levels of work the differences were twenty to thirty beats per minute higher in the females. The higher pulse rates in the women reflect both the heat stress and the physical work and are higher in the women mainly because the work is relatively harder for them. Oxygen consumption expressed as V-10 milliliters per kilogram of body weight was about 15 to 20% higher in women than in men. The highest level of physical work used in the test required about 43% of the predicted maximum aerobic capacity for the older men, 30% for the young men, 66% for the older women, and 44% for the younger women. W i n g 9 ? reviewed the results of 15 studies performed in different laboratories on the effect thermal stress has on mental performance. It is quite apparent from these studies that thermal stress is an important factor where the worker has to make critical decisions, make fine discriminations, or has to perform fast and skillful actions because safety will depend on constant alertness. The number of errors made will increase if the worker is exposed to heat even before body temperature or pulse rate reaches critical levels. Figure 1-1 in the recommended standard is adapted from Wing's97 review paper. Although Wing recommended these limits only as tentative upper performance limits, they are considered to be the best presently available. Since Wing's values were expressed in ET, they were converted by using Walters'9® graph on correlation between ET and WBGT. As shown in Figure 1-1 of the recommended standard, unimpaired mental performance can be maintained below 86°F WBGT for 4 hours and probably even longer, although this needs experimental confirmation. Since environmental conditions above 86°F WBGT are permissible only for jobs with a work load below 200 Kcal/hr for men and below 150 Kcal/hr for women, Figure 1-1 of the recommended standard has to be taken into consideration only in sedentary jobs. # V-ll It is impossible that for unimpaired mental performance as work loads above 200 Kcal/hr, the 86°F WBGT may be too high. However, there are no data available either supporting or contradicting this assumption. Since then this problem was investigated in several studies and discussed at two Workshop sessions at the University of Pittsburgh. At these workshops the leading experts in problems of industrial heat stress agreed that the Brouha method should be used as a means of monitoring cardiovascular strain in industry. Figure 8 shows data obtained in PHS field studies on the dehydration of workers exposed to hot environments. There is a correlation between daily sweat loss and dehydration: the higher the sweat loss the more dehydrated the worker will be at the end of the work shift. However, this correlation was quite different in the four plants. The heavy equipment operators sweated the least, but dehydrated most. At about the same level of daily sweat loss, the foundry men and chemical plant workers dehydrated significantly less. Finally, the aluminum reduction workers whose daily sweat loss was the highest did not dehydrate more than workers of the chemical plant. # V-12 When analyzing for causes of the differences in the extent of dehydration, it was discovered that aluminum reduction plant workers were supplied from their drinking fountains a 0.1% salt solution. Thus, it was made sure that the salt they lost by sweating was replaced each work day. For the chemical plant workers and the foundry men salt tablets were available at the drinking fountains. The heavy equipment operators were not supplied with any additional salt, except that salt ingested with their midday lunch. These results suggest that salt supplementation may play an important role in preventing dehydration. Another difference between the working condition of the heavy equip ment operators and the workers of the other three plants was in the avail ability of drinking water. Whereas the heavy equipment operators had to go out of their regular path and disembark from their vehicles to have a drink of water, all the workers in the rest of the plants had to do was to go a few steps to the nearest drinking fountain. This circumstance may have also contributed to the higher level of dehydration of the heavy equipment operators. Indeed, it was observed that the workers were not drinking as often as necessary to replace their water loss if they had to make some effort to reach the source of water. These results indicate the importance of making drinking water available close to the job site and recovery places where the workers- daily sweat loss exceeds 2 liters. In Figure 8 a horizontal broken line is drawn at the 1.5% dehydration level. This is done because the results of earlier NIOSH studies suggested that if the level of dehydration exceeds 1.5% of body weight the V-13 physiological responses, such as the body temperature and heart rate, start to increase, indicating an increase of strain. In this respect it may be worth mentioning that among the heavy equipment operators the accident frequency was double that observed at other locations where the same operations were performed, but in comfortable climatic conditions. It may be assumed that the dehydrated heavy equipment operators, unaware of their diminished performance capacity, may have been unable to react fast enough and correctly in situations where sudden action would have been necessary to prevent an accident. This again may be interpreted as a warning as to the importance of proper fluid and salt replacement in hot jobs. # Summary of the Basis for the Work Practices Standard The work of L i n d e , 84 £n the development of the prescriptive zone (PZ) is undoubtedly the basis for the best approach for the development of an environmental standard for heat stress because it combines both the climatic and work load conditions that are imposed upon the worker in hot industries. There are, however, a number of practical shortcomings and unresolved questions related to this approach. These unresolved questions which will require additional research to validate the hypotheses presently proposed as the best technique for evaluation of heat stress conditions dictates the necessity for the development of the work practices standard as outlined in this document as opposed to an environmental standard. The additional research is such that it would be impossible to utilize an environmental standard at this time without stringent limitations being placed upon both the worker and management. Such an approach would be unrealistic. V-14 The This must also be considered in relationship to the normal work clothes of the industrial worker, as well as any other protective clothing that such a worker may be wearing. # V-15 All of the above factors can have a significant impact upon the level of heat stress to which a worker might be permitted to be exposed without adverse affects. At this time, such factors without sufficient validation would result in severe limitations on any environmental levels that might be proposed. The information does exist, however, to allow for environmental measurements that can be utilized to initiate work practices that will protect the industrial worker. Additional research is being conducted with regard to how the questions, indicated above, might be resolved. # Environmental Measurements The climatic conditions are expressed in wet-bulb globe temperature (WBGT) on both the Fahrenheit and Centigrade scales. Assessment of the WBGT Index The numerical value of the WBGT Index is calculated by the following equations: 1. Indoors or outdoors with no solar load WBGT = 0.7 WB + 0.3 GT # Instrumentation The instruments required for determining the WBGT Index are a natural wet-bulb thermometer, a globe thermometer, and when outdoors in sunshine, a dry-bulb thermometer. A satisfactory wet-bulb thermometer may be constructed using a mercury-in-glass thermometer having a range of 30 to 120°F with 0.5°F graduations, and guaranteed to be accurate within + 0.5°F throughout its range. A centigrade thermometer of comparable accuracy may also be used. A highly absorbent woven cotton wick shall cover the thermo meter bulb and at least 1-1/4 inches of the thermometer stem above the bulb. The lower end of the wick shall be immersed in a reservoir of V-17 distilled water. There shall be one inch of wetted wick exposed to the air between the top of the reservoir and the bottom of the bulb. The wick should be wet to the top at all times. Under unusually hot or dry conditions this may be difficult to achieve, and special pro visions may be necessary, such as an auxiliary water supply or manual wetting. The globe thermometer should consist of a 6-inch diameter thin copper sphere, the outside of which is painted a matte black. Either Krylon No. 1602 Ultra Flat Black Enamel or 3 M No. 101-C10 Nextel Black Velvet coating is available in spray cans and will provide an satisfactory surface. A mercury-in-glass thermometer, having a range of 30 to 220°F with 1°F graduations and guaranteed to be accurate to + 1°F, should be inserted through the shell with the thermometer bulb located at the center of the globe. The thermometer mounting and the globe support may be arranged in several ways. One convenient method is to use a globe having a spud with a 1/A inch pipe tapping. The thermometer can be inserted through a hole drilled through the spud and supported at the proper height by a ring of rubber tubing, and the complete assembly can be supported by a clamp around a 1/A inch nipple screwed into the spud. Another satisfactory method is to insert the thermometer through a rubber stopper in a hole in the top of the globe. The globe is then supported from the bottom by a 3/16 inch rod threaded into a matching spud. The globe thermometer should be allowed 20 minutes to reach equilibrium. # V-18 When a dry-bulb temperature is necessary it may be obtained with a mercury-in-glass thermometer as specified above for the wet-bulb thermo meter. The dry-bulb thermometer should be shielded from solar radiation, but shielding must be applied in such a manner that air circulation over the thermometer bulb is not restricted. Mercury-in-glass thermometers have been indicated as the sensing elements in the above described instruments. Thermocouples, thermistors, or any other sensors which will provide the same accuracy are equally acceptable. In some cases these may have an advantage over the ordinary thermometer in that the signals from such sensors may be readily recorded. A suggested arrangement of the instruments is given in Figure 9. Further instrument details and techniques for their use may be found in references.99'100'101 In addition to the above described instrumentation which requires the calculation of the WBGT index value, there are instruments described in Qo in9 ihq the literature ' ' or available on the market which sense the required temperatures and automatically integrate them to give a readout in WBGT- Another such instrument is currently (March, 1972) being developed by NIOSH. Instrumentation for the determination of the WBGT Index should always be located so that the readings obtained will be truly representative of the environmental conditions to which the workman is exposed. Sensors should be at about the mean height of the worker, and due consideration should be given to the location of radiation sources and the direction of air movement. A record shall be maintained of the WBGT Index observed at each of the various hot work sites. V-19 # Medical The purpose of the pre-placement examination of persons applying for hot jobs is the same as for evaluating the health status of a prospective employee for any job, namely, to determine his mental, physical and emotional qualifications to perform his job assignment with reasonable efficiency and without risk to his own health and safety or to that of his fellow employees.10T he examining physician, however, will recognize the particular requirements for persons whose jobs involve significant heat exposure. He should be probing in taking the employees' history, both medical and occupational, in order to discern possible evidence of intolerance co heat either occupational or off the job. By the same token, a history of successful adaptation to heat exposure on previous jobs is perhaps the best criterion on which to predict effectiveness of a worker's future performance under heat stress, assuming that levels of work demands and heat exposure are equivalent and that no significant alteration has occurred in his health status since his previous employment. For new employees without previous occupational exposure to heat, they should not be assigned to hot jobs where the environmental conditions exceed 79°F WBGT for men and 76°F WBGT for women until they are acclimatized. It has been established that both heat tolerance and also physical work capacity decline with age.10^'10D uring both the history taking and the physical examination, the examiner should direct careful attention particularly to detect evidence of chronic functional or organic impairments not only of the cardiovascular system V-20 but also of the kidneys, liver, endocrines, lungs, and skin. Significant disease of any of these systems should be disqualifying for new employement on jobs involving severe heat exposure, or for those previously employed on such jobs if the disease is progressive despite treatment. Careful inquiry should be made on use of drugs, particularly hypotensive agents, diuretics, antispasmodics, sedatives, tranquilizers, and anti depressants as well as the abuse of drugs, particularly amphetamines, hard narcotics, and alcohol. Many of these drugs impair normal responses to heat stress and others alter behaviour, thus, exposing the employee or fellow workers to health and safety hazards. Evidence of therapeutic use of one or more of these categories of drugs or personal abuse of alcohol and other drugs should be disqualifying. Other qualifications depend on the job demands independently from heat exposure, for example, statutory requirements to qualify as a vehicle operator, craneman, locomotive engineer, etc., would obviously need to be met as well as nonstatutory requirements for jobs in a particular industry. A glucose tolerance test, renal clearance studies, X-ray examination of the renal pelvis and biliary system with contrast media, pulmonary function tests and other special tests are recommended when indicated in addition to routine 12-lead ECG 14" x 17" chest X-ray, and the usual blood and urine analyses. Workers employed on jobs which regularly expose them to levels of heat stress which have been determined to approach or equal permissible limits prescribed by the heat standard should be examined periodically on an annual basis or more frequently if indicated. The examination should be conducted during the summer season. In employees after the age of V-21 forty-five, physical and laboratory examinations should be designed to detect conset of chronic impairments of the cardiocirculatory and cardio respiratory systems and also to detect metabolic, skin, and renal disease. In cases of older employees who had not undergone the pre-placement examination, and whose health records indicated pre-existing chronic diseases of the systems referred to in the section on pre-employment examination, the examination should determine the extent to which such impairments have progressed. For all employees on hot jobs undergoing periodic examination, any history of acute illness or injury, either occupational or nonoccupational, during the interval between examinations, should be carefully evaluated. Repeated accidental injuries on the job or frequent sick absence should alert the physician to possible heat intolerance of the employee or the possibility of an aggravating stress with heat in combination, such as CO. Nutritional status should be noted and advice offered to correct overweight. In industrial establishments in which heat stress approaches or equals permissible limits only during the summer season, periodic examin ations should be administered during the summer. In establishments in which heat stress at the permissible level occurs throughout the year, the periodic examination can be administered at any time regardless of season. The first periodic examination of workers already employed on hot jobs who had not undergone the pre-placement examination required for new employees should be conducted within a year. Guidelines for qualifications should be the same as for new employees but with due allowance made for successful performance on the job, which as indicated earlier is perhaps the most important criterion in evaluating a worker's capacity to adapt to heat stress on the job. # V-22 In cases of those previously employed but with a record of health impairment or significant impairments found first on periodic examinations, the examiner should determine whether pre-existing impairments had been effectively controlled by treatment. If progressive, despite treatment, these findings should disqualify the employee from continuing on the same job. In case of impairments detected for the first time, the examiner should evaluate these in light of possible aggravation by heat stress. If such a likelihood exists, the employee should be reevaluated periodically at intervals shorter than those recommended for routine periodic examinations. For a new employee undergoing his first periodic examination, the examiner should note evidence of heat intolerance, including a history of repeated accidental injury on the job, episodes of heat disorder, or frequent sick absence. In such cases, the examiner should assess the employees capacity to continue on the same job and consider recommending his transfer if indicated. The supervisor and selected personnel should be trained in recognizing the signs and symptoms of heat disorder and in administering first aid. As described earlier, the most serious emergency is heat stroke signaled by the signs of dry, hot, red, or mottled skin, mental confusion, delirium, convulsions, or coma, and a high and rising rectal temperature, usually 106°F and above but occasionally lower, between 104 and 106°F. First aid treatment requires immediate removal to a cooler area, soaking the clothing in cold water, and fanning vigorously. The final treatment is conducted in a medical facility but first aid must not be delayed. # V-23 In severe heat exhaustion, the victim may faint on standing, but unlike heat stroke the skin is wet and cool. He should be given water by mouth if conscious, and transported to the medical facility without delay. It is essential that water intake during the workday should about equal the amount of sweat produced. Work in a hot environment may result in sweat productions of 1 to 3 gallons a day. If this water lost in the sweat is not replaced, dehydration with its debiliating effects will result. Thirst is an inadequate drive to stimulate one to drink that much more water. An ample supply of cool water readily available to the workers is required and the worker should be encouraged to take a drink of water each 15 to 20 minutes preferably using disposable paper cups rather than drinking directly from the fountain. Large amounts of salt may be lost in the sweat particularly by the individual not acclimatized to heat. The salt must be replaced daily to prevent heat induced salt deficiency heat illness. The acclimatized individual looses much less salt in his sweat. Salt V-25 can be replaced by liberally salting ones food or by using a 0.1% salt solution drinking water. About 1 level tablespoon of table salt to fifteen quarts of water will make a 0.1% salt solution. Enteric coated salt tablets may also be used; however, they must be taken with ample water to prevent gastric irritation. It is particularly important that salt depletion is prevented by supplemental salt intake during the first few days of heat exposure when the worker is not yet acclimatized. Each employee exposed to heat should weigh himself at the beginning and end of the workday to insure that fluid intake has been sufficient to prevent serious dehydration. Weight loss at the end of the workday should not exceed 1.5% of the worker's body weight. Each employee should be instructed on how to recognize the symptoms of heat disorders and illnesses including dehydration exhaustion, heat syncope, heat cramps, salt deficiency exhaustion, prickly heat and heat stroke. Recognition of early warning signs so that corrective or evasive action can be taken is one of the best means of preventing health damage. The major heat disorders are shown in Figure 3 and have been discussed in the section on Medical Considerations. The most prevalent of the heat disorders is undoubtedly heat syncope (possibly along with heat edema) which is seldom a debilitating disorder. (over many days), the end result is the same. In extreme examples, as for men lost in a desert with no water to drink to replace sweat losses, 16 death can occur in 12 hours and is usually inevitable within 48 hours. Even for individuals in a temperate climate, such as castaways at sea, water deprivation will usually result in death in 7-10 days. Death from water depletion will occur if 9-10 liters (18-20 pints) is lost from the body, and loss of 4 liters (8 pints) without replacement leads to intense thirst, a rapid heart rate, and a high body temperature. Water intake must equal the water loss by sweat if this disorder is to be avoided; workers exposed to hot climates must be encouraged to drink an ample supply of water or flavored drinks which must be readily available to them. Again, there is no specific environmental condition above which this disorder occurs, since it depends simply on the replacement of the fluid loss which occurs even in comfortable conditions; however, the hotter the environment is, the greater is the fluid loss by sweating and the worker will thereby come closer to water depletion. Salt is also lost in the sweat. The concentration of salt in the sweat is higher in unacclimatized men than in acclimatized men, but the concentration also depends on the dietary salt intake, which is usually in excess of the body's needs.If salt lost in the sweat exceeds the dietary intake, a salt depletion occurs. If this is not corrected, a vicious cycle can occur, since salt depletion can lead to loss of appetite and nausea, leading in turn to a further salt depletion; moderately severe salt depletion results in vomiting and diarrhea, with further loss of salt. If this cycle is not inter rupted, death inevitably follows. Those who suffer salt depletion complain of weariness and weakness and may suffer muscle cramps; headaches, giddiness, V-28 and other symptoms are common. While those who are not acclimatized are at greatest risk, the disorder can occur in any individual who sweats a lot and whose dietary salt intake is low. Supplementary salt of 5 to 15g daily may be required by unacclimatized men to avoid salt depletion, though this may be reduced by half or more after 10 days of work in the heat. While at least some of this supplementary salt can be obtained by the additional salting of food, it may be necessary to supply salted drinks or salt tablets to be taken with drinking water. The most severe heat disorder is heatstroke, the mortality rate for 16 which has been found to be between 25% and 75%. The variability in mortality depends on the length of time elapsing between the onset of the disorder and the start of treatment and the highest body temperature attained during the episode. Heatstroke always constitutes an urgent medical emergency, in which the basic requirement is to cool the patient rapidly. Heatstroke is a state of thermoregulatory failure usually of sudden onset, following exposure to hot environments, and is characterized by a disturbance of the central nervous system (often expressed as convulsions), by a failure of sweating (so that the skin is hot and dry), and by a high deep body temper ature. The body temperature at the time of onset of the disorder is usually in excess of 40.5°C (105°F) although cases have been reported at 39.5°C (103°F). The treatment of heatstroke must be vigorous and immediate, under the careful control of a physician. The environmental conditions in which heatstroke has been reported have been plotted on a psychrometric chart (Figure 10) and are surprisingly low. # V-29 But the values reported do not include the degree of radiant heat load, nor do they disclose the rate of work of the victims prior to the onset of the disorder; both of these contributions to the total heat load were probably high in many cases. Nevertheless, heatstroke has been known to occur in environmental conditions that are not particularly severe. Additional contributory causes can be of many origins -heavy clothing, water depletion, age

Scopolamine Poisoning -Continued Heroin is mixed ("cut") frequently with other substances primarily to increase its weight for retail sale (e.g., mannitol and starch) and to add pharmacologic effects (e.g., dextromethorphan and lidocaine). During 1995 and 1996, health departments and poison-control centers in New York City (NYC); Newark, New Jersey; Philadelphia; and Baltimore reported at least 325 cases of drug overdoses requiring medical treatment in persons who had used "street drugs" sold as heroin that probably also contained scopolamine, an anticholinergic drug. This report summarizes the clinical and epidemiologic features of these cases, which represent a new type of drug overdose.On March 16, 1995, eight persons were treated in the emergency department (ED) of a Bronx hospital for acute onset of agitation and hallucinations approximately 1 hour after "snorting" heroin. On physical examination, all these persons had clinical manifestations of anticholinergic toxicity (i.e., tachycardia, mild hypertension, dilated pupils, dry skin and mucous membranes, and diminished or absent bowel sounds); five had urinary retention. All were initially lethargic and became agitated and combative after emergency medical service (EMS) personnel treated them with parenteral naloxone, which is routinely used for suspected heroin overdose to reverse the toxic effects of opioids (e.g., coma and respiratory depression). All patients received diazepam or lorazepam for sedation, and signs and symptoms resolved during the next 12-24 hours. During March 17-April 5, 1995, a total of 10 persons who reported using heroin presented with similar clinical findings to hospital EDs in the Bronx and Manhattan. Seven patients reported having used heroin with the street names "Point on Point" or "Sting." Specimens of "Sting" heroin obtained from two patients on April 5 and analyzed by gas chromatography-mass spectrophotometry (GC-MS) by the Bureau of Laboratories, New York City Department of Health (NYCDOH), contained heroin and scopolamine. The GC-MS patterns of the scopolamine suggested it was synthetic rather than derived from a plant source. As a result of this finding, these patients were treated for suspected scopolamine poisoning with physostigmine (an antidote for anticholinergic toxicity). While receiving physostigmine intravenously for 5-10 minutes, their paranoia, hallucinations, and agitation resolved (1 ). During March 17-April 10, 1995, NYCDOH issued press releases warning of scopolamine-adulterated heroin sold under the street names "Point on Point" and# "Sting." During March 16, 1995-May 27, 1996, the New York City Poison Control Center (NYPCC) recorded 121 cases that met a case definition of both historical or clinical evidence of heroin use and clinical manifestations consistent with anticholinergic toxicity. NYPCC continues to receive several reports each week of presumed combined heroin/scopolamine overdoses that respond to physostigmine treatment. # Newark During a 24-hour period on December 28-29, 1995, a Newark hospital ED treated 22 persons who, approximately 30 minutes after using heroin with the street name "Polo," developed clinical manifestations of anticholinergic toxicity. Naloxone treatment increased agitation and hallucinations, and physostigmine treatment resolved the signs of toxicity. On December 29, the New Jersey Poison Center (NJPC) informed all EDs in the state about the syndrome of severe anticholinergic toxicity associated with the use of "Polo" heroin. Later that day, after GC-MS testing of a sample of heroin obtained from a patient identified both heroin and scopolamine, the New Jersey Department of Health (NJDOH) held an emergency press conference to alert the public to this drug combination. NJDOH and NJPC identified a total of 61 persons with 1) recent histories of snorting or ingesting heroin with the street name "Polo" and 2) clinical manifestations of anticholinergic toxicity for which treatment had been provided at 13 EDs in the Newark metropolitan area during December 28-30, 1995. During December 31, 1995-June 1, 1996, NJPC was consulted 2-3 times each week about patients with similar conditions. # Philadelphia During February 19-21, 1996, a total of 12 patients who had injected or snorted heroin and had clinical manifestations of anticholinergic toxicity were treated in EDs at four hospitals in northeastern Philadelphia and reported to the Delaware Valley Poison Control Center (DVPCC). DVPCC estimated that in the Philadelphia area, during February 19-21, a total of 35 persons were treated for apparent combined scopolamine/ heroin overdose, and during March 15-May 5, six persons were treated. On May 9, a total of 27 persons presented to one Philadelphia hospital ED between 4:30 p.m. and 11 p.m. because of drug overdoses after taking heroin (mostly by injection). Of these, 16 were admitted to the hospital for observation because of tachycardia, hallucinations, or semi-coma. In addition to these cases, DVPCC was consulted about apparent anticholinergic toxicity among 72 heroin users during May 9-11, and among 12 during May 22-23. # Baltimore During May 10-12, 1996, a total of 22 persons presented to one hospital ED with clinical manifestations of anticholinergic toxicity. Although these persons reported taking heroin with street names of "Homicide" and "Super Buick," GC-MS testing of a specimen identified scopolamine, quinine, and dextromethorphan but no heroin. # Testing of Heroin by the Drug Enforcement Administration The Drug Enforcement Administration monitors the purity of and adulterants in heroin through "street" purchases of heroin (i.e., the "Domestic Monitor Program" ) and testing of heroin obtained during criminal justice operations. From June 1979 through February 1996, DMP did not detect scopolamine in specimens sold as heroin. During 1995, DMP made a total of 806 purchases, including 195 from Maryland, New Jersey, New York, and Pennsylvania; none contained scopolamine. During 1996, of the 147 DMP purchases, including 46 from Maryland, New Jersey, New York, and Pennsylvania, only two (made in March 1996 in Elizabeth and Passaic, New Jersey) contained scopolamine. In addition, four of 23,288 non-DMP specimens believed to be heroin and obtained through criminal justice operations contained scopolamine. The earliest was obtained in October 1995 in Bohemia, New York; two in March 1996 in Philadelphia; and one in March 1996 in NYC. -bscure the classical effects and differences. Although some of these patients improve dramatically with intravenous physostigmine therapy, such treatment should be administered only by experienced staff and with appropriate patient monitoring because of the potential for serious side effects, including seizures, bronchospasm, and bradycardia. For many patients, treatment may be restricted to sedation and observation, and manifestations may resolve over a period of hours. Naloxone remains the treatment of choice for coma and severe respiratory distress associated with possible drug overdose. Because of the complexities of both the diagnosis and treatment of patients with mental status changes and possible drug overdose, practitioners caring for such patients should consult their local poison-control center. Surveillance based on data from the system of poison-control centers in the Northeast was critical in recognizing the cause of this new type of drug overdose among heroin users and alerting health departments. The impact of the effects of these drug overdoses was limited further by timely recognition of the combined heroin and anticholinergic toxicity, use of sedation or physostigmine to treat the patients, and prompt investigation and reporting by state and local health departments. The continued occurrence of drug overdoses associated with use of scopolamine-containing heroin indicates the need for clinicians, public health programs, and organizations working with drug users to be aware of this problem; new cases should be reported promptly to the local poison-control center and health department. # Scopolamine Poisoning -Continued # Trends in Rates of Homicide -United States, 1985-1994 Homicide -Continued During 1993, a total of 26,009 homicides were reported in the United States; 71% were firearm-related, and one third of all homicides occurred among persons aged 15-24 years (1 ). Since 1985, national homicide rates have increased sharply, especially firearm-related homicides and homicides among persons aged 15-24 years. However, based on data from the Supplementary Homicide Report compiled by the Federal Bureau of Investigation and reports from some cities, homicide rates have been stable or declining since 1993. To examine this trend and to assess the relative contributions of firearm-and nonfirearm-related homicide to these recent changes, CDC analyzed national vital statistics data for 1985-1994. This report summarizes this analysis, which indicates that overall rates of homicide increased from 1985 to 1991 and decreased from 1992 to 1994, and that during these two periods, rates for total firearm-related homicides and homicide among persons aged 15-24 years increased then stabilized but remained at record-high levels. Data for 1985-1993 (the most recent year for which complete data are available) were from final mortality statistics (FMS), and data for 1994 were from the Current Mortality Sample (CMS). FMS are based on information from death certificates submitted by all 50 states and the District of Columbia, and CMS data provide national estimates based on a 10% systematic sample of death certificates received monthly by the vital statistics offices in the 50 states, the District of Columbia, and New York City. A homicide was defined as death resulting from injury purposefully inflicted by another person (including those caused by law enforcement officers or legal intervention), for which the underlying cause listed on the death certificate was International Classification of Diseases, Ninth Revision (ICD-9), codes E960-E978. Population estimates are based on data from the Bureau of the Census (2 ). Trends for both firearmand nonfirearm-related homicides for all ages and for persons aged 15-24 years were reviewed. To assess the accuracy with which the CMS data reflect final statistics, 1993 CMS and FMS homicide rates were compared. During sequential quarters of 1993, compared with FMS quarterly homicide rates, CMS rates differed by -0.4%, -4.6%, +1.2% and -4.6%, indicating the accuracy of weighted CMS rates for estimating final homicide rates. Quarterly homicide rates were analyzed using piecewise regression models to account for the observed changes in linear relations over time. Three time periods (1985-1987, 1988-1991, and 1992-1994) were selected for analysis based on a preliminary review of scatter plots of observed rates and their apparent changes in slopes. Statistical testing was conducted to determine whether the slope of the predicted values of the regression line (i.e., predicted rates) changed over each of these time periods. Statistical testing for a discontinuous piecewise regression model also was conducted to determine whether the rate changed significantly at the beginning of each new time period (i.e., "jump point"). No significant jump points were observed, and analyses consistently indicated that the slope of the regression line for 1985-1987 was similar to that for 1988-1991. Therefore, regression lines are presented only for two periods: 1985-1991 and 1992-1994. Overall results and interpretation of the piecewise model using two pieces are no different from those using a model with three pieces. During 1985-1991, the overall rate of homicide in the United States increased significantly (p<0.01) (slope=<0.1, 4% annually); during 1992-1994, the rate decreased significantly (p<0.01) (slope=-0.1, 1% annually) (Figure 1). During 1985-1991, nonfirearm-related homicide rates remained stable, and firearm-related homicide rates increased significantly (p<0.01). During 1992-1994, nonfirearm-related homicide rates declined significantly (p<0.01), and firearm-related homicide rates stabilized. During 1985-1991, the rate of total homicide increased significantly for persons aged 15-24 years (p<0.01) (slope=0.4, 16% annually). Firearm-related homicide rates for this age group also increased during 1985-1991 (p<0.01) (slope=0.4, 23% annually) (Figure 2), with most of the increase occurring during 1988-1991. During 1992-1994, the rates of total and firearm-related homicide were stable. For all other age groups, the trend in firearm-related homicide rates followed a similar pattern, with significant increases during 1985-1991 (p<0.01) and stable rates during 1992-1994 (Figure 2). Nonfirearm-related homicide rates for persons aged 15-24 years and all other ages were lower than firearm-related homicide rates and were stable during 1985-1991 and decreased significantly during 1992-1994 (p<0.01). Analysis of firearm-related homicide rates by sex for persons aged 15-24 years indicates that rates for males and females reflected the overall trend for this age 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 Quarter and Year Symbol=Observed Line=Predicted *Per 100,000 population. † Final Mortality Statistics were used for 1985-1993. Current Mortality Sample was used for 1994. Rate 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 Quarter and Year Editorial Note: The findings in this report confirm that the overall homicide rate increased rapidly during the late 1980s and began to decline in 1992; in addition, nonfirearm-related homicide rates decreased, and the percentage of firearm-related homicides increased. During 1985-1994, the percentage of firearm-related homicides among all homicides in the total population increased from 60% to 72% and among persons aged 15-24 years, from 67% to 87% (3 ). These increases illustrate that changes in overall homicide rates primarily reflect changes in firearm-related homicides. The stabilization of firearm-related homicide rates during 1992-1994-particularly among those aged 15-24 years-reflects a change from the increasing rates in previous years, even though rates remain at record-high levels. The findings in this report also indicate the usefulness of CMS data as a source of information for monitoring homicide in the United States. Because of the timely availability of CMS data and their accuracy in reflecting final mortality-based homicide rates, these data enable more timely analyses of temporal trends, objective policy formulation, and measurement of progress toward public health goals. The findings in this report are subject to at least two limitations. First, because of the small numbers based on CMS data, rates were not examined among age-, race-, and sex-specific subgroups. Second, estimates for some causes of death may be incomplete or skewed because reporting of the underlying cause of death data may not have been complete when the monthly sample was obtained (the data for this potential undercount are adjusted in the annual summary ). Strategies for preventing homicide and violence require integration of approaches from multiple disciplines, including criminal justice, education, social services, community advocacy, and public health. For example, public health approaches to prevent violence have focused on 1) changing individual knowledge, skills, and/or attitudes; 2) changing the social and physical environments; and 3) increasing community awareness of the causes and prevention of violence. The public health community also has recognized the influence of social class and poverty on violence. Communities increasingly are adopting programs emphasizing strategies to enhance the skills of youth and parents to reduce violence. These strategies include, for example, 1) school-based curricula that teach coping, communication, and mediation skills (4 ); 2) family-intervention programs that focus on parental training to positively alter parental practices and family cohesion (5 ); and 3) preschool efforts to develop intellectual and social skills (6 ). Because evaluation of prevention strategies is a critical component of public health interventions, CDC is evaluating the effectiveness of selected programs in reducing violent behavior and injury (7 ). Homicide and assaultive violence now are recognized as global public health problems. Although the U.S. homicide rate ranks higher overall and higher for males aged 15-24 years than those of other highly industrialized countries (8,9 ), in many lessindustrialized countries homicide rates exceed those in the United States (8 ). To address this global problem, in May 1996 the 190 nations of the World Health Organiza-tion (WHO) passed a resolution declaring violence a worldwide public health problem, urging member states to assess the public health impact of violence, and requesting the Director-General of WHO to initiate a science-based public health approach to violence prevention. This resolution provides a scientific framework for action throughout the world addressing global violence. The SOII is a collaborative federal/state program administered by BLS and is based on employer reports from approximately 250,000 private industries in the United States (2 ); the sampling frame is representative at the national level and at the state level for most states (data for 1993 were the most recent available). § Employers identify injuries and illnesses that meet recordkeeping requirements ¶ of the Occupational Safety and Health Administration (OSHA); based on these data, BLS estimates the national incidence of work-related injuries and illnesses. For those injuries and illnesses resulting in lost work days, employers provide demographic information and data about the nature and circumstances of injuries and illnesses. Because employment data provided by employers were not stratified by age, injury and illness rates could not be calculated for specific age groups. # Homicide -Continued # Work-Related Injuries and Illnesses Associated With # National Estimates In 1993, persons aged <18 years incurred an estimated 21,620 injuries and illnesses involving lost work days. Of these, 24% involved 1 lost work day; 43%, 2-5 days; 13%, 6-10 days; 13%, 11-30 days; and 8%, ≥31 days (median: 3 days). Most (96%) injuries and illnesses occurred among persons aged 16-17 years, and males accounted for 59% of cases. Sprains/strains were the most commonly reported problem (31%), followed by cuts/lacerations (17%), contusions/abrasions (13%), heat burns (8%), and fractures/dislocations (5%). Injured and ill persons were employed most frequently by eating and drinking establishments (39%), followed by grocery stores (14%), nursing and personal-care facilities (6%), and department stores (5%). The most common occupations were food preparation and service workers (i.e., waiters and waitresses, cooks, and food counter and kitchen workers) (37%), followed by cashier (10%), stock handler or bagger (9%), health or nursing aide (7%), and janitor and cleaner (5%). Common events resulting in injury included falls on the same level (i.e., falls to floors and falls onto or against objects) (21%), overexertion (i.e., from lifting, pulling, pushing, turning, wielding, holding, carrying, or throwing objects) (17%), striking against objects (i.e., bumping into, stepping on, kicking, and being pushed or thrown into or against objects) (10%), contact with hot objects or substances (9%), being struck by falling objects (7%), and being struck by a slipping hand-held object (e.g., knife, razor, or tool) (6%). # State-Specific Variations In general, national patterns were reflected at the state level, although there were state-specific variations. Median number of lost work days ranged from 1 day (Nebraska and Vermont) to 6 days (Alabama, Arkansas, New York, and Wyoming) (Table 1). The most common worksites were eating and drinking establishments and grocery stores. However, in Alaska, laundry, cleaning, and garment services and the manufacture of specific food products each accounted for 16%-17% of cases. In Cali- § The base sample for SOII is designed to produce national estimates. However, each year, approximately 40 states participate in a federal/state cooperative program through which, in these states, the base sample is augmented to generate state-specific estimates that meet the individual needs of participating states. In 1993, 42 states participated in this program. ¶ OSHA requires employers to record information on every occupational illness and injury that involves one or more of the following: loss of consciousness, restriction of work or motion, transfer to another job, or medical treatment (other than first aid). Employers who are selected for the SOII sample but who are not usually required to keep these records are provided with a copy of instructions and recordkeeping forms for the survey. fornia, worksites providing social and rehabilitation services accounted for 24% of cases. In Florida, Nevada, and South Carolina, 12%-15% of incidents occurred in worksites providing amusement and recreation services. In Hawaii, nearly one fourth (24%) of incidents occurred in construction/special trade worksites (e.g., carpentry and painting). Hotels and motels were the most common site of work-related injuries and illnesses in Vermont (27%) and second most common in Utah (11%). The types of events and exposures resulting in injuries and illnesses varied from national patterns in some states. Exposures to caustic, noxious, or allergenic substances accounted for 11%-23% of cases in Alaska, Montana, Nebraska, Nevada, New Mexico, and Wyoming. Exposure to sun accounted for 22% of cases in Vermont, and falls through roofs accounted for 28% of injuries in Wyoming. Editorial Note: The findings in this report are the first to provide comparable statespecific data for work-related injuries and illnesses among persons aged <18 years; however, the inability to calculate state-specific rates limits comparisons between states. Although many state-specific patterns of injuries and illnesses reflected national patterns, the variations identified are important for targeting prevention efforts at the state level. Workers' compensation data can provide supplemental information to assist state-specific intervention efforts (3-7 ). The approximately 22,000 injuries and illnesses involving lost work days among children aged <18 years in 1993 is probably an underestimate because SOII excludes some categories (e.g., self-employed workers, farms with <11 employees, private households, and government employees) (2 ); employment data suggest that at least 11% of working children aged <18 years are not represented by the SOII (1 ). These estimates exclude injuries and illnesses that did not result in lost work days or in death. During 1992, an estimated 64,000 children aged <18 years were treated in emergency departments for work-related injuries; approximately 70 die from work-related injuries each year (8 ). Safety and health regulations, such as those promulgated and enforced by OSHA, apply to workers of all ages. In addition, children aged <18 years are protected by provisions of child labor laws. For example, federal child labor laws specifically prohibit cooking and baking by persons aged 14-15 years (9 ); however, in this analysis, one third of cases among children aged 14-15 years occurred among persons identified as cooks. During 1983-1990, 1475 serious injuries among persons aged <18 years were associated with violations of federal child labor laws (10 ), and studies during the 1980s suggest that 38%-86% of work-related deaths among children were associated with activities prohibited by federal child labor laws (8 ). The risks for work-related injuries and illnesses among workers of all ages can be reduced through adherence to routine precautions such as prescribed housekeeping practices; training and safe work procedures; use of proper shoes, gloves, and protective clothing; and maintenance and use of equipment with safety features. In addition, workers aged 15 pounds more often than once per minute or ever to lift objects >30 pounds; tasks involving continuous lifting should never last more than 2 hours (8 ). Children aged <18 years should not participate in work requiring routine use of respirators (a means of protecting workers from inhaling hazardous substances) (8 ). Employers should be knowledgeable about and comply with child labor laws, and school guidance counselors and physicians who sign work permits for children also should be familiar with child labor laws and ensure that the work they approve does not involve prohibited activities. Most persons aged <18 years enter the workplace with minimal prior experience for a job. During the summer of 1992, more than half (54%) of persons aged 14-16 years treated in emergency departments for work injuries reported that they had received no training in prevention of the injury they sustained and that a supervisor was present at the time of injury in only approximately 20% of the cases (8 ). Differences in maturity and developmental level regarding learning styles, judgement, and behavior should be considered when providing training for youth in occupational safety and health. Additional state-specific data and information about prevention of work-related injuries can be obtained from NIOSH, telephone (800) 356-4674 or (513) 533-8328. Although preventing blood exposures is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection, appropriate postexposure management is an important element of workplace safety (1 ). Information suggesting that zidovudine (ZDV) postexposure prophylaxis (PEP) may reduce the risk for HIV transmission after occupational exposure to HIV-infected blood (2 ) prompted a Public Health Service (PHS) interagency working group*, with expert consultation † , to update a previous PHS statement on management of occupational exposure to HIV with the following findings and recommendations on PEP (1 ). § # Background Although failures of ZDV PEP have occurred (3 ), ZDV PEP was associated with a decrease of approximately 79% in the risk for HIV seroconversion after percutaneous exposure to HIV-infected blood in a case-control study among health-care workers (2 ). In a prospective trial in which ZDV was administered to HIV-infected pregnant women and their infants, a direct effect of ZDV prophylaxis on the fetus and/or infant may have contributed to the observed 67% reduction in perinatal HIV transmission (4 ); the protective effect of ZDV was only partly explained by reduction of the HIV titer *The interagency working group comprised representatives of CDC, the Food and Drug Administration (FDA), the Health Resources and Services Administration, and the National Institutes of Health. Information included in these recommendations may not represent FDA approval or approved labeling for the particular products or indications in question. Specifically, the terms "safe" and "effective" may not be synonymous with the FDA-defined legal standards for product approval. † CDC and the National Foundation for Infectious Diseases cosponsored a workshop, HIV Post-Exposure Management for Health Care Workers, on March 4-5, 1996; proceedings of the workshop will be published in the American Journal of Medicine. § Single copies of this report will be available free until June 7, 1997, from the CDC National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003; telephone (800) 458-5231 or (301) 217-0023. in maternal blood (5 ). PEP also prevented or ameliorated retroviral infection in some studies in animals (6,7 ). The average risk for HIV infection from all types of reported percutaneous exposures to HIV-infected blood is 0.3% (3 ). In the case-control study (2 ), risk was increased for exposures involving 1) a deep injury to the health-care worker, 2) visible blood on the device causing the injury, 3) a device previously placed in the sourcepatient's vein or artery (e.g., a needle used for phlebotomy), or 4) a source-patient who died as a result of acquired immunodeficiency syndrome (AIDS) within 60 days postexposure (and therefore was presumed to have a high titer of HIV) (2 ). Identification of these risk factors in the case-control study suggests that the risk for HIV infection exceeds 0.3% for percutaneous exposures involving a larger blood volume and/or higher HIV titer in blood. The risks after mucous membrane and skin exposures to HIV-infected blood (on average, approximately 0.1% and <0.1%, respectively ) probably also depend on volume of blood and titer of HIV. The risk is probably higher for skin contact that is prolonged, involves an area that is extensive or in which skin integrity is visibly compromised, and/or involves a higher HIV titer. Although information about the potency and toxicity of antiretroviral drugs is available from studies of HIV-infected patients, it is uncertain to what extent this information can be applied to uninfected persons receiving PEP. In HIV-infected patients, combination therapy with the nucleosides ZDV and lamivudine (3TC) has greater antiretroviral activity than ZDV alone and is active against many ZDV-resistant HIV strains without significantly increased toxicity (8 ). Adding a protease inhibitor provides even greater increases in antiretroviral activity; among protease inhibitors, indinavir (IDV) is more potent than saquinavir at currently recommended doses and appears to have fewer drug interactions and short-term adverse effects than ritonavir (8 ). Few data exist to assess possible long-term (i.e., delayed) toxicity resulting from use of these drugs in persons not infected with HIV. In currently recommended doses, ZDV PEP usually is tolerated well by health-care workers; short-term toxicity associated with higher doses primarily includes gastrointestinal symptoms, fatigue, and headache (3,7 ). The toxicity of other antiretroviral drugs in persons not infected with HIV has not been well characterized. In HIV-infected adults, 3TC can cause gastrointestinal symptoms and, in rare instances, pancreatitis. IDV toxicity includes gastrointestinal symptoms and, usually after prolonged use, mild hyperbilirubinemia (10%) and kidney stones (4%); the latter may be limited by drinking at least 48 oz (1.5 L) of fluid per 24-hour period (8 ). During the first 4 weeks of IDV therapy, the reported incidence of kidney stones was 0.8% (Merck Research Laboratories, unpublished data, 1996). As stated in the package insert, the concurrent use of IDV and certain other drugs, including some nonsedating antihistamines, is contraindicated. Based on limited data, ZDV use in the second and third trimesters of pregnancy and early infancy was not associated with serious adverse effects in mothers or infants (4,9 ); data are limited regarding the safety of ZDV during the first trimester of pregnancy or of other antiretroviral agents during pregnancy. Although 3TC has been associated with pancreatitis in HIV-infected children (8 ), whether 3TC causes fetal toxicity is unknown. # Recommendations The following recommendations are provisional because they are based on limited data regarding efficacy and toxicity of PEP and risk for HIV infection after different types of exposure. Because most occupational exposures to HIV do not result in infection transmission, potential toxicity must be carefully considered when prescribing PEP. When possible, these recommendations should be implemented in consultation with persons having expertise in antiretroviral therapy and HIV transmission. Changes in drug regimens may be appropriate, based on factors such as the probable antiretroviral drug resistance profile of HIV from the source patient; local availability of drugs; and medical conditions, concurrent drug therapy, and drug toxicity in the exposed worker. These recommendations were not developed to address nonoccupational (e.g., sexual) exposures. 1. Chemoprophylaxis should be recommended to exposed workers after occupational exposures associated with the highest risk for HIV transmission. For exposures with a lower, but nonnegligible risk, PEP should be offered, balancing the lower risk against the use of drugs having uncertain efficacy and toxicity. For exposures with negligible risk, PEP is not justified (Table 1). Exposed workers should be informed that a) knowledge about the efficacy and toxicity of PEP is limited; b) for agents other than ZDV, data are limited regarding toxicity in persons without HIV infection or who are pregnant; and c) any or all drugs for PEP may be declined by the exposed worker. 2. At present, ZDV should be considered for all PEP regimens because ZDV is the only agent for which data support the efficacy of PEP in the clinical setting. 3TC should usually be added to ZDV for increased antiretroviral activity and activity against many ZDV-resistant strains. A protease inhibitor (preferably IDV because of the characteristics summarized in this report) should be added for exposures with the highest risk for HIV transmission (Table 1). Adding a protease inhibitor also may be considered for lower risk exposures if ZDV-resistant strains are likely, although it is uncertain whether the potential additional toxicity of a third drug is justified for lower risk exposures. For HIV strains resistant to both ZDV and 3TC or resistant to a protease inhibitor, or if these drugs are contraindicated or poorly tolerated, the optimal PEP regimen is uncertain; expert consultation is advised ¶ . 3. PEP should be initiated promptly, preferably within 1-2 hours postexposure. Although animal studies suggest that PEP probably is not effective when started later than 24-36 hours postexposure (6,7 ), the interval after which there is no benefit from PEP for humans is undefined. Initiating therapy after a longer interval (e.g., 1-2 weeks) may be considered for the highest risk exposures; even if infection is not prevented, early treatment of acute HIV infection may be beneficial (10 ). The optimal duration of PEP is unknown; because 4 weeks of ZDV appeared protective (2 ), PEP should probably be administered for 4 weeks, if tolerated. 4. If the source patient or the patient's HIV status is unknown, initiating PEP should be decided on a case-by-case basis, based on the exposure risk and likelihood of HIV infection in known or possible source patients. If additional information becomes available, decisions about PEP can be modified. ¶ An HIV strain is more likely to be resistant to a specific antiretroviral agent if it is derived from a patient who has been exposed to the agent for a prolonged period of time (e.g., 6-12 months or longer). In general, resistance develops more readily in persons with more advanced HIV infection (e.g., CD4+ T-lymphocyte count of <200 cells/mm 3 ), reflecting the increasing rate of viral replication during later stages of the illness. # Workers with occupational exposures to HIV should receive follow-up counseling and medical evaluation, including HIV-antibody tests at baseline and periodically for at least 6 months postexposure (e.g., 6 weeks, 12 weeks, and 6 months), and should observe precautions to prevent possible secondary transmission (1 ). If PEP is used, drug-toxicity monitoring should include a complete blood count and renal and hepatic chemical function tests at baseline and 2 weeks after starting PEP. If subjective or objective toxicity is noted, dose reduction or drug substitution should be considered with expert consultation, and further diagnostic studies may be indi- *Any exposure to concentrated HIV (e.g., in a research laboratory or production facility) is treated as percutaneous exposure to blood with highest risk. † Recommend-Postexposure prophylaxis (PEP) should be recommended to the exposed worker with counseling (see text). Offer-PEP should be offered to the exposed worker with counseling (see text). Not offer-PEP should not be offered because these are not occupational exposures to HIV (1 ). § Regimens: zidovudine (ZDV), 200 mg three times a day; lamivudine (3TC), 150 mg two times a day; indinavir (IDV), 800 mg three times a day (if IDV is not available, saquinavir may be used, 600 mg three times a day). Prophylaxis is given for 4 weeks. For full prescribing information, see package inserts. ¶ Highest risk-BOTH larger volume of blood (e.g., deep injury with large diameter hollow needle previously in source patient's vein or artery, especially involving an injection of source-patient's blood) AND blood containing a high titer of HIV (e.g., source with acute retroviral illness or end-stage AIDS; viral load measurement may be considered, but its use in relation to PEP has not been evaluated). Increased risk-EITHER exposure to larger volume of blood OR blood with a high titer of HIV. No increased risk-NEITHER exposure to larger volume of blood NOR blood with a high titer of HIV (e.g., solid suture needle injury from source patient with asymptomatic HIV infection). Possible toxicity of additional drug may not be warranted (see text). † † Includes semen; vaginal secretions; cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids. § § For skin, risk is increased for exposures involving a high titer of HIV, prolonged contact, an extensive area, or an area in which skin integrity is visibly compromised. For skin exposures without increased risk, the risk for drug toxicity outweighs the benefit of PEP. # Contributors to the Production of the MMWR (Weekly) Weekly

Routine vaccination of children is an effective way to reduce hepatitis A incidence in the United States. Since licensure of hepatitis A vaccine during 1995-1996, the hepatitis A childhood immunization strategy has been implemented incrementally, starting with the recommendation of the Advisory Committee on Immunization Practices (ACIP) in 1996 to vaccinate children living in communities with the highest disease rates and continuing in 1999 with ACIP's recommendations for vaccination of children living in states, counties, and communities with consistently elevated hepatitis A rates. These updated recommendations represent the final step in the childhood hepatitis A immunization strategy, routine hepatitis A vaccination of children nationwide. Implementation of these recommendations will reinforce existing vaccination programs, extend the benefits associated with hepatitis A vaccination to the rest of the country, and create the foundation for eventual consideration of elimination of indigenous hepatitis A virus transmission. This report updates ACIP's 1999 recommendations concerning the prevention of hepatitis A through immunization (CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices . MMWR 1999:48:1-37) and includes 1) new data on the epidemiology of hepatitis A in the era of hepatitis A vaccination of children in selected U.S. areas, 2) results of analyses of the economics of nationwide routine vaccination of children, and 3) recommendations for the routine vaccination of children in the United States. Previous recommendations for vaccination of persons in groups at increased risk for hepatitis A or its adverse consequences and recommendations regarding the use of immune globulin for protection against hepatitis A are unchanged from the 1999 recommendations. persons in groups shown to be at high risk for infection and children living in communities with high rates of disease (2). In 1999, as the next step in a strategy of incremental implementation of recommendations for routine vaccination of children, ACIP expanded the recommendations to include vaccination of children living in states, counties, and communities in which hepatitis A rates were consistently above the national average (3). Coincident with implementation of these recommendations, hepatitis A rates have declined to the lowest level ever recorded (4). Because declines were largest in the areas in which routine vaccination of children was occurring, rates are now more equivalent across regions, with the highest rates occurring among children in parts of the country where vaccination has not been recommended (5). This statement includes recommendations for the final step in this incremental strategy, routine hepatitis A vaccination of children nationwide. Implementation of these recommendations will reinforce existing vaccination programs, extend the benefits associated with hepatitis A vaccination to the rest of the country, and create the foundation for eventual consideration of elimination of indigenous HAV transmission.# Introduction During 1980-1995, approximately 22,000-36,000 cases of hepatitis A were reported annually in the United States, representing an estimated average of 271,000 infections per year when anicteric disease and asymptomatic infections are taken in account (1). During 1995-1996, highly effective hepatitis A vaccines became available in the United States for use among persons aged >2 years, providing an opportunity to reduce hepatitis A incidence substantially and potentially eliminate indigenous transmission of hepatitis A virus (HAV). In 1996, the Advisory Committee on Immunization Practices (ACIP) first made recommendations to prevent hepatitis A through immunization, focusing primarily on vaccinating # Primary Changes in the Statement Changes in recommendations include the following: - updated data regarding the epidemiology of hepatitis A since the advent of hepatitis A vaccination of children in selected areas of the United States, - results of recent economic analyses of nationwide routine vaccination of children, and - recommendations for the routine vaccination of children aged >1 year in the United States. Previous recommendations for 1) vaccination of persons in groups at increased risk for hepatitis A or its adverse consequences and 2) use of immune globulin (IG) for protection against hepatitis A are unchanged (3). # Clinical and Diagnostic Features of Hepatitis A Clinical Illness HAV, a 27-nm RNA agent classified as a picornavirus, can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days (range: 15-50 days) (6). Illness caused by HAV infection typically has an abrupt onset that can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. The likelihood of having symptoms with HAV infection is related to age. In children aged 70% of patients (8). Signs and symptoms typically last 50 years; persons with chronic liver disease are at increased risk for acute liver failure (5,(10)(11)(12)(13)(14)(15). In infected persons, HAV replicates in the liver, is excreted in bile, and is shed in stool. Peak infectivity of infected persons occurs during the 2-week period before onset of jaundice or elevation of liver enzymes, when concentration of virus in stool is highest (16). Concentration of virus in stool declines after jaundice appears. Children can shed HAV for longer periods than do adults, lasting up to 10 weeks (17) after onset of clinical illness; infants infected as neonates in one nosocomial outbreak shed HAV for up to 6 months (18). Chronic shedding of HAV in feces does not occur; however, recurrent shedding occurs during relapses among persons who have relapsing illness (19). Viremia occurs soon after infection and persists through the period of liver enzyme elevation, but at concentrations several orders of magnitude lower than in stool (20,21). # Diagnosis Hepatitis A cannot be differentiated from other types of viral hepatitis on the basis of clinical or epidemiologic features alone. Serologic testing to detect immunoglobulin M (IgM) antibody to the capsid proteins of HAV (IgM anti-HAV) is required to confirm a diagnosis of acute HAV infection. Sensitive tests for IgM and immunoglobulin G (IgG) anti-HAV in saliva have been developed but are not licensed in the United States (22). In the majority of persons, serum IgM anti-HAV becomes detectable 5-10 days before onset of symptoms (21,23). IgG anti-HAV, which appears early in the course of infection, remains detectable for the person's lifetime and provides lifelong protection against the disease. Two serologic tests are licensed for the detection of antibodies to HAV: 1) IgM anti-HAV and 2) total anti-HAV (i.e., IgM and IgG anti-HAV, referred to in this report as anti-HAV) (24). In the majority of patients, IgM anti-HAV declines to undetectable levels 1 year after infection have been reported, as have likely false-positive tests in persons without evidence of recent HAV infection (25)(26)(27). Total anti-HAV testing is used in epidemiologic studies to measure the prevalence of previous infection or by clinicians to determine whether a person with an indication for preexposure prophylaxis is already immune. HAV RNA can be detected in the blood and stool of the majority of persons during the acute phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has been used to determine the relatedness of HAV isolates for epidemiologic investigations (28)(29)(30). However, only a limited number of research laboratories have the capacity to use these methods. # Epidemiology of Hepatitis A Modes of Transmission Person-to-person transmission through the fecal-oral route is the primary means of HAV transmission in the United States. Transmission occurs most frequently among close contacts, especially in households and extended family settings (31). Because the majority of children have asymptomatic or unrecognized infections, they play a key role in HAV transmission and serve as a source of infection for others (32,33). In one study of adults without an identified source, 52% of their households included a child aged <6 years, and the presence of a young child was associated with HAV transmission in the household (32). In studies in which serologic testing of the household contacts of adults without an identified source of infection was performed, 25%-40% of contacts aged <6 years had serologic evidence of acute HAV infection (IgM anti-HAV) (17,32). Common-source outbreaks and sporadic cases also can occur from exposure to fecally contaminated food or water. Uncooked foods have been recognized frequently as a source of outbreaks (34). Cooked foods also can transmit HAV if cooking is inadequate to kill the virus or if food is contaminated after cooking, as occurs commonly in outbreaks associated with infected food handlers (34)(35)(36)(37). Waterborne outbreaks of hepatitis A are infrequent in developed countries with well-maintained sanitation and water supplies. The majority of waterborne outbreaks are associated with sewage-contaminated or inadequately treated water (38)(39)(40). Outbreaks in the context of floods or other natural disasters (e.g., hurricanes) have not been reported in the United States. Depending on conditions, HAV can be stable in the environment for months (41). Heating foods at temperatures >185°F (>85°C) for 1 minute or disinfecting surfaces with a 1:100 dilution of sodium hypochlorite (i.e., household bleach) in tap water is necessary to inactivate HAV (42). On rare occasions, HAV infection has been transmitted by transfusion of blood or blood products collected from donors during the viremic phase of their infection (20,43). Since 2002, nucleic acid amplification tests such as polymerase chain reaction (PCR) have been applied to the screening of source plasma used for the manufacture of plasma-derived products (44). In experimentally infected nonhuman primates, HAV has been detected in saliva during the incubation period (45). However, transmission by saliva has not been demonstrated. # Disease Patterns Prevaccine Era Hepatitis A epidemiology in the United States has fundamentally changed with licensure of hepatitis A vaccine and implementation of national ACIP recommendations for its use. Before vaccine licensure during 1995-1996, hepatitis A incidence was primarily cyclic, with peaks occurring every 10-15 years. In the United States, during 1980-1995, approximately 22,000-36,000 hepatitis A cases were reported annually to CDC (rate: 9.0-14.5 cases per 100,000 population), but incidence models indicate that the number of infections was substantially higher (1,5). One such analysis estimated an average of 271,000 infections per year during 1980-1999, representing 10.4 times the reported number of cases (1). Each year in the United States, an estimated 100 persons died as a result of acute liver failure attributed to hepatitis A. The costs associated with hepatitis A are substantial. Surveillance data indicate that 11%-22% of persons with hepatitis A are hospitalized (3). The average duration of work loss for adults who become ill has been estimated at 15.5 days for nonhospitalized patients and 33.2 days for hospitalized patients (46). Estimates of the annual direct and indirect costs of hepatitis A in the United States have ranged from $300 million to $488.8 million in 1997 dollars (3,46). A recent Markov model analysis estimated economic costs of $133.5 million during the lifetime of a single age cohort of children born in 2005, in the absence of vaccination (CDC, unpublished data, 2005). Variation by Age, Race/Ethnicity, and Region. During the prevaccine era, the reported incidence of hepatitis A was highest among children aged 5-14 years, with approximately one third of reported cases involving children aged <15 years (Figure 1) (5). Because young children frequently have unrecognized or asymptomatic infection, a relatively smaller proportion of infections among children than adults are detected by routine disease surveillance. Incidence models indicate that during 1980-1999, the majority of HAV infections occurred among children aged <10 years, and the highest incidence was among those aged 0-4 years (1). Before the use of hepatitis A vaccine, rates among American Indians and Alaska Natives were more than five times higher than rates in other racial/ethnic populations, and rates among Hispanics were ap- # ACIP recommendations proximately three times higher than rates among non-Hispanics (Figure 2) (5,(47)(48)(49). Since the 1960s, the highest hepatitis A rates and the majority of cases occurred in a limited number of states and counties concentrated in the western and southwestern United States (Figure 3) (4). Despite year-to-year fluctuations, rates in these areas consistently remained above the national average. In 11 states (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, and Washington) with consistently elevated rates, representing 22% of the U.S. population, average annual hepatitis A incidence was >20 cases per 100,000 during 1987-1997 (twice the national average of approximately 10 cases per 100,000 population); cases among residents of these states accounted for an average of 50% of reported cases (3). An additional 18% of cases occurred among residents of six states (Arkansas, Colorado, Missouri, Montana, Texas, and Wyoming) with average annual rates above (but less than twice) the national average during this time. Approximately 31% of the U.S. population had serologic evidence of previous HAV infection, when measured in the Third National Health and Nutrition Examination Survey (NHANES-III) conducted during 1988-1994 (50). Anti-HAV prevalence varied directly with age: among persons aged 6-11 years, prevalence was 9%; 20-29 years, 19%; 40-49 years, 33%; and >70 years, 75%. Age-adjusted anti-HAV prevalence was considerably higher among Mexican-American (70%) compared with black (39%) and white (23%) participants, and among foreign-born (69%) compared with U.S.-born (25%) participants. Sources of Infection. In the prevaccine era, the majority of U.S. cases of hepatitis A resulted from person-to-person transmission of HAV during communitywide outbreaks (31,51). The most frequently reported source of infection (in 12%-26% of cases) was household or sexual contact with a person with hepatitis A (52). Cyclic outbreaks occurred among users of injection and noninjection drugs and among men who have sex with men (MSM) (53)(54)(55)(56)(57), and up to 15% of nationally reported cases occurred among persons reporting one or more of these behaviors. Other potential sources of infection (e.g., international travel and recognized foodborne outbreaks) were reported among 3%-6% of cases (52). For approximately 50% of persons with hepatitis A, no source was identified for their infection. Communitywide Epidemics. During communitywide epidemics, infection was transmitted from person to person in households and extended family settings. These epidemics typically spread throughout the community, and no single risk factor or risk group could be identified that accounted for the majority of cases (31). Once initiated, epidemics often persisted for 1-2 years and proved difficult to control (58,59). Because children often have unrecognized or asymptomatic infection, they played a key role in sustaining HAV transmission during these epidemics. # Vaccine Era With the licensure of inactivated hepatitis A vaccines by the Food and Drug Administration (FDA) during 1995-1996, hepatitis A became a disease that was not only common but also vaccine-preventable. Since 1996, and particularly since ACIP's 1999 recommendations for routine vaccination of children living in areas with consistently elevated hepatitis A rates, national hepatitis A rates have declined sharply (4). The 1999 recommendations called for routine vaccination of children living in states and communities in which the average hepatitis A rate during a baseline period of 1987-1997 was >20 cases per 100,000 population, approximately twice the national average, and for consideration of hepatitis A vaccination of children in those states and communities in which the average rate during the baseline period was at least the national average (3). In 2004, a total of 5,683 cases (rate: 1.9 cases per 100,000 population) were reported, representing an estimated 24,000 acute clinical cases when underreporting is taken into account. This rate was the lowest ever recorded and was 79% lower than the previously recorded low in 1992 (5). This decline is reflected in other fundamental shifts in hepatitis A epidemiology. Variation by Age, Race/Ethnicity, and Region. Beginning in the late 1990s, national age-specific rates declined more rapidly among children than adults; as a result, in recent years, rates have been similar among all age groups (Figure 1) (4). Historic differences in rates among racial/ethnic populations also have narrowed in the vaccine era. For example, recent rates among American Indians and Alaska Natives represent a 99% decline compared with the prevaccine era and are now approximately the same or lower than those of other racial/ ethnic populations (49). Rates among Hispanics also declined 87% during this period, from 20.6 cases per 100,000 population during 1990-1997 to 2.7 per 100,000 in 2004, but remain higher than those for non-Hispanics (Figure 2) (4,5). Elimination of historic geographic differences in incidence rates has also occurred, and since 2001, rates in states where vaccination was recommended have been approximately equal to the rest of the United States (5). In recent years, counties with higher rates have varied from year to year and have been distributed throughout the country (Figure 3) (4). Incidence declined sharply in states with historically consistently elevated rates included in the 1999 ACIP recommendations for routine vaccination of children. As a result, the majority of hepatitis A cases during recent years have been reported from states with historically low rates in which hepatitis A vaccination of children has not been widely implemented (4). In addition, the narrowing or elimination of national differences in age, race/ethnicity, and state-specific rates can be attributed largely to changes that occurred in the states in which routine hepatitis A vaccination of children was recommended and implemented. In 2004, for example, approximately two thirds of the nearly 6,000 cases were reported from states without childhood vaccination recommendations (60). The 2004 rate among all Hispanics in these states remained four times higher than among non-Hispanics and was seven times higher among Hispanic compared with non-Hispanic children. The highest rate in any demographic subgroup occurred among Hispanic children in states for which routine hepatitis A vaccination of children is not recommended (60). Sources of Infection. In recent years, sexual or household contact with a person with hepatitis A has been reported in a smaller proportion of cases but continued to account for 13% of cases during 2002-2004 (5). The proportion of persons with hepatitis A reporting exposure to child care centers also has declined to approximately 9% (5). The number of international travel-associated cases has remained approximately the same, but as overall incidence has declined, the proportion of cases attributable to this exposure has increased, accounting for an average of 13% of cases during 2002-2004 (5). During this time, >25% of cases among children aged <15 years could be attributed to international travel. Approximately 75% of all travel-related cases were associated with travel to Mexico or to Central or South America (5). Outbreaks among MSM and users of illicit drugs also continue to occur (5,57). # MMWR May 19, 2006 # Groups at Increased Risk for Hepatitis A Travelers Persons from developed countries who travel to developing countries are at substantial risk for acquiring hepatitis A (61). Such persons include tourists, immigrants and their children returning to their country of origin to visit friends or relatives, military personnel, missionaries, and others who work or study abroad in countries that have high or intermediate endemicity of hepatitis A (Figure 4). Hepatitis A remains one of the most common vaccine-preventable diseases acquired during travel. One study estimated the risk among persons who did not receive IG or vaccine before departure to be four to 30 cases per 100,000 months of stay in developing countries (62). The risk might be higher among travelers staying in areas with poor hygienic conditions, varies according to the region and the length of stay, and appears to be increased even among travelers who reported observing protective measures and staying in urban areas or luxury hotels (CDC, unpublished data, 2005). In the United States, children account for approximately 50% of reported travel-related cases (5). In one study of Hispanic children in San Diego with hepatitis A, two thirds reported international travel (to Mexico) during the incubation period; travel was the only exposure associated with infection in a case-control study (63). Travelers who acquire hepatitis A during their trips also might transmit to others on their return. # MSM Hepatitis A outbreaks among MSM have been reported frequently. Cyclic outbreaks have occurred in urban areas in the United States, Canada, Europe, and Australia and can occur in the context of an outbreak in the larger community (28,31,53,(64)(65)(66)(67). Seroprevalence surveys have not consistently demonstrated an elevated prevalence of anti-HAV compared with a similarly aged general population (68,69). Certain studies have identified specific sex practices associated with illness, whereas others have not demonstrated such associations (53,67,68). Since 1996, ACIP has recommended hepatitis A vaccination of MSM (2). Although precise data are lacking, vaccine coverage appears to be low (53). # Users of Injection and Noninjection Drugs During the preceeding 2 decades, outbreaks have been reported with increasing frequency among users of injection and noninjection drugs in Australia, Europe, and North America (31,54,56,57,70). In the United States, outbreaks have frequently involved users of injected and noninjected methamphetamine, who have accounted for up to 48% of reported cases during outbreaks (57,71). Cross-sectional serologic surveys have demonstrated that injection-drug users have a higher prevalence of anti-HAV than the general U.S. population (68,72). Transmission among injection-drug users probably occurs through both percutaneous and fecaloral routes (71). Since 1996, ACIP has recommended hepatitis A vaccination of users of illicit drugs, but vaccine coverage data are not available (2). # Persons with Clotting-Factor Disorders During 1992-1993, outbreaks of hepatitis A were reported in Europe among persons with clotting-factor disorders who had been administered solvent-detergent-treated, "highpurity" factor VIII concentrates that presumably had been contaminated from plasma donors incubating hepatitis A (73). In the United States, data from one serologic study suggested that persons with hemophilia might be at increased risk for HAV infection (74). HAV is resistant to solvent-detergent treatment, and during 1995-1996, one study identified six patients with clotting-factor disorders who had hepatitis A after having been administered solvent-detergent-treated factor VIII # FIGURE 4. Geographic distribution of hepatitis A endemicity, 2005* - For multiple countries, estimates of prevalence of antibody to hepatitis A virus (anti-HAV), a marker of previous HAV infection, are based on limited data and might not reflect current prevalence. In addition, anti-HAV prevalence might vary within countries by subpopulation and locality. As used on this map, the terms "high," "medium," and "low" endemicity reflect available evidence of how widespread infection is within each country rather than precise quantitative assessments. and factor IX concentrates (43). However, changes in viral inactivation procedures, high hepatitis A vaccine coverage, and improved donor screening have decreased the risk for HAV transmission from clotting factors. During May 1998-July 2002, no new cases of HAV infection attributed to blood products were identified in an analysis of serosurveillance data from 140 participating hemophilia treatment centers (75). # Persons Working with Nonhuman Primates Outbreaks of hepatitis A have been reported among persons working with nonhuman primates that are susceptible to HAV infection, including Old and New World species (76,77). Primates that were infected were those that had been born in the wild, not those born and raised in captivity. # Risk for Severe Adverse Consequences of Hepatitis A Among Persons with Chronic Liver Disease Although not at increased risk for HAV infection, persons with chronic liver disease are at increased risk for fulminant hepatitis A (12,14,15). Death certificate data indicate a higher prevalence of chronic liver disease among persons who died of fulminant hepatitis A compared with persons who died of other causes (10). # Risk for Hepatitis A in Other Groups and Settings # Food-Service Establishments and Food Handlers Foodborne hepatitis A outbreaks are recognized relatively infrequently in the United States. Outbreaks typically are associated with contamination of food during preparation by an HAV-infected food handler; a single infected food handler can transmit HAV to dozens or even hundreds of persons (34,36,37,(78)(79)(80)(81). However, the majority of food handlers with hepatitis A do not transmit HAV. Food handlers are not at increased risk for hepatitis A because of their occupation. However, among the approximately 40,000 adults with hepatitis A reported during 1992-2000 for whom an occupation was known, 8% were identified as food handlers, reflecting the large number of persons employed in the food service industry (34). Evaluating HAV-infected food handlers is a common and labor-intensive task for public health departments. In a 1992 common-source outbreak involving 43 persons, the estimated total medical and disease control cost was approximately $800,000 (82). Outbreaks associated with food, especially green onions and other raw produce, that has been contaminated before reaching a food-service establishment have been recognized increasingly in recent years (29,30,(83)(84)(85)(86)(87)(88). Low attack rates are common, and outbreaks often have been recognized in association with a single restaurant in which no infected food handler was identified on subsequent investigation (29,83,88). # Child Care Centers Outbreaks among children attending child care centers and persons employed at these centers have been recognized since the 1970s, but their frequency has decreased as overall hepatitis A incidence among children has declined in recent years (5,7,89). Because infection among children is typically mild or asymptomatic, outbreaks often are identified only when adult contacts (typically parents) become ill (7,90). Poor hygiene among children who wear diapers and the handling and changing of diapers by staff contribute to the spread of HAV infection; outbreaks rarely occur in child care centers in which care is provided only to children who are toilet trained. Although child care centers might have been the source of outbreaks of hepatitis A in certain communities, disease in child care centers more commonly reflects extended transmission from the community. Despite the occurrence of outbreaks when HAV is introduced into child care centers, results of serologic surveys do not indicate a substantially increased prevalence of HAV infection among staff at child care centers compared with prevalence among control populations (91). # Health-Care Institutions Nosocomial HAV transmission is rare. Outbreaks have occasionally been observed in neonatal intensive-care units because of infants acquiring infection from transfused blood and subsequently transmitting hepatitis A to other infants and staff (18,92,93). Outbreaks of hepatitis A caused by transmission from adult patients to health-care workers are typically associated with fecal incontinence, although the majority of hospitalized patients who have hepatitis A are admitted after onset of jaundice, when they are beyond the point of peak infectivity (94,95). Data from serologic surveys of health-care workers have not indicated an increased prevalence of HAV infection in these groups compared with that in control populations (96). # Institutions for Persons with Developmental Disabilities Historically, HAV infection was highly endemic in institutions for persons with developmental disabilities (97). As fewer children have been institutionalized and as conditions in institutions have improved, the incidence and prevalence of HAV infection have decreased, although outbreaks can occur in these settings. # MMWR May 19, 2006 # Schools In the United States, the occurrence of cases of hepatitis A in elementary or secondary schools typically reflects disease acquisition in the community. Child-to-child disease transmission in the school setting is uncommon; if multiple cases occur among children at a school, the possibility of a common source of infection should be investigated (30,84). # Workers Exposed to Sewage Data from serologic studies conducted outside the United States indicate that workers who had been exposed to sewage had a possible elevated risk for HAV infection; however, these analyses did not control for other risk factors (e.g., socioeconomic status) (98-100). In published reports of three serologic surveys conducted among U.S. wastewater workers and appropriate comparison populations, no substantial or consistent increase in the prevalence of anti-HAV was identified among wastewater workers (101)(102)(103). No work-related instances of HAV transmission have been reported among wastewater workers in the United States. # Strategy to Prevent and Control Hepatitis A Through Vaccination With the availability of hepatitis A vaccines beginning in 1995, hepatitis A became a disease that was not only common but also vaccine-preventable (104). Use of these highly effective vaccines provided the opportunity to protect persons from infection, reduce disease incidence by preventing transmission, and ultimately eliminate indigenous HAV transmission. Soon after hepatitis A vaccines became available in the United States, a strategy of routine vaccination of children was recognized to have the potential to achieve a sustained reduction in the overall incidence of hepatitis A by preventing infection among persons in age groups that accounted for at least one third of cases and eliminating a major source of infection for others. However, hepatitis A vaccines could not be readily incorporated into the routine infant and early childhood schedule because they were not licensed for children aged <2 years. To overcome these logistical barriers to use of hepatitis A vaccines among children, a novel vaccination strategy was developed on the basis of distinct features of hepatitis A epidemiology and experience gathered from demonstration projects and other research and involving incremental implementation of routine childhood hepatitis A vaccination. Initial recommendations primarily involved vaccination of persons in populations at increased risk for hepatitis A and, as the first step in the incremental strategy, of children living in communities with the highest disease rates (2). Vaccination of persons in groups at increased risk for hepatitis A (e.g., travelers) or its adverse outcomes (e.g., persons with chronic liver disease) provided protection to these persons but had little effect on national disease rates because the majority of cases did not occur among persons in these groups. Although routine vaccination of children living in communities with the highest rates of disease was effective in reducing disease rates in these communities, the impact on national disease incidence was limited because the majority of nationally reported cases occurred outside these communities. A further step in the incremental implementation of routine vaccination of children was possible because areas with consistently elevated hepatitis A rates could be identified that contributed the majority of cases to the national disease burden (3). To date, the 1999 ACIP recommendations for routine vaccination of children living in these areas with consistently elevated rates have been implemented primarily by voluntary measures. The 2004 National Immunization Survey among children aged 24-35 months indicated first-dose coverage of approximately 54% in states for which vaccination is recommended, 27% in states for which it is to be considered, and 2% in the rest of the country (CDC, unpublished data, 2005). Although limited information on trends is available, these coverage estimates represent increases of 2%-3% compared with the previous year (105). Coincident with implementation of these recommendations, national disease incidence has declined to historic lows, with the largest declines occurring in the age groups and parts of the country for which vaccination is recommended (4). The majority of disease (and the highest incidence) occurs in areas for which hepatitis A vaccination of children has not been recommended previously. Examination of historical incidence trends in these areas and theoretic models of incidence dynamics after introduction of a new vaccine suggest that incidence might increase again, although to what level is unknown (106). A decade has passed since hepatitis A vaccines first became available in the United States. Multiple considerations make this an appropriate time to implement the final step in the incremental strategy, thereby bringing hepatitis A vaccination policy into line with that of other routinely recommended childhood vaccines. First, hepatitis A vaccine became available for children aged 12-23 months in 2005, allowing for its incorporation into the routine early childhood vaccination schedule. Second, as disease rates equalize across regions of the United States, questions remain regarding the validity and ultimate sustainability of the interim limited strategy. Continuation of this policy in light of current hepatitis A epidemiology means that vaccination of children is not presently recommended for the areas with the highest overall and age-specific disease incidence. Nationwide hepatitis A vaccination of children is likely to result in further narrowing of current demographic disparities and in lower overall rates. Ultimately, elimination of indigenous HAV transmission in the United States is an attainable goal. # Prophylaxis Against Hepatitis A Virus Infection Immune Globulin IG is a sterile preparation of concentrated antibodies (immunoglobulins) made from pooled human plasma processed by cold ethanol fractionation (107). In the United States, only plasma that has tested negative for hepatitis B surface antigen (HBsAg), antibody to human immunodeficiency virus (HIV), and antibody to hepatitis C virus (HCV) is used to produce IG. In addition, FDA requires that the process used to produce IG include a viral inactivation step or that final products test negative for HCV RNA by PCR. Anti-HAV concentrations differ among IG lots, and slightly lower concentrations have been observed over the preceding 30 years, probably because of the decreasing prevalence of previous HAV infection among plasma donors (108). However, no clinical or epidemiologic evidence of decreased protection has been observed. IG provides protection against hepatitis A through passive transfer of antibody. Both IG administered intramuscularly (IM) and IG for intravenous administration (IGIV) contain anti-HAV, but IG administered intramuscularly is the product used for the prevention of HAV infection. No transmission of hepatitis B virus (HBV), HIV, HCV, or other viruses has been reported from intramuscular IG (109,110). The concentrations of IgG anti-HAV achieved after administration of IG intramuscularly are below the level of detection of the majority of commercially available diagnostic tests (111). When administered for preexposure prophylaxis, 1 dose of 0.02 mL/kg IM confers protection for <3 months, and 1 dose of 0.06 mL/kg IM confers protection for 3-5 months (Table 1). When administered within 2 weeks after an exposure to HAV (0.02 mL/kg IM), IG is 80%-90% effective in preventing hepatitis A. Efficacy is greatest when IG is administered early in the incubation period; when administered later in the incubation period, IG might only attenuate the clinical expression of HAV infection (112). IG is available in single-use (2 mL) and multidose (10 mL) vials. Preparations are formulated without a preservative. For administration of IG, an appropriate muscle mass (i.e., the deltoid or gluteal muscle) should be chosen into which a substantial volume can be injected, using a needle length appro-priate for the person's age and size. If a gluteal muscle is used, the central region of the buttock should be avoided; only the upper outer quadrant should be used, and the needle should be directed anteriorly to minimize the possibility of injury to the sciatic nerve (113). Serious adverse events from IG are rare. Anaphylaxis has been reported after repeated administration to persons with known immunoglobulin A (IgA) deficiency; thus, IG should not be administered to these persons (114). Pregnancy or lactation is not a contraindication to IG administration. IG does not interfere with the immune response to oral poliovirus vaccine or yellow fever vaccine, or, in general, to inactivated vaccines. However, IG can interfere with the response to other live, attenuated vaccines (e.g., measles, mumps, and rubella vaccine and varicella vaccine) when administered either as individual or combination vaccines. Administration of MMR should be delayed for >3 months and varicella vaccine for >5 months after administration of IG for hepatitis A prophylaxis. IG should not be administered <2 weeks after administration of MMR or <3 weeks after varicella vaccine unless the benefits of IG administration exceed the benefits of vaccination (113,115). If IG is administered <2 weeks after administration of MMR or <3 weeks after administration of varicella vaccine, the person should be revaccinated, but not sooner than 3 months after IG administration for MMR or 5 months for varicella vaccine (113). # Hepatitis A Vaccine Inactivated and attenuated hepatitis A vaccines have been developed and evaluated in human clinical trials and in nonhuman primate models of HAV infection (116); however, only vaccines made from inactivated HAV have been evaluated for efficacy in controlled clinical trials (117)(118)(119). The vaccines containing HAV antigen that are currently licensed in the United States are the single-antigen vaccines HAVRIX ® (manufactured by GlaxoSmithKline, Rixensart, Belgium) and VAQTA ® (manufactured by Merck & Co., Inc., Whitehouse Station, New Jersey) and the combination vaccine TWINRIX ® (containing both HAV and HBV antigens; manufactured by GlaxoSmithKline). All are inactivated vaccines. # Preparation Inactivated hepatitis A vaccines are prepared by methods similar to those used for inactivated poliovirus vaccine (120,121). Cell-culture-adapted virus is propagated in human fibroblasts, purified from cell lysates by ultrafiltration and exclusion gel chromatography or other methods, formalin inactivated, and adsorbed to an aluminum hydroxide adjuvant; 2-phenoxyethanol is used as a preservative for HAVRIX and TWINRIX, and VAQTA is formulated without a preservative. For HAVRIX and TWINRIX, the antigen content of the final aqueous preparation is determined by reactivity in a quantitative immunoassay for HAV antigen, and final vaccine potency (per dose) is expressed as enzyme-linked immunosorbent assay (ELISA) units (EL.U.). For VAQTA, the antigen content is expressed as units (U) of HAV antigen. # Vaccine Storage and Shipment Hepatitis A vaccine should be stored and shipped at temperatures ranging from 35.6°F-46.4°F (2°C-8°C) and should not be frozen. However, the reactogenicity and immunogenicity of HAVRIX after storage at 98.6°F (37°C) for 1 week and the stability profile of VAQTA when stored at this temperature for >12 months do not differ from those of vaccines stored at the recommended temperature (122; Merck & Co., Inc., unpublished data, 1996). # Route of Administration, Vaccination Schedule, and Dosage The vaccine should be administered intramuscularly into the deltoid muscle. A needle length appropriate for the person's age and size should be used (113). VAQTA is licensed in two formulations, which differ according to the person's age. Persons aged 12 months-18 years should receive 25 U per dose in a 2-dose schedule; persons aged >18 years should receive 50 U per dose in a 2-dose schedule (Table 2). HAVRIX is available in two formulations, which differ according to the person's age: for persons aged 12 months-18 years, 720 EL.U. per dose in a 2-dose schedule; and for persons aged >18 years, 1,440 EL.U. per dose in a 2-dose schedule (Table 3). A pediatric formulation of 360 EL.U. per dose administered in a 3-dose schedule is no longer available. TWINRIX is licensed for use in persons aged >18 years. TWINRIX is a combined hepatitis A and hepatitis B vaccine containing 720 EL.U. of hepatitis A antigen (half of the HAVRIX adult dose) and 20 mcg of recombinant hepatitis B surface antigen protein (the same as the ENGERIX-B adult dose) (Table 4). Primary immunization consists of 3 doses, administered on a 0-, 1-, and 6-month schedule, the same schedule as that commonly used for single-antigen hepatitis B vaccine. TWINRIX contains aluminum phosphate and aluminum hydroxide as adjuvant and 2-phenoxyethanol as a preservative. After 3 doses of TWINRIX, antibody responses to both antigens are equivalent to responses seen after the singleantigen vaccines are administered separately on standard schedules (123,124). # Vaccine Performance Detection of Anti-HAV After Vaccination. Concentrations of antibody achieved after passive transfer by IG or active induction by vaccination are 10-to 100-fold lower than those produced after natural infection and can be below the level of detection of certain commercially available diagnostic assays (111). To measure lower levels of antibody, more sensitive immunoassays were developed for immunogenicity studies that correlate more closely with neutralizing antibody assays (111). Anti-HAV concentrations are measured in comparison with a World Health Organization reference immunoglobulin reagent and are expressed as milli-International Units per milliliter (mIU/mL). The lower limits of detection have typically been approximately 100 mIU/mL by unmodified commercially available assays and 10 mIU/mL by more sensitive assays. A positive anti-HAV result by a standard assay indicates protection. However, after vaccination, persons who are anti-HAV negative by standard assays might nevertheless have protective levels of antibody. The absolute lower limit of anti-HAV required to prevent HAV infection has not been defined. In vitro studies using cell-culture-derived virus indicate that low levels of antibody (e.g., 20 mIU/mL, or >33 mIU/mL in more recent studies, as measured with modified enzyme immunoassays, and studies conducted with VAQTA have used levels >10 mIU/mL as measured with a modified radioimmunoassay (127,128). Immunogenicity in Adults. All licensed vaccines are highly immunogenic in persons aged >18 years when administered according to the recommended schedules (128)(129)(130). Protective antibody levels were identified in 94%-100% of adults 1 month after the first dose. After the second dose, all persons had protective levels of antibody, with high geometric mean antibody concentrations (GMCs). Limited data are available regarding the timing of the appearance of neutralizing antibody. Among a sample of vaccinated persons, 54%-62% were positive for neutralizing antibody 14 days after the first dose, and 94%-100% were positive at 1 month (128; GlaxoSmithKline, unpublished data, 1994). Immunogenicity in Children and Adolescents. Both vaccines are highly immunogenic when administered to children and adolescents according to multiple schedules; 97%-100% of persons aged 2-18 years had protective levels of antibody 1 month after receiving the first dose, and 100% had protective levels 1 month after the second dose, with high GMCs (128)(129)(130)(131)(132)(133). Children with Down syndrome responded to vaccination as well as other children and had similar levels of protective antibody (134). Immunogenicity in Infants. Available data indicate that inactivated hepatitis A vaccines are immunogenic in children aged <2 years who do not have passively acquired maternal antibody. All such infants administered hepatitis A vaccine subsequently had protective antibody levels, with the final GMCs varying depending on the dosage and schedule (135)(136)(137)(138)(139). Infants with passively acquired maternal antibody had reduced GMCs after vaccination (see Factors Associated with Reduced Immunogenicity) (135,136). # IgM Anti-HAV After Vaccination. Hepatitis A vaccination can induce IgM anti-HAV that is detectable by standard assays, particularly if the test is conducted soon after vaccination. IgM anti-HAV has been detected 2-3 weeks after administration of one dose of vaccine in 8%-20% of adults (140; CDC, unpublished data, 1995). Efficacy. The efficacy of HAVRIX was evaluated in a doubleblind, controlled, randomized clinical trial conducted in Thailand among approximately 40,000 children aged 1-16 years living in villages that had high rates of hepatitis A (117). After 2 doses of vaccine (360 EL.U. per dose) administered 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval = 79%-99%). A doubleblind, placebo-controlled, randomized clinical trial using VAQTA was conducted among approximately 1,000 children aged 2-16 years living in a New York community that had a high rate of hepatitis A (118). The protective efficacy against clinical hepatitis A was 100% (lower bound of the 95% CI = 87%) after administration of 1 dose (25 U) of vaccine. Efficacy After Exposure. Studies of chimpanzees indicate that hepatitis A vaccine can prevent HAV infection if administered shortly after exposure (141). Because the incubation period of hepatitis A can be 50 days, the fact that during a clinical efficacy trial, no cases of hepatitis A occurred in vaccine recipients beginning 17 days after vaccination also suggests a possible postexposure effect (118,142). In a limited randomized trial, investigators determined that hepatitis A vaccine was 79% efficacious in preventing IgM anti-HAV positivity after household exposure to hepatitis A compared with no treatment. However, the CI was extremely wide (7%-95%), and investigators did not assess the efficacy of the vaccine compared with IG (143). Results of an appropriately designed clinical trial comparing the postexposure efficacy of vaccine with that of IG are needed to determine if hepatitis A vaccine without IG can be recommended to prevent hepatitis A after exposure (144). Effectiveness in Populations. The effectiveness of hepatitis A vaccine in populations has been studied in demonstration projects and by analysis of surveillance and vaccine coverage data. The earliest such studies focused on communities with the historically highest hepatitis A rates, such as Alaska Native and American Indian communities. Demonstration projects conducted soon after hepatitis A vaccines became available indicated that routine vaccination of children living in these communities was feasible and that when relatively high vaccination coverage was achieved and sustained, ongoing epidemics were interrupted and a reduction in disease incidence was sustained (145)(146)(147). For example, a 1992-1993 communitywide epidemic among Alaska Natives in one rural area ended within 4-8 weeks of vaccinating May 19, 2006 approximately 80% of children and young adults (146). After publication in 1996 of ACIP recommendations for routine vaccination of children in these areas, surveys indicated that vaccine coverage among preschool-and school-aged American Indian and Alaska Native children was 50%-80%, suggesting that recommendations were being implemented (2,49). By 2000, hepatitis A incidence among American Indians and Alaska Natives had declined 97% compared with the beginning of the decade and was lower than the overall U.S. rate (49). These low rates have been sustained in subsequent years; the 2004 rate of 0.1 case per 100,000 population among American Indian and Alaska Natives was the lowest of any racial/ ethnic population (5). Results of a demonstration project in Butte County, California, provided evidence that considerable reductions in overall incidence also could be achieved in populations with consistently elevated hepatitis A rates with a program of ongoing routine vaccination of children that achieved fairly modest coverage (148). During the 6-year project, 66% of the approximately 45,000 eligible children aged >2 years received >1 dose of hepatitis A vaccine. The number of reported cases declined 94%, and the four cases reported in 2000 during the last year of the project was the lowest number ever reported in the county since hepatitis surveillance began in 1966. The most comprehensive indication of the performance of hepatitis A vaccines in populations is derived from analysis of trends in hepatitis A incidence after publication of ACIP's 1999 recommendations for routine vaccination of children living in 17 states with consistently elevated hepatitis A rates. The 2003 rate (2.5 cases per 100,000 population) in these states represented a decline of approximately 88% compared with the average rate (21.1 cases per 100,000 population) during the baseline prevaccine period on which the recommendations were based of (4). Rates among regions with and without statewide recommendations for routine vaccination of children are now approximately equal (Figure 5). Compared with 1990-1997, rates declined most dramatically among children aged 2-18 years, and the proportion of cases among children declined from 35% to 19%. Because hepatitis A incidence has been cyclic in the United States, the precise contribution of vaccination of children to the observed decline in rates has been difficult to quantify. Modeling studies suggested that during 1995-2001, an estimated 97,800 hepatitis A cases were averted because of the direct effects of immunization and herd immunity, including 39% of potential cases in 2001 (149). Available information concerning vaccine use indicates that the observed declines in rates among children appear to have been achieved with modest levels of vaccine coverage, suggesting a strong herd immunity effect (105,150). Declines in rates among adults also suggest that vaccination of children might have reduced transmission in other age groups through herd immunity. Similar findings have been reported from other countries (e.g., Israel and parts of Spain) in which routine hepatitis A vaccination of infants or children has been implemented (151,152). Results of modeling the relationship between hepatitis A incidence and vaccine coverage have also indicated a strong herd immunity effect, accounting for more than one third of the estimated number of cases prevented by vaccination (149). Interest has been expressed regarding use of hepatitis A vaccine to interrupt ongoing communitywide epidemics by vaccinating children in these populations, but the strategy has proved difficult to implement. Typically, first-dose coverage was low (20%-45%), and the impact of vaccination always was limited to vaccinated age groups that did not represent the majority of cases (59). Efforts are probably better directed towards sustained routine vaccination of children to maintain high levels of immunity and prevent future epidemics. Long-Term Protection. All 31 adults who received 3 doses of HAVRIX (720 EL.U. per dose at 0-, 1-, and 6-month intervals) had anti-HAV levels >15 mIU/mL 12 years after the initial dose (153). Ten years after vaccination, all 307 adults administered 2 doses of 1,440 EL.U. of HAVRIX had anti-HAV levels >20 mIU/mL (154). Protective levels of anti-HAV were still observed in 544 (99%) of 549 children evaluated 5-6 years after receiving VAQTA (155). A recent review concluded that estimates of antibody persistence derived from kinetic models of antibody decline indicate that protective levels of anti-HAV could be present for >25 years in adults and >14-20 years in children (156). Whether other mecha- nisms (e.g., cellular memory) also contribute to long-term protection is unknown. Surveillance data and population-based studies are being used to monitor the long-term protective efficacy of hepatitis A vaccine and to determine the possible need for a booster dose. In the longest such follow-up study reported to date, no cases of hepatitis A have been detected among children studied for 9 years after vaccination (157). Vaccination Schedules. Results of multiple studies indicate that, among adults administered hepatitis A vaccine according to a schedule that mixed the two currently licensed vaccines, the proportion that subsequently had protective antibody levels did not differ from that of adults vaccinated according to the licensed schedules, and final GMCs were high (158,159). Although using the vaccines according to the licensed schedule is preferable, on the basis of the similar immunogenicity of both vaccines in adults and children, these data indicate that the two brands of hepatitis A vaccine can be considered interchangeable. Limited data are available regarding response to a delayed second vaccine dose. In one study, 85 (97%) of 88 persons aged >18 years who had received 1 dose of VAQTA (50 U) had anti-HAV levels >10 mIU/mL 18 months later. None reported a history of hepatitis A, and all responded to a second dose. Final GMCs were not different compared with persons vaccinated according to a 0-, 6-month schedule (160). In another study, 132 (84%) of 156 persons aged 1 month-64 years who had responded to 1 dose of HAVRIX (720 EL.U. for children aged 20 mIU/mL a mean of 27 months later. None of these persons reported a history of hepatitis A. All but one of these persons responded to a second dose, with a substantial rise in antibody levels (161). In a third study, 18 (72%) of 25 adults who had received 1 dose of HAVRIX 4-8 years previously had anti-HAV levels >10 mIU/mL, and all 25 responded to a second dose of vaccine with a substantial increase in anti-HAV levels (162). Factors Associated with Reduced Immunogenicity. The presence of passively acquired anti-HAV at the time of vaccination appears to diminish the immune response. Administration of IG concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who subsequently had protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but GMCs of adults who received IG were substantially lower 1 month after completion of the vaccine series than GMCs of adults who had been administered hepatitis A vaccine alone (163,164). However, their antibody levels were >100-fold higher than levels considered to be protective, suggesting that the reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG is not clinically significant in the short term. The effect of reduced GMCs on long-term protection is unknown. Reduced vaccine immunogenicity also has been observed in infants who had passively acquired antibody because of previous maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules (135)(136)(137). In the majority of studies, all infants subsequently had protective levels of antibody, but the final GMCs were approximately one third to one tenth those of infants born to anti-HAV-negative mothers and vaccinated according to the same schedule. Infants with passively acquired antibody who receive hepatitis A vaccine had substantially lower concentrations of anti-HAV 6 years later compared with vaccinated infants with no passively acquired antibody (165). Despite lower antibody levels after the primary series, the majority of infants with passively acquired antibody had an anamnestic response to a booster dose 1-6 years later (136,165,166). Passively acquired antibody declines to undetectable levels in the majority of infants by age 1 year (167,168). Hepatitis A vaccine is highly immunogenic for children who begin vaccination at age >1 year, regardless of maternal anti-HAV status (136,168). Hepatitis A vaccine using a standard dose and schedule is immunogenic for children and adults with HIV infection. Those with higher CD4 counts (>300 cells/mm 3 ) respond nearly as well as persons who are not immunocompromised, but adults with lower CD4 counts are less likely to acquire protective levels of antibody. Protective levels of antibody developed after vaccination in 61%-87% of HIV-infected adults (169)(170)(171) and in 100% of 32 HIV-infected children (172). Lower CD4 cell count at the time of vaccination, but not the CD4 cell count nadir, was associated with lack of response, suggesting that immunologic reconstitution with highly active antiretroviral therapy might restore the ability to respond to vaccination (173). Vaccination of children or adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults. However, final antibody levels were substantially lower for each group of chronic liver disease patients than for healthy adults (174)(175)(176)(177)(178)(179). Immunogenicity in liver transplant recipients has varied among studies. In one study, none of the eight patients who had received a liver transplant responded to hepatitis A vaccination; in another study, only six (26%) of 23 liver transplant recipients responded (176,179). However, hepatitis A vaccine was immunogenic for liver transplant patients in another study, with 38 (97%) responding to a standard dose and schedule (180). Only 28 (72%) of 39 kidney transplant recipients in this study subsequently had protective levels of antibody. A follow-up study indicated that antibody levels might decline more rapidly for MMWR May 19, 2006 both liver and kidney transplant recipients compared with typical rates of decline for healthy patients (181). Limited data indicate that age might reduce the immunogenicity of hepatitis A vaccine. In certain studies, the proportion of persons aged >40 years who had protective antibody levels was similar to that of persons aged <40 years, but final antibody levels were lower in the older age group (130,(182)(183)(184). Additional factors associated with decreased immunogenicity to other vaccines (e.g., smoking and obesity) have not been evaluated for the currently licensed formulations of hepatitis A vaccine. No data are available pertaining to response rates to revaccination among persons who do not respond to the primary vaccine series. Simultaneous Administration with Other Vaccines. Limited data from studies conducted among adults indicate that simultaneous administration of hepatitis A vaccine with diphtheria, poliovirus (oral and inactivated), tetanus, typhoid (both oral and IM), cholera, Japanese encephalitis, rabies, or yellow fever vaccines does not decrease the immune response to either vaccine or increase the frequency of reported adverse events (185)(186)(187). Studies indicating that hepatitis B vaccine can be administered simultaneously with hepatitis A vaccine without affecting either vaccine's immunogenicity or increasing the frequency of adverse events led to the licensure of TWINRIX (188). Studies conducted among infants and young children aged <18 months have demonstrated that simultaneous administration of hepatitis A vaccine with diphtheria-tetanus-acellular pertussis (DTaP), Haemophilus influenzae type b (Hib), hepatitis B, MMR, or inactivated poliovirus vaccines does not affect the immunogenicity and reactogenicity of these vaccines (136,(189)(190)(191)(192). # Side Effects and Adverse Events Data on adverse events are derived from prelicensure clinical studies worldwide, reports following licensure of HAVRIX in Europe and Asia, other postlicensure studies, and reports to the national Vaccine Adverse Events Reporting System (VAERS) following licensure of HAVRIX and VAQTA in the United States. # Local Reactions Approximately 50,000 persons were administered HAVRIX in prelicensure clinical studies (190). No serious adverse events were attributed definitively to hepatitis A vaccine. Among adults, the most frequently reported side effects occurring <3 days after the 1,440-EL.U. dose were soreness at the injection site (56%), headache (14%), and malaise (7%). In clinical studies among children, the most frequently reported side effects were soreness at the injection site (15%), feeding problems (8%), headache (4%), and injection-site induration (4%). The frequency of side effects after administration of TWINRIX was similar to those reported when the two single-antigen vaccines were administered (123,124,191). Approximately 10,000 persons were administered VAQTA in prelicensure clinical studies, and no serious adverse events were reported among participants (192). Among adults, the most frequent side effects that occurred <5 days after vaccination included tenderness (53%), pain (51%), and warmth (17%) at the injection site and headache (16%). Among children, the most common side effects reported were pain (19%), tenderness (17%), and warmth (9%) at the injection site. In one placebo-controlled trial among children, adverse reactions among vaccine recipients did not differ substantially from those that occurred among persons who received placebo (118). # Serious Adverse Events An estimated 1.3 million persons in Europe and Asia were vaccinated with HAVRIX before the vaccine's licensure in the United States in 1995. Reports of serious adverse events, without regard to causality, received by the vaccine manufacturer included anaphylaxis, Guillain-Barré syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme (SmithKline Beecham Biologicals, unpublished data, 1995). The majority of these events occurred among adults, and approximately one third occurred among persons receiving other vaccines concurrently. For serious adverse events for which background incidence data can be estimated (e.g., Guillain-Barré syndrome and brachial plexus neuropathy), rates for vaccine recipients were not higher than would be expected for an unvaccinated population (CDC, unpublished data, 1995). No serious adverse events were reported for approximately 40,000 children who were administered the 360-EL.U. dose of HAVRIX in the protective efficacy study (117). In a postlicensure study of 11,417 children and 25,023 adults who were administered VAQTA, no serious adverse events occurred that were considered to be associated with administration of vaccine (Merck & Co., Inc., unpublished data, 2005). A published postlicensure evaluation of safety among 2,000 child and adult recipients identified no serious adverse events associated with VAQTA (193). Since (FDA, unpublished data, 2005). The most common events were fever, injection-site reactions, rash, and headache. The 871 reports of serious adverse events included reports of Guillain-Barré syndrome, transaminitis, and idiopathic thrombocytopenic purpura, which had been described previously in a published safety review, and seizures among children (194). The relation, if any, between the vaccine and reported serious events was not clear. In the original safety review, reported adverse events were similar for VAQTA and HAVRIX (194). The safety of the vaccine will continue to be assessed through ongoing monitoring of data from VAERS and other surveillance systems. Any adverse event suspected to be associated with hepatitis A vaccination should be reported to VAERS. Information on how to report adverse events is available at / cber/vaers/vaers.htm; forms for this purpose can be obtained at telephone 800-822-7967. # Contraindications and Precautions Hepatitis A vaccine should not be administered to persons with a history of a severe allergic reaction to a previous dose of hepatitis A vaccine or to a vaccine component. The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretic risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk for hepatitis A in pregnant women who might be at high risk for exposure to HAV. Because hepatitis A vaccine is inactivated, no special precautions need to be taken when vaccinating immunocompromised persons. # Prevaccination Serologic Testing for Susceptibility Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection. Vaccination of a person who is immune because of previous infection does not increase the risk for adverse events. In populations that have expected high rates of previous HAV infection, prevaccination testing may be considered to reduce costs by not vaccinating persons who are already immune. Testing of children is not indicated because of their expected low prevalence of infection. For adults, the decision to test should be based on 1) the expected prevalence of immunity, 2) the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and 3) the likelihood that testing will not interfere with initiation of vaccination. For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations for which the prevalence of infection is likely to be >33% should be cost-effective (195). Persons for whom prevaccination testing will likely be most cost-effective include adults who were either born in or lived for extensive periods in geographic areas that have a high or intermediate endemicity of hepatitis A (Figure 4); older adolescents and adults in certain population groups (i.e., American Indians, Alaska Natives, and Hispanics); and adults in certain groups that have a high prevalence of infection (e.g., injectiondrug users). In addition, prevalence might be high enough among all older adults to warrant prevaccination testing. Overall anti-HAV prevalence among persons aged >40 years, determined by NHANES-III testing, was >33% (50). Therefore, if the cost of screening is one third the cost of the vaccine series, prevaccination testing of any person aged >40 years would likely be cost-effective. Commercially available tests for total anti-HAV should be used for prevaccination testing. # Postvaccination Testing for Serologic Response Postvaccination testing is not indicated because of the high rate of vaccine response among adults and children. In addition, not all testing methods approved for routine diagnostic use in the United States have the sensitivity to detect low anti-HAV concentrations after vaccination. # Cost-Effectiveness of Hepatitis A Vaccination of Children The cost-effectiveness of nationwide routine hepatitis A vaccination was evaluated in an analysis that used a Markov model to follow a single U.S. birth cohort of approximately 4 million persons from birth in 2005 through age 95 years or death. Compared with no childhood vaccination, routine vaccination at age 1 year would result in 183,806 fewer infections and 32 fewer deaths in each cohort (CDC, unpublished data, 2005). The cost-effectiveness ratio was estimated at $173,000 per life year gained and $24,000 per qualityadjusted life year (QALY) gained. Compared with 2003 vaccine coverage levels, the incremental cost-effectiveness ratio of routine nationwide vaccination at age 1 year was $73,000 per QALY gained. When out-of-cohort herd immunity was taken into account, vaccination at age 1 year yielded a societal cost of $1,000 per QALY gained. Another economic analysis that included the estimated reduction in secondary cases among household contacts of infected children yielded similar results (196). # MMWR May 19, 2006 # Recommendations for Use of Hepatitis A Vaccine and Immune Globulin Preexposure Protection Against HAV Infection The following recommendations for hepatitis A vaccination are intended to further reduce hepatitis A morbidity and mortality in the United States and make possible consideration of eventual elimination of HAV transmission. Hepatitis A vaccination is recommended routinely for children, for persons who are at increased risk for infection, and for any person wishing to obtain immunity. # Children - All children should receive hepatitis A vaccine at age 1 year (i.e., 12-23 months). Vaccination should be completed according to the licensed schedules (Tables 2 and 3) and integrated into the routine childhood vaccination schedule. Children who are not vaccinated by age 2 years can be vaccinated at subsequent visits. - States, counties, and communities with existing hepatitis A vaccination programs for children aged 2-18 years are encouraged to maintain these programs. In these areas, new efforts focused on routine vaccination of children aged 1 year should enhance, not replace, ongoing programs directed at a broader population of children. - In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children aged 2-18 years can be considered. Such programs might especially be warranted in the context of increasing incidence or ongoing outbreaks among children or adolescents. # Persons At Increased Risk for HAV Infection # Persons Traveling to or Working in Countries That Have High or Intermediate Endemicity of Infection All susceptible persons traveling to or working in countries that have high or intermediate hepatitis A endemicity (Figure 4) should be vaccinated or receive IG before departure (Tables 1-4). Hepatitis A vaccination at the ageappropriate dose is preferred (Tables 2-4). Prevaccination testing should be considered for older travelers or for younger persons in certain population groups (see Prevaccination Serologic Testing for Susceptibility). Travelers to Australia, Canada, western Europe, Japan, or New Zealand (i.e., countries in which endemicity is low) are at no greater risk for infection than persons in the United States. Data are not available regarding the risk for hepatitis A for persons traveling to certain areas of the Caribbean, although vaccine or IG should be considered if travel to areas that have questionable sanitation is anticipated. The first dose of hepatitis A vaccine should be administered as soon as travel is considered. Travelers who are administered vaccine can be assumed to be protected within 4 weeks after receiving the first vaccine dose. Persons administered singleantigen hepatitis A vaccine often will have detectable anti-HAV by 2 weeks after the first vaccine dose; the proportion of persons who will have detectable anti-HAV at 2 weeks might be lower when lower vaccine dosages are used (e.g., in TWINRIX). However, no data are available regarding the risk for hepatitis A among persons vaccinated 2-4 weeks before departure. Because protection might not be complete until 4 weeks after vaccination, for optimal protection, persons traveling to an area in which risk is high <4 weeks after the initial dose also may be administered IG (0.02 mL/kg), but at a different anatomic injection site. Travelers departing in <4 weeks who do not or cannot receive IG should nonetheless receive hepatitis A vaccine and be informed that they might not be optimally protected from acquiring hepatitis A in the immediate future (i.e., subsequent 2-4 weeks). Completion of the vaccine series according to the licensed schedule (Tables 2-4) is necessary for long-term protection. Travelers who are allergic to a vaccine component or who elect not to receive vaccine should receive a single dose of IG (0.02 mL/kg), which provides effective protection against hepatitis A for up to 3 months (Table 1). Travelers whose travel period is >2 months should be administered IG at 0.06 mL/kg; administration must be repeated if the travel period is >5 months (Table 1). # MSM MSM (both adolescents and adults) should be vaccinated. Prevaccination testing is not indicated for the vaccination of adolescents and young adults in this population but might be warranted for older adults (see Prevaccination Serologic Testing for susceptibility). Studies have suggested that the majority of MSM would accept hepatitis A vaccination if recommended by their providers (53). Health-care providers in primary-care and specialty medical settings in which MSM receive care should offer hepatitis A vaccine to patients at risk. Implementation strategies to overcome barriers and increase coverage (e.g., use of standing orders) should be considered. # Users of Injection and Noninjection Drugs Vaccination is recommended for users of injection and noninjection illicit drugs. Prevaccination testing is not indicated for the vaccination of adolescent users of illicit drugs but might be warranted for certain adults. The need might depend on the particular characteristics of the population of drug users, including the type and duration of drug use. Providers should obtain a thorough history to identify patients who use or are at risk for using illicit drugs and might benefit from hepatitis A vaccination. Implementation strategies to overcome barriers and increase coverage (e.g., use of standing orders) should be considered. # Persons Who Have Occupational Risk for Infection Persons who work with HAV-infected primates or with HAV in a research laboratory setting should be vaccinated. Studies conducted among U.S. workers exposed to raw sewage do not indicate increased risk for HAV infection. No other populations have been demonstrated to be at increased risk for HAV infection because of occupational exposure. # Persons with Clotting-Factor Disorders Susceptible persons who are administered clotting-factor concentrates, especially solvent-detergent-treated preparations, should receive hepatitis A vaccine. Changes in clotting factor preparation practices and donor screening have greatly reduced the risk for hepatitis A for recipients of clotting factors. # Vaccination of Persons with Chronic Liver Disease Susceptible persons with chronic liver disease should be vaccinated. Available data do not indicate a need for routine vaccination of persons with chronic HBV or HCV infections without evidence of chronic liver disease. Susceptible persons who are either awaiting or have received liver transplants should be vaccinated. # Hepatitis A Vaccination During Outbreaks The frequency of large communitywide outbreaks has diminished considerably since implementation of the recommended childhood hepatitis A vaccination programs. Implementation of the recommendations in this report should further reduce occurrence of outbreaks. If communitywide outbreaks occur, accelerated vaccination may be considered as an additional control measure. Factors to consider in deciding whether to initiate an outbreak-control vaccination program include the feasibility of rapidly vaccinating the target population of children, adolescents, or young adults, and program cost. Ongoing vaccination of children should be sustained to maintain high levels of immunity and prevent future epidemics. Limited outbreaks, especially those involving adults at increased risk (e.g., illicit drug users or MSM), are likely to continue to occur until higher vaccine coverage is achieved in these populations. Vaccination programs to control these outbreaks have been difficult to implement. Programs to control hepatitis A outbreaks among users of illicit drugs, especially methamphetamine, that focused on vaccination in county jails and similar venues (e.g., court-ordered diversion programs) have met with some limited success, at least in terms of the provision of vaccine (57). In general, efforts to control and prevent hepatitis A outbreaks among adults in these populations should be focused primarily on initiating and sustaining routine vaccination of these persons. The frequency of outbreaks in child care centers has also decreased in recent years and should continue to decrease with more widespread vaccination of young children. Limited data exist regarding the role of hepatitis A vaccine in controlling outbreaks in these settings. If outbreaks are recognized in child care centers, use of IG as recommended is effective in limiting transmission to employees and families of attendees (see Postexposure Prophylaxis with IG). Previously unvaccinated children receiving postexposure prophylaxis with IG should also receive hepatitis A vaccine. Persons who work as food handlers can contract hepatitis A and potentially transmit HAV to others. One national economic analysis concluded that routine vaccination of all food handlers would not be economical from a societal or restaurant owner's perspective (197). Nonetheless, to decrease the frequency of evaluations of food handlers with hepatitis A and the need for postexposure prophylaxis of patrons, consideration may be given to vaccination of employees who work in areas where state and local health authorities or private employers determine that such vaccination is appropriate. Food handlers who receive hepatitis A vaccine should be provided with a record of the immunization. Those who do not should be informed of the signs and symptoms of hepatitis A and taught food preparation practices that reduce the risk for fecal contamination. # Postexposure Prophylaxis with IG Persons who have been recently exposed to HAV and who have not previously received hepatitis A vaccine should be administered a single dose of IG (0.02 mL/kg) as soon as possible. Efficacy when administered >2 weeks after exposure has not been established. Persons who have been administered 1 dose of hepatitis A vaccine at >1 month before exposure to HAV do not need IG. Because hepatitis A cannot be reliably diagnosed on clinical presentation alone, serologic confirmation of HAV infection in index patients by IgM anti-HAV testing is recommended before postexposure treatment of contacts. Screening of con-tacts for immunity before administering IG is not recommended because screening would result in delay. If hepatitis A vaccine is recommended for a person being administered IG (e.g., a person with a recent exposure but also an indication for vaccination), it may be administered simultaneously with IG at a separate anatomic injection site. Unlike IG, hepatitis A vaccine is not licensed for use as postexposure prophylaxis. The completion of studies comparing IG with hepatitis A vaccine for postexposure prophylaxis is needed before vaccine can be recommended in this setting. IG should be administered to previously unvaccinated persons in the following situations. # Close Personal Contact IG should be administered to all previously unvaccinated household and sexual contacts of persons with serologically confirmed hepatitis A. In addition, persons who have shared illicit drugs with a person who has serologically confirmed hepatitis A should receive IG and hepatitis A vaccine. Consideration should also be given to providing IG to persons with other types of ongoing, close personal contact with a person with hepatitis A (e.g., regular babysitting). # Child Care Centers IG should be administered to all previously unvaccinated staff and attendees of child care centers or homes if 1) one or more cases of hepatitis A are recognized in children or employees or 2) cases are recognized in two or more households of center attendees. In centers that do not provide care to children who wear diapers, IG need be administered only to classroom contacts of an index patient. When an outbreak occurs (i.e., hepatitis A cases in three or more families), IG also should be considered for members of households that have children (center attendees) in diapers. Hepatitis A vaccine may be administered at the same time as IG for children receiving postexposure prophylaxis in child care centers. # Common-Source Exposure If a food handler receives a diagnosis of hepatitis A, IG should be administered to other food handlers at the same establishment. Because common-source transmission to patrons is unlikely, IG administration to patrons typically is not indicated but may be considered if 1) during the time when the food handler was likely to be infectious, the food handler both directly handled uncooked foods or foods after cooking and had diarrhea or poor hygienic practices, and 2) patrons can be identified and treated <2 weeks after the exposure. In settings in which repeated exposures to HAV might have occurred (e.g., institutional cafeterias), stronger consideration of IG use might be warranted. In the event of a common-source out-break, IG should not be administered to exposed persons after cases have begun to occur because the 2-week period during which IG is effective will have been exceeded. # Schools, Hospitals, and Work Settings IG is not routinely indicated when a single case occurs in an elementary or secondary school, an office, or other work settings, and the source of infection is outside the school or work setting. Similarly, when a person who has hepatitis A is admitted to a hospital, staff should not routinely be administered IG; instead, careful hygienic practices should be emphasized. IG should be administered to persons who have close contact with index patients if an epidemiologic investigation indicates HAV transmission has occurred among students in a school or among patients or between patients and staff in a hospital. CDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 2.5 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU) . CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training. CDC will award 0.2 continuing education units to participants who successfully complete this activity. # Continuing Nursing Education (CNE). This activity for 2.8 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. You must complete and return the response form electronically or by mail by MAY 19, 2009, to receive continuing education credit. If you answer all of the questions, you will receive an award letter for 2. 5 # Goal and Objectives This report provides updated recommendations made by the Advisory Committee on Immunization Practices (ACIP) concerning vaccination to prevent hepatitis A virus (HAV) infection in the United States. The goal of this report is to guide clinical practice and policy development related to the prevention of HAV infection. Upon completion of this educational activity, the reader should be able to 1) identify recommendations for the routine hepatitis A vaccination of children in the United States, 2) describe the epidemiology of hepatitis A in selected areas of the United States after implementation of ACIP's 1996 and 1999 recommendations for use of hepatitis A vaccine, 3) list the primary target groups for routine hepatitis A vaccination, and 4) describe the characteristics of currently licensed hepatitis A vaccines. To receive continuing education credit, please answer all of the following questions. # Which best describes your professional # In recent years, the majority of hepatitis A cases have been reported from states with historically low rates of hepatitis A in which hepatitis A vaccination of children has not been implemented widely. A. True. B. False.

As the nation's prevention agency, CDC strives to accomplish its vision of "Healthy People in a Healthy World...Through Prevention." For women, this involves working to better understand the health issues that have an adverse impact on women, disproportionately affect women, occur only in women, or have an impact on infant outcomes as a direct result of a pregnancy-related event. Women's health once focused primarily on puberty, pregnancy, and menopause. Now, women's health is recognized as being broad in focus and warranting additional attention and study and involves not only chronic conditions but individual lifestyle choices and environmental and organizational factors. This publication focuses on some of the specific issues affecting women's health: falls and resulting hip fractures, sports injuries, breast and cervical cancer, and congenital toxoplasmosis. For each report, prevention recommendations and specific research recommendations are provided. Much still needs to be done. The publication addresses diverse and seemingly unconnected women's health issues; however, these issues are very much connected, and several themes run throughout each of the reports. For example: - Prevention -whether primary or secondary -continues to reduce or prevent injury, disease, death, and disability. Prevention is an essential component to maintaining health. ii MMWR March 31, 2000 Contents Reducing Falls and Resulting Hip Fractures Among Older Women .# - Science continues to strengthen and support public health action on the individual, local, and national level. - Although much progress has been made in the area of women's health to reduce morbidity and mortality, more prevention research needs to be done. - Public health affects every phase of our lives: how we live, work, and play. Whether the topic is falls in the home, injuries associated with leisure or workrelated activities, screening for toxoplasmosis, or implementation of an early detection program, prevention plays a vital role. Our partners in prevention (e.g., other health agencies, business, education, communities, and individuals) also play a vital role by developing and implementing prevention strategies and policies and by promoting healthy behaviors and environments. After reviewing each of these reports, examine current practices that have an impact on women's health where you live, work, and play. Are there opportunities for improvement? As costs related to disease, disability, and injury continue to increase, the role of prevention to maintain health becomes more critical. Prevention is about staying healthy and living well-and prevention works for women. # Yvonne Green Associate Director Office on Women's Health # SCOPE OF THE PROBLEM Falls are the leading cause of injury deaths and disabilities among persons aged ³65 years. In the United States, one of every three older adults falls each year (2,3 ). In 1997, nearly 9,000 persons aged ³65 years died from falls (4 ). Of those who fall, 20%-30% sustain moderate to severe injuries that reduce mobility and independence and increase the risk for premature death (5 ). Older adults are hospitalized for fall-related injuries five times more often than they are for injuries from other causes (5 ), and women are nearly three times more likely than men to be hospitalized for a fall-related injury (5 ). The most prevalent fall-related injuries among older adults are fractures of the hip; spine; upper arm; forearm; and bones of the pelvis, hand, and ankle (6 ). Of these, the most serious injury is hip fracture, a leading cause of morbidity and excess mortality among older adults (7 ). During 1988During -1996, the estimated number of hospital admissions for hip fracture increased from 230,000 to 340,000 (Figure 1). In 1996, 80% of the admissions for hip fracture occurred among women (8 ). The rate of hospitalization for hip fracture differs by sex. The hip fracture hospitalization rate for persons aged ³65 years is significantly higher for women than men (9 ). During 1988-1996, the rates for women increased significantly, from 972 per 100,000 to 1,356; for men, rates remained stable (9 ). A Healthy People 2010 objective is to reduce the hip fracture hospitalization rate among women aged ³65 years to no more than 879 per 100,000 (objective 15-28a). Hip fracture hospitalization rates are substantially higher for white women than black women. In 1996, the hospitalization rate for white women aged ³65 years was 1,174 per 100,000, five times the rate for black women (9 ). A Healthy People 2010 objective is to reduce hip fracture hospitalization rates among white women aged ³65 years to no more than 932 per 100,000 (objective 15-28a). The overall increase in hip fracture hospitalization rates can be explained in part by the increasing U.S. population of very old adults (i.e., persons aged ³85 years). Today, a larger proportion of the population is living to age ³85 years than in the past because of reduced mortality from cardiovascular and other chronic diseases. Since 1987, death rates from coronary heart disease, stroke, and cancer have declined, and the proportion of adults aged ³70 years living with some functional limitation- has increased (10 ). Frail older adults are twice as likely to fall as healthier persons (11 ). Hip fractures are expensive. A recent study documented that the cost of a hip fracture (including direct medical care, formal nonmedical care, and informal care provided by family and friends) was $16,300-$18,700 during the first year following the injury (12 ). In 1991, hip fracture accounted for an estimated $2.9 billion in Medicare costs (13 ). On the basis of the annual cost of hip fracture in 1984, an assumption that the average cost will remain constant, an inflation rate of 3%-5%, and the increasing number of hip fractures, the estimated total annual cost of hip fracture in the United States could reach $82-$240 billion by the year 2040 (14 ). An even more important factor than the monetary cost of hip fracture is the injury's impact on a person's life in the form of loss of independence and decreased quality of life. Nationwide, only 50% of older adults hospitalized for hip fracture are able to return home or live independently after the injury (15,16 ). # ETIOLOGIC OR RISK FACTORS Approximately 95% of hip fractures are caused by falls (17 ). Other causes include being knocked over and being injured in a motor-vehicle crash; <2% of hip fractures occur spontaneously (e.g., as the result of a metabolic bone disease) (17 ). Not all falls are *Defined as having difficulty with two or more activities of daily living. # FIGURE 1. Estimated number of hospital admissions for hip fracture among persons aged ³65 years -United States, 1988-1996 Source: CDC's National Hospital Discharge Survey. 1988 1989 1990 1991 1992 1993 1994 1995 1996 equally likely to cause hip fracture. Biomechanical studies have demonstrated that, although both bone strength and the force of the impact are important factors, the point of impact must be on or near the hip for a fall to cause a hip fracture (18 ). Many factors contribute to falls and subsequent fall injury. Fall risk increases rapidly with advancing age for persons aged ³65 years (19 ). Other fall risk factors include lack of current or previous physical activity (20,21 ), muscle weakness or balance problems that can contribute both to the risk for falling and the inability to break the impact of a fall (2,22,23 ), functional limitations (e.g., difficulty with activities of daily living such as dressing or bathing) (22,24 ), cognitive impairment or dementia (2 ), use of psychoactive medications (e.g., tranquilizers or antidepressants), some combinations of medications (2,25 ), environmental factors (e.g., tripping hazards) (26 ), having fallen previously (27 ), having more than one chronic disease (28 ), having had a stroke (28 ), Parkinson disease (29 ) or a neuromuscular disease (30 ), urinary incontinence (31 ), and visual difficulties (32,33 ). Less clear is the fall risk associated with wearing shoes with thick, soft soles (e.g., jogging shoes) that can affect balance and proprioception or become a tripping hazard by catching in carpeting (34 ). Similar to fall risk, hip fracture risk increases sharply with advancing age (19 ). Women aged ³85 years are nearly eight times more likely than women aged 65-74 years to be hospitalized for hip fracture (9 ). White women aged ³65 years are at higher risk for hip fracture (19 ) than black women, in part because the prevalence and severity of osteoporosis-a condition that predisposes to bone fragility-is greatest among white women. Other risk factors include low body mass index (weight in kilograms divided by height in meters squared /height squared ) (7,35,36 ), previous history of osteoporosis (27 ), and having sustained a previous hip fracture (27 ). Falls are caused by personal (intrinsic) and environmental (extrinsic) factors. Personal risk factors include problems with gait and balance, functional impairments or limitations in activities of daily living, visual problems, and behavioral risk factors (e.g., lack of physical activity and taking certain psychoactive medications such as tranquillizers or antidepressants). Environmental factors include home hazards (e.g., clutter; no stair railings; loose rugs or other tripping hazards; no grab bars in the bathroom; and poor lighting, especially on stairs). Frequently, a fall is the result of an interaction between personal and environmental factors. # RECOMMENDATIONS FOR PREVENTION Because approximately 95% of hip fractures result from falls (17 ), minimizing fall risk is a practical approach to reducing these serious injuries. Primary prevention of fallrelated injuries involves reducing the occurrence of falls; secondary prevention of fall-related injuries involves preventing injuries when falls occur. # Primary Prevention Primary prevention of fall-related injuries among older adults can be targeted to persons living independently in the community or residents of nursing homes. Research has established that effective fall intervention programs employ a multifaceted approach and incorporate both behavioral and environmental elements: exercises to improve strength and balance, environmental modifications, education about fall prevention, medication review and assessment to minimize side effects, and risk factor reduction (36)(37)(38)(39). # Community Intervention Approximately 90% of adults aged ³65 years live in the community and many fall prevention programs target these persons; however, few of these programs have been evaluated for effectiveness. During 1990-1992, a prospective, multifaceted, fallprevention study was conducted among 301 community-dwelling men and women who were aged ³70 years and had at least one fall risk factor (e.g., sedative use or some limitation in arm or leg strength) (36 ). A total of 153 persons participated in an intervention that consisted of behavioral instructions and training to reduce specific risk factors (e.g., persons with gait or balance impairments received specialized training in these areas), exercise programs to increase strength, and medication adjustments. After 1 year, the group that received the intervention had 30% fewer falls than the control group. Further research is needed to evaluate the effectiveness of such a program among all persons aged ³65 years living independently in the community. Physical Activity. Increasing physical activity can be an effective component of fall prevention programs. Activities that improve strength, balance, and coordination can reduce the risk for falls and fall-related injuries among healthy (40,41 ) and frail persons (42 ). Studies have demonstrated a 40%-60% reduction in hip fracture risk with increasing levels of physical activity (36,43 ). Although fall prevention programs have focused on several techniques to improve strength, balance, coordination, mobility, and flexibility, Tai Chi is probably the most frequently studied type of exercise (40 ). Effective programs have been employed with persons of different ages and with varied physical abilities; however, persons with functional limitations might require more individualized physical activity programs (44 ). Environmental Modifications. Because approximately 50%-60% of all falls among older adults occur at home, fall prevention programs should address home hazards that can contribute to falls (45 ). Home-visiting programs (e.g., those using visiting nurses) provide opportunities to identify potential fall hazards and take corrective action. These programs can increase awareness of fall risks among informal caregivers, (e.g., family and friends who frequently visit the homes of older adults) and the older adults themselves. Health Education. Fall prevention programs frequently include health education and health promotion materials about reducing fall hazards that are distributed at central locations (e.g., senior centers or health fairs). However, educational materials alone might not promote behavioral changes. Many programs employ home-hazard checklists that can be used by the caregiver or health agency personnel (e.g., a visiting nurse or home health aide) to help persons identify fall hazards and to suggest corrective action (e.g., eliminating potential tripping hazards such as clutter and throw rugs, adding stair railings, improving lighting, adding nonslip floor surfaces, and installing grab bars in bathrooms). Checklists are also given to residents to help them assess personal and environmental risks and take preventive action, including behavioral changes (45 ). Research is needed to evaluate and assess the effectiveness of educational materials and home-hazard checklists to promote fall-risk reduction activities and behaviors. Risk Factor Reduction. Approaches that address specific risk factors can supplement fall prevention program efforts. Medical approaches might include reducing fall risk factors (e.g., maximizing control of concomitant chronic diseases) and reducing hip fracture risk factors (e.g., counseling women aged ³65 years against inappropriate weight loss). # MMWR March 31, 2000 # Nursing-Home Intervention Nursing-home residents, who constitute approximately 5% of the population aged ³65 years, are at particularly high risk for fall-related injuries. Approximately one half of the estimated 1.7 million nursing-home residents in the United States fall at least once each year, and 11% sustain a serious fall-related injury (46 ). A randomized trial of seven pairs of nursing homes that included 500 residents evaluated an intensive, multifaceted intervention of extensive environmental modifications (e.g., obtaining wheel locks for beds, changing lighting, modifying floor plans, and purchasing raised toilet seats), medication review, and increased attention to individual resident needs (39 ). Repeat falls declined 19% among nursing-home residents who had fallen at least once during the previous year. However, approximately one third of the safety recommendations implemented in the study group were discontinued within 3 months of the completion of the study. Strategies are needed to institutionalize fall prevention interventions in the nursing-home setting, and additional programs designed for high-risk nursing-home residents need to be implemented and evaluated. # Secondary Prevention Secondary prevention strategies are being developed to reduce the incidence of hip fracture among older women (47 ). Most hip fractures are caused by falling directly on the hip, and biomechanical studies have demonstrated that a pad that shunts the energy away from the point of impact is highly effective in reducing the force of a fall on the proximal femur (48 ). A 1993 clinical study in a Copenhagen nursing home demonstrated that hip protectors reduced the risk for hip fracture by approximately 50% (47 ). During 1994-1996, researchers in Finland conducted a study to determine whether nursinghome residents would wear an undergarment with energy-shunting hip pads. The findings indicated that 63% of the residents wore the pads (49 ). U.S. manufacturers have considered producing and marketing an undergarment with energy-absorbing hip pads, but how acceptable and effective this garment might be among community-dwelling older adults is unknown. A promising technologic innovation for preventing fall-related injuries is a recently developed safety floor (50 ). Under laboratory conditions, this flooring material provides a firm walking surface and, if a fall occurs, reduces the force of impact through the use of special energy-absorbing flooring material. Field trials are under way in nursing homes to evaluate the effectiveness of this material in preventing fall-related hip fractures among nursing-home residents. professionals, caretakers, and other persons concerned about reducing injuries among older adults. Researchers do not know all the factors that contribute to falls and fall-related injuries or how personal and environmental factors interact to cause a fall. These factors have been difficult to identify because persons frequently cannot explain the causes or circumstances surrounding fall events. In one prospective study, one fourth to one third of the participants did not remember a fall that occurred 3-6 months earlier (51 ). Older adults might either blame themselves for falling or consider falls to be an inevitable consequence of the aging process. Longitudinal prospective studies are needed to accurately assess the associations between fall risk factors (e.g., interactions between intrinsic and extrinsic factors), the occurrence of falls, and fall outcomes (e.g., frequency of falls, whether an injury results, and level of injury severity). To decrease the incidence and severity of fall-related injuries, injury-prevention programs for older adults need to integrate research findings into multifaceted, communitylevel programs that include both implementation and evaluation components. A model program would employ a prospective design to accurately record fall occurrences and establish whether a fall resulted in an injury. Such a program should incorporate four critical elements: a) education and skill-building activities to increase knowledge about fall risk factors, b) exercise to increase strength and improve balance, c) home safety modifications and repairs to reduce fall hazards, and d) medication review to maximize control of comorbid conditions while reducing adverse side effects. Because persons must take an active role to reduce their risk for falling, a model fall prevention program should also include effective strategies to promote behavioral changes. Because of the increasing number of persons aged ³65 years in the United States, the need is increasing to develop an effective national plan to address the problem of falls and fall-related injuries within the constraints of limited health-care resources. To accomplish this goal, efforts are needed to increase collaboration among national experts from various disciplines (e.g., gerontologists, health educators, behavioral epidemiologists, home designers, and ergonomic experts), to reach consensus regarding the priority research areas and program issues, and to work toward long-term strategies for reducing falls and fall-related injuries among older adults. Some subgroups of older adults (e.g., women aged ³85 years and older adults with functional limitations) might have different fall-injury risks than most communitydwelling older adults (44 ). Efforts are needed to adapt existing fall prevention programs or develop new interventions to reduce falls in these groups. Finally, in addition to existing behavioral and environmental interventions, new fall prevention approaches (e.g., characterizing footwear that promotes stability and developing more effective home lighting) need to be developed. # CONCLUSION Persons aged ³65 years constitute the fastest-growing segment of the U.S. population. The average life expectancy for both men and women is increasing, in part because of healthier life styles and better control and treatment of chronic conditions (e.g., cardiovascular disease). Without effective intervention strategies, the number of hip fractures will increase as the U.S. population ages. Fall prevention programs have effectively reduced falls in select populations by 30%-50%, using multifaceted approaches that include various combinations of education, exercise, medication assessment, risk factor reduction, and environmental modifications. Such programs need to be expanded to include multiple intervention components tailored for diverse populations of older adults and evaluated for effectiveness. In addition, secondary prevention strategies (e.g., reducing the amount of energy transferred to the hip) are needed to prevent hip fracture when falls occur. The problem of fall-related hip fractures will continue to increase unless effective intervention strategies are developed and implemented to improve fall prevention interventions and expand existing programs. Older adults must take an active role in reducing their risk for falling. Because most older adults live independently, fall prevention programs must include effective strategies to promote behavioral changes. Innovative and effective fall prevention strategies are needed to reduce future morbidity and mortality associated with hip fractures, increase independence, and improve quality of life for the growing number of older adults. # Exercise-Related Injuries Among Women: Strategies for Prevention from Civilian and Military Studies Etiologic Factors: Injury risks increase as the amount of training increases (increased exposure). The same exercise parameters that can be modified to enhance physical fitness (i.e., frequency, duration, and intensity) also influence the risk for injury in a dose-response manner. Higher levels of current physical fitness (aerobic fitness) protect the participant against future injury. A history of previous injury is a risk factor for future injury. Smoking cigarettes has been associated with increased risk for exercise-related injury. Studies conducted in military populations suggest that the most important risk factor for injuries among persons engaged in vigorous weightbearing aerobic physical activity might be low aerobic fitness rather than female sex. Recommendations for Prevention: Because of the limited scientific research regarding women engaging in exercise, general recommendations are provided. Women starting exercise programs should be realistic about their goals and start slowly at frequency, duration, and intensity levels commensurate with their current physical fitness condition. Women should be informed about the early indicators of potential injury. Women who have sustained an injury should take precautions to prevent reinjury (e.g., ensuring appropriate recovery and rehabilitation). Research Agenda: In general, a combination of factors affects the risk for exerciserelated injury in women. How these factors act singly and in combination to influence injury risk is not well understood. Additional research regarding exercise-related injury in women is needed to answer many of the remaining epidemiologic questions and to help develop exercise programs that improve health while reducing the risk for injury. # MMWR March 31, 2000 Conclusion: Exercise is an important component in improving and maintaining health; however, injury is also an accompanying risk. A review of key military and civilian research studies regarding exercise-related injuries provides some clues to reducing these injuries in women. Greater adherence to exercise guidelines can help decrease these risks. # BACKGROUND In 1996, the U.S. Surgeon General's report on physical activity brought together for the first time current knowledge regarding the health benefits of regular physical activity (1 ). The report concluded that persons who are inactive can improve their current and future health by becoming moderately active on a regular basis. In addition, the report indicated that activity does not need to be strenuous to achieve some health benefits, but that greater health benefits can be achieved by increasing the amount (frequency, duration, or intensity) of physical activity. Although many studies have documented the hazards of inactivity, few have assessed the adverse effects of increased physical activity (e.g., injury). Increased physical activity increases the risk for injury. Although opportunities for women to participate in sports and organized fitness activities have increased substantially during the preceding century, little is known about the risks for injuries associated with increased physical activity and exercise for women. This report reviews key military and civilian research studies regarding musculoskeletal injury associated with common weight-bearing exercise (e.g., running, walking, and aerobics) and provides general recommendations for preventing exercise-related injuries among women. Recent public health reports have reviewed the scientific evidence supporting the association between physical activity and several health benefits (1,2 ). Documented health benefits of regular physical activity include reducing the risk for coronary heart disease, noninsulin-dependent diabetes, hypertension, colon cancer, osteoporosis, and other disorders (1 ). Physical activity decreases the symptoms and might reduce episodes of anxiety and depression (1 ). In addition, regular physical activity improves physical fitness (e.g., cardiorespiratory endurance and muscle strength); reduces body fat; and builds and maintains healthy bones, joints, and muscles (1 ). Physical activity enhances strength, balance, and coordination (1 ). These benefits might be particularly important in preventing falls and maintaining independence in older adults. As a consequence of these health benefits, regular physical activity is highly recommended for women and men of all ages (1 ). The U.S. Surgeon General's report indicated that approximately 60% of adult women in the United States did not engage in the recommended amount of physical activity, and 25% did not participate in physical activity during their leisure time (1 ). Physical inactivity is more common in women than men (1,3 ). To help increase the proportion of persons engaged in regular physical activity, two of the Healthy People 2010 objectives are to a) reduce to £20% the proportion of persons aged ³18 years who engage in no leisure-time physical activity (objective 22-1) and b) increase to ³30% the proportion of persons aged ³18 years who engage in regular, preferably daily, moderate physical activity for at least 30 minutes per day (objective 22-2). Because regular physical activity is considered essential to health, it has been included as one of the leading health indicators for health promotion and disease prevention in the United States (4 ). Although physical activity has many health benefits, exercise has corresponding injury risks. Participants are at risk for exercise-related traumatic or overuse injuries. Some of the consequences of these injuries can be long-term (e.g., osteoarthritis and adverse health effects resulting from inactivity because of an injury). Injury causes many persons to stop participating in exercise (2,5 ). Efforts to increase physical activity and exercise in women must also be balanced with efforts to prevent injury. Because lifestyles have become more sedentary and work has become less physically demanding, planned physical activity intended to improve physical fitness has become more important. Consequently, many adults choose to participate in exercise programs or sports. Health-related exercise programs and sports are excellent ways for women to increase their physical activity. Opportunities for young women to participate in sports have substantially increased in recent decades. Since passage of the 1972 Title IX legislation that prevented sex discrimination in educational settings, the number of young women who participate in high school athletics has increased from approximately 300,000 during the early 1970s to nearly 2.7 million (one in three high school women) in the 1998-99 school year (6,7 ). This increased participation in high school athletics has fostered increased participation in college and elite athletics as well. Women now comprise approximately one third of all college athletes and 37% of U.S. Olympic athletes (7 ). Many adult women participate in recreational aerobic activities. The National Sporting Goods Association reported that an estimated 37.4 million women participate more than twice a week in common aerobic activities (i.e., aerobic dance, cycling, exercise walking, exercising with equipment, calisthenics, swimming, and running) (8 ). Walking is the most prevalent physical activity among adults in the United States (1,9 ). If trends of increased participation in women's sports expand to include increased participation in recreational and other physical activities, the number of exercise-related injuries can also be expected to increase. Injuries occur in association with physical activity, exercise, and sports (10-13 ), but the incidence and underlying causes of such injuries are not well understood. At the peak of the fitness boom in the 1980s, researchers knew little about exercise-related injuries and injury rates, even for common activities (e.g., walking and running) (12 ). During that period, researchers were only beginning to study the epidemiology of and risk factors for exercise-related injuries (12,14 ). Today, injury risk factors for physically active men remain poorly defined, and the specific risks for women who exercise are even less understood. Studies of runners have provided the most thorough examination of injury incidence and some related risk factors in civilian populations (5,12,(14)(15)(16)(17). Studies of military populations provide sex-specific information on injury risks associated with physical training and exercise; activities are controlled, and complete and detailed health records, physical examinations, and physical fitness assessments are available (18,19 ). Studies of basic combat training, which occurs in all branches of the military and involves running, marching, and other weight-bearing aerobic activities, can often provide information relevant to civilian populations. Uniformity of training within military units provides unique control for the variability observed in exercise routines in the civilian population. Examination of military studies provides some data on exposure risks (18,20 ) and intrinsic risk factors (e.g., sex, previous injuries, health behaviors, sports participation, physical fitness, and anatomic factors) (19)(20)(21)(22)(23)(24). # MMWR March 31, 2000 This report describes civilian and military research related to weight-bearing aerobic exercise and injuries. Aerobic exercises (e.g., running, walking, and aerobic dance) are highlighted in this report because they are popular and commonly prescribed activities. Military studies of training-related injuries are presented to identify shared and sexspecific intrinsic risk factors. Risks for men will be discussed briefly for comparative purposes. This report focuses on modifiable risk factors, which underlie the recommendations for prevention and future research. # Definitions In this report, distinctions between the terms "physical activity," "exercise," and "physical training" are important. Physical activity has been defined as movement created by skeletal muscle contractions, resulting in energy expenditure. Exercise is a type of physical activity that is planned, repetitive, and designed to improve or maintain at least one of the health-related components of physical fitness (25 ). Physical training (as used in the military) is organized exercise intended to enhance fitness. The terms exercise and physical training are used interchangeably. Physical fitness can be categorized into five health-related components: a) cardiorespiratory endurance (aerobic fitness), b) muscle endurance, c) strength, d) flexibility, and e) body composition (1,25 ). The focus of this report is on exercise for women aimed at enhancing cardiorespiratory endurance (aerobic fitness). When discussing research results from cited literature, the terms "significant" and "not significant" refer to a documented p-value of 0.05, respectively, unless otherwise stated. Musculoskeletal injuries related to exercise can be classified as either traumatic (acute) injuries (e.g., sprains and fractures) or overuse injuries (e.g., tendinitis, bursitis, and stress fractures). A distinction is also made between extrinsic and intrinsic risk factors for musculoskeletal injury. Extrinsic risk factors refer to the parameters of training (e.g., frequency, duration, and intensity) and the conditions associated with the environment in which the exercise takes place. Intrinsic risk factors refer to the personal and internal characteristics of the participant (Table 1). # SCOPE OF THE PROBLEM # Findings from Civilian Studies The incidence of exercise-related injury among women in the civilian population is not well documented. Civilian studies of male and female exercise participants provide some indication of the frequency of such injuries. Surveys demonstrate that the incidence of self-reported running-related injury is high. Annually, approximately 25%-65% of male and female runners report being injured to the extent that they reduced or stopped training (5,13,(15)(16)(17)(18)26 ). In addition, 14%-50% of these injured runners seek medical care for their injuries (5,13,(15)(16)(17)(18), representing substantial health-care costs for treatment and rehabilitation. Prospective studies that incorporated follow-up of injury among runners and other persons involved in vigorous physical activities suggest that the incidence of injuries might be even higher (11,(27)(28)(29). In an 18-month study of runners training for a marathon, 85% experienced ³1 injury, and 174 injuries were reported among the 73 participants (159 injuries per 100 runners per year) (27 ). In a 12-week study of aerobic dancers, 200 (49%) of 411 participants reported complaints associated with aerobics, and approximately 25% had to modify or stop participation because of an injury (28 ). In a study of participants engaged in several recreational sporting activities, 475 injuries occurred among 986 participants during a 12-week period (192 injuries per 100 participants per year) (11 ). In a 6-month study of walkers who averaged 14 miles per week, 21% stopped walking for ³1 week because of injury (29 ). Although injuries during fitness activities are common, few studies of women or men who participate in recreational fitness activities are available to quantify risk or identify modifiable risk factors. # Findings from Military Studies Many civilian fitness activities (e.g., walking and jogging) have corollaries in military physical training (e.g., marching and running). The incidence of injury and related intrinsic risk factors for these activities have been more thoroughly studied in military populations than in civilians. Because physical fitness is required for military readiness, recruits undergo a vigorous basic training (BT) course, and substantial research has been devoted to methods of enhancing fitness and understanding the causes of training-related injuries. Studies from the U.S. Army 8-week BT have documented cumulative injury rates from 42% to 67% among women during the course of training (19,20,30 ). Of women in the U.S. Air Force, 33% incurred an injury during the 6-week BT (20 ). Similarly, 22% of women in the U.S. Navy sustained an injury during the 9-week BT, and 49% of women in the U.S. Marine Corps were injured during the 11-week BT (20 ). The range of injury incidence (22%-67%) among women in the different services and over time might be explained by differences in the duration and intensity of BT. Most of the injuries to both women and men engaged in military BT are overuse injuries (e.g., achilles tendinitis, patellar-femoral syndrome, plantar fasciitis, and stress fractures). Most injuries occur to the lower extremities. Studies during Army BT indicate that 60%-80% of BT injuries are related to overuse, and 80%-90% occur to the lower extremities (21,22,30 ). Injuries in the military have substantial effects on training and combat readiness because they require greater rehabilitation and recovery time than illnesses. Approximately 50% of health-care visits in these young, vigorously active military populations are injury-related (20 ). The rate ratios of injury-to-illness sick call visits for women in the Army, Marine Corps, and Air Force are 1.0, 1.0, and 0.8, respectively. Furthermore, the rates of limited duty days (i.e., days when a trainee cannot fully function on duty) are often substantially higher from an injury than from illness (20,24 ). In one Army study, women were assigned 129 injury-related limited duty days per 100 female trainees per month compared with 6 illness-related limited duty days per 100 trainees per month. The rate ratio between injury and illness limited-duty days was 22, even though 50% of sick-call visits were for illnesses (20 ). Among men, the rates of limited duty for injury were five times higher than the rates of limited duty for illness. In the physically active and generally healthy military populations, injury can be expected to account for a substantial proportion of morbidity, health-care costs, and rehabilitation time in comparison with illnesses. The burden of injuries among physically active civilian populations might reflect a similar pattern. # Risk Factors for Exercise-Related Injuries Risk factors for exercise-related injuries can be either extrinsic or intrinsic to the participant (Table 1). This report focuses on extrinsic training factors, perhaps the most important factors in determining injury risks, and addresses selected intrinsic factors. The association between training parameters and injury risks in civilian and military populations will be examined first because they are potentially the most important. # Extrinsic Training Factors The same training parameters that are modified to achieve a training effect (i.e., frequency, duration, and intensity of exercise) are also the most important factors re-lated to injury. Several surveys of distance runners indicate a relation between a higher number of miles run per week and a higher incidence of injury in both women and men (5,10,13,15,26 ). Several studies have demonstrated that the relative risk (RR) of injury among civilian women and men is a function of the miles run per week (Table 2) (5,15,26 ). One classic study indicated that as the average weekly training mileage increased in 10mile increments from 50 miles per week, the incidence of injury for women increased from 29% to 57%. The incidence of injury for men increased in a similar manner (5 ). Two additional studies reported similar sex-specific trends (15,26 ). The annual incidence of injury among female and male runners was approximately the same, and the RRs of injury for both sexes increased with increasing miles run. These and other studies suggest that, for weight-bearing exercise (e.g., running), injury rates increase as the amount of training increases in a dose-response manner. In a study that examined the benefits of aerobic fitness and injury risks associated with increased duration or frequency of training among men, injury rates increased with duration of exercise (when frequency and intensity remained constant). Participants received limited additional aerobic fitness benefits when they exercised 45 minutes compared with 30 minutes. As duration of running increased from 15 minutes to 30 minutes to 45 minutes per workout, injury rates increased from 22% to 24% to 54%, respectively, whereas aerobic fitness (measured by maximal oxygen uptake) improved only 9%, 16%, and 17%, respectively. Although a plateau in fitness occurred, more exercise increased the incidence of injury. This study also demonstrated that frequency of exercise (number of training sessions per week), although positively related to aerobic fitness, was also positively related to injury (31 ). A similar study of male walkers and joggers demonstrated that injury rates were more related to total mileage walked and jogged than to the intensity of exercise. This study controlled the total amount of activity in two groups of participants during a 6month period. Both groups exercised the same duration per day (30 minutes); however, the walkers exercised more frequently (more days per week) than the joggers to accumulate approximately the same mileage. The walkers averaged 120 minutes of exercise per week, and the joggers averaged 90 minutes per week; however, the total distance accumulated by both groups was approximately the same (13.7 km per week and 14.7 km per week, respectively). At the end of the 6-month study period, the two groups had similar injury rates: 21% of the walkers and 25% of the joggers had sustained injuries sufficiently severe to require terminating their activity for ³1 week (29 ). Studies such as these indicate that the total amount of training is an important determinant of injury risk. These studies were conducted with men, and similar studies of women are needed. Studies of military populations have also examined the relation between training frequency and duration, gains in cardiorespiratory fitness, and injury risk. As mileage during physical training increases, both aerobic fitness and the risk of injury increases. Similar to the findings in civilian populations (31 ), military studies have documented thresholds in physical training, above which increased training does not improve fitness levels but continues to increase the likelihood of injury (18)(19)(20). These studies of military populations examined the association between training parameters and injury risk among men only. Additional studies among women are needed. # MMWR 23 # Intrinsic Training Factors Military BT provides a unique opportunity to study some intrinsic risk factors for exercise-related injuries. Unlike civilian fitness participants, regimentation in military training requires that trainees do the same type and amount of training. Researchers studying military populations have systematically examined several intrinsic factors and their relation to musculoskeletal injury risk. The most consistently identified intrinsic risk factors have been a) sex, b) age, c) history of previous injury, d) adverse health behaviors (e.g., smoking tobacco), e) previous physical activity (e.g., sedentary lifestyle), and f) current level of physical fitness. Sex. Sex has consistently been identified as a risk factor for injury in military BT. In studies from the 1980s to 1997 that examined women and men at the same training site who performed essentially the same physical training, incidences of injuries for women were 1.7-2.2 times higher than those for men (19,20,21,30,32,33 ) (Table 3). In addition, rates of some specific injuries during military training (e.g., stress fractures) are higher for women than men (20,24,30,33,34 ). In Army training, RR for stress fractures is 2-10 times higher for women than men engaged in the same training regimen (20,21,30,(34)(35)(36). In the Marine Corps recruit training, the risk for stress fractures is 3.7 times higher for women than men (20 ). Some specific injuries (e.g., anterior cruciate ligament tears in the knee) occur more frequently in female athletes (37 ). However, in studies comparing civilian runners (the most extensively studied civilian recreational fitness activity), the overall rates of exercise-related injury are similar among women and men. Researchers suggest that female civilian runners have the same injury rates as men because they can modulate their training frequency, duration, and intensity (unlike military trainees) to accommodate their fitness levels and the minor overuse injuries that might occur (10 ). Injury studies among military populations suggest that without controlling for physical fitness, at any fixed level of activity, women will be at greater risk for injury than men (Table 3). Age. Results of military studies regarding the effects of age on training and injuries have been inconsistent. Some studies have revealed that during BT, female (38 ) and male trainees aged >23 years are at greater risk for injury (22,38,39 ). Other military studies have indicated no statistically significant difference in injury risk by age (20,36,40 ). Studies of civilian runners have also had inconsistent results. Some studies have demonstrated that age is not an important risk factor, whereas others have demonstrated that rates of injury decrease with age (10,13,15,16,26 ). Among civilian women, older age was not associated with elevated risk (10 ). Unlike military trainees, older participants in civilian studies might have been able to decrease their risk by modulating the frequency, duration, or intensity of their personal training regimens (10 ). Alternatively, a "survivor effect" might exist, whereby persons who have sustained injury change activities or cease participation and thus are unavailable for inclusion in studies (10 ). Data from military and civilian studies suggest that among adults aged <45 years, age alone is not a strong predictor of injury in exercise. History of Previous Injury. A history of previous musculoskeletal injury has also been reported as a risk factor for injury in both civilian and military studies. In a systematic review of the literature regarding the prevention of ankle sprains in sports, the most commonly identified risk factor for an ankle sprain was a previous ankle sprain (41 ). Overuse injuries occurred twice as frequently in trainees with a previous history of ankle sprain (19 ). A previous ankle sprain is also a risk factor for injuries among male trainees in Army BT (22 ). In addition, data from the Marine Corps suggest that previous injuries pose a risk for future injury (20,40 ). These findings are consistent with civilian studies of female and male distance runners, in which RR for an injury in a person who has had an injury during the preceding year was 1.8-2.4 for women and 1.7-2.7 for men (15,26 ). Health-Related Behaviors. Health behaviors engaged in before entry into military service (e.g., smoking tobacco and participating in regular physical activity) can influence a woman's injury risk during BT. Smoking. Both female and male smokers who participate in Army or Marine Corps BT are at a significantly higher risk for injury than nonsmokers (20 ). Women who were smokers on entry into the Army were 25% more likely to be injured in BT; injury rates were 77% for smokers and 62% for nonsmokers (20 ). Similarly, the risk for injury among women in the Marine Corps who smoked before beginning BT was 1.7 times higher than for those who were nonsmokers (20 ). Male smokers in Army and Marine Corps BT were 1.9 times and 2.3 times more likely to have an injury, respectively, than their nonsmoking male counterparts (20,22 ). Studies have not indicated whether civilian athletes or exercise participants who smoke tobacco are at greater risk for injury. However, in a literature review of the potential association between smoking and injuries, researchers estimated that smokers were two times more likely than nonsmokers to sustain unintentional injuries in the workplace, although some of these injuries might not be related to physical activity (42 ). Data from these studies suggest that women who smoke are at a higher risk for training-related injuries than women who do not smoke. Previous Physical Activity. Although some health behaviors (e.g., smoking) might increase injury risk, previous regular physical activity might be protective against injury. This protective effect has been documented in men in the Army and Marine Corps (20)(21)(22)32,39 ). Among male trainees in the Army, running before entry into the service might be protective. For military women, the association between previous regular physi-cal activity and injury risk has not been documented (20,32,36 ). Researchers documented that, for men, more years of participating in running was protective against injury; however, for women, more years of participating in running might be associated with higher risk for injury (15 ). These results are difficult to interpret because of possible survivor effects (e.g., injured runners cease to run). Because no comparable data in civilian populations of women exist, no conclusions can be drawn regarding the influence of previous regular physical activity as a protective factor against injury among women. Further research is needed regarding the influence of previous physical activities and exercise-related injury risk among women and men in both military and civilian populations. Current Level of Physical Fitness. A person's current level of physical fitness has been one of the most important predictors of injury in military studies (19)(20)(21)24,32,33,40 ). Of the five health-related components, low levels of aerobic fitness and, to a lesser extent, low muscular endurance have consistently been associated with injury risk during BT. Other factors (e.g., body composition and strength) demonstrated weaker and less consistent associations with injury risk. Aerobic fitness, as measured by timed performance of 1-to 2-mile runs during Army or Marine Corps physical fitness entry tests, has been the single most consistently and strongly associated intrinsic risk factor for subsequent training-related injury. During Army BT, women who scored in the slowest quartile on the initial entry physical fitness test experienced 1.5-1.7 times greater injury risk than women in the fastest quartile (21,36 ) (Table 4). Findings were similar for women in Marine Corps BT: women in the slowest quartile experienced 2.4 times greater risk for injury than women in the fastest quartile. Women and men with the slowest run times (i.e., least aerobically fit) were consistently at greater risk for injury than those with the fastest run times (i.e., most aerobically fit). Comparable trends were documented among female Army cadets at West Point Academy, New York (24 ). Among men, the inverse relation of aerobic fitness and injury risk is similar to that of women. Male trainees with slower run times were at greater risk for injury than those who ran the fastest (20,36 ). In addition to being at greater risk for injury, women who had the slowest run times experienced 2.5 times the risk of stress fractures and stress reactions compared with women who had faster run times (20,32 ). Similar findings were documented among women in Marine Corps BT (20,40 ). Researchers demonstrated that the least aerobically fit and least physically active trainees were 3.5 times more likely than persons who were the most fit and most active to sustain a stress fracture (23 ). A prospective study of Army trainees in BT demonstrated an association between maximal oxygen consumption (ml O 2 per kg body weight per minute), which is a measure of aerobic fitness, and subsequent risk for injury. Maximal oxygen consumption (VO 2 max) was measured in trainees running on a treadmill before the start of BT. For women in successive tertiles of VO 2 max, risk for injury increased from 39% in the highest tertile to 50% in the middle tertile, to 55% in the lowest. Similarly, men with the lowest VO 2 max were at greatest risk for injury (36). Prospective studies among civilians examining the association between aerobic fitness and injury are not available. Military research suggests that higher levels of baseline physical fitness is protective, at least at the start of a training program. Further research is needed to determine the degree and duration of this protection. # MMWR March 31, 2000 Higher levels of muscular endurance and strength can also be protective against injury in military BT. For both women and men, greater muscular endurance (measured by the number of push-ups completed in 2 minutes) was associated with fewer training-related injuries (20 ). When categorized into quartiles, risk for injury decreased for women who could do more push-ups. The cumulative incidence of injury was 57% for women who completed the least number of push-ups in 2 minutes and 38% for women who did the most push-ups. Similarly, Army women who could not lift >34 kg had RR for injury of 1.4 compared with women who could lift >46 kg (20 ). The relation of body composition to exercise-related injury risk is complex. Some studies indicate no association between body composition and exercise-related injury risk (20,36 ). When an association between measures of body fat and injury incidence for women in Army BT has been identified, the relation has been bimodal (U-shaped). Women with the least and the most body fat were at greater risk for injury (21,32,40 ). Among women in Army BT, the risk for injury varies by body mass index (BMI). To obtain BMI, weight in kilograms is divided by height in meters squared (weight / ). The cumulative incidence of injuries in successive quartiles of increasing BMI were 56% (lowest quartile), 46%, 38%, and 63% (highest quartile). The corresponding RRs were 1.5, 1.2, 1.0, and 1.6, respectively. BMI for women ranged from 18 kg/m 2 to 27 kg/m 2 (32 ). A study of civilian male distance runners demonstrated a statistically significant bimodal relation between BMI and injury (16 ). A study of civilian female runners indicated a statistically not significant but also bimodal relation between BMI and injury (15 ). Additional research is needed to better determine the relation # MMWR 27 between body fat, BMI, and incidence of injury; these studies should control for physical fitness and previous physical activity. # The Relation Between Sex and Level of Physical Fitness The observation that low levels of physical fitness on entry into BT is related to injuries during BT is particularly relevant to the issue of injuries among women. The incidence of injuries among women in Army BT is consistently 1.6-2.1 times higher than the incidence for men in Army BT. However, several studies also document that on entry into the Army, women are less physically fit than men (20,21,32,35,43 ). On average, women have slower run times, perform fewer push-ups, and have a higher percentage of body fat than men. What would be the effect of controlling for level of fitness when making comparisons between men and women? In several studies, injury risks were stratified by quartiles or quintiles of run times to enable comparison of groups of women and men who performed similarly on the initial-entry physical training test (20,32,35,43 ). In these studies, initial RRs of injury for women were higher than for men, with RRs ranging from 1.6 to 2.1. However, when stratified by aerobic fitness (run times), the stratumspecific risk ratios all approached 1.0, and the summary risk ratios declined (range = 0.9-1.2). In a logistic regression model that controlled for physical fitness (i.e., run times, numbers of push-ups and sit-ups, and strength), age, and race, the odds ratio for women versus men was 1.1 (20,43 ). Slower run times were the only component of fitness associated with increased odds of injury. Odds of injury progressively increased for successive quintiles of run time from fastest to slowest: 1.0, 1.4, 1.5, 2.5, and 3.2, respectively. In another logistic regression model, female sex was initially a risk factor, with an odds ratio of 2.5 for women compared with men, until run time was entered into the model. When corrected for run times, the odds ratio for females declined to 1.0; however, run time remained a significant predictor (32 ). These findings suggest that the most important underlying risk factor for injuries among military trainees engaged in vigorous aerobic weight-bearing activities (e.g., running and marching) is aerobic fitness level and not female sex (33,43 ). Studies that compare injury risks between men and women with similar fitness levels have not been conducted in civilian populations. Because the findings in this report are derived from studies of special populations (e.g., runners and military trainees), they might not be generalizable to other U.S. populations. A review of the studies in these special populations provides guidance toward establishing general principles that will be valuable in preventing injuries and guiding research in the general population. # RECOMMENDATIONS FOR PREVENTION Scientific research regarding injuries related to physical training and exercise has focused on men rather than women, on military trainees rather than physically active civilians, and on competitive rather than recreational athletes. In addition, the studies of military populations generally involve a young, healthy population. Studies of recreational athletes in the civilian population are difficult to conduct and might not be able to completely control for the frequency, duration, and intensity of activity, as is possible in studies of military populations. In addition, measures of current physical fitness might be difficult to obtain. # MMWR March 31, 2000 Based on the limited scientific research regarding physical activity, exercise, and injuries among women and generally agreed on "best practices," the following recommendations are made to reduce the risk of exercise-related injury among women: - Although most healthy women do not need to visit their physician before starting a moderate-intensity exercise program, women aged >50 years or women who have either a chronic disease or risk factors for a chronic disease should consult their physician to ensure that their exercise program is safe and appropriate. - The choice of an exercise program should be tailored to a woman's current physical fitness level. Resources that include examples of activities categorized by exercise intensity levels are available and can aid women in choosing activities based on their respective physical fitness levels. - Decisions regarding the frequency, duration, and intensity of exercise should be individualized, based on the woman's current level of physical fitness, history of physical activity, and history of injury. - Women, particularly those with lower fitness levels, should begin participating in exercise at a lower level of training (frequency, duration, and intensity) and progress slowly. Women who are sedentary and start a new exercise program or activity might need to begin with intervals of activity as short as 5-10 minutes of light-intensity activity and gradually increase to the desired intensity and/or duration of participation. - Participants should be aware of early signs of potential injury (i.e., increasing muscle soreness, bone and joint pain, excessive fatigue, and performance decrements). Coaches, personal trainers, and instructors should be alert to these signs among the women they are supervising. - When a participant senses any of the warning signs (i.e., increasing muscle soreness, bone and joint pain, excessive fatigue, performance decrements, or current injury), she should incrementally decrease training (i.e., reduce frequency, duration, or intensity) until symptoms diminish or cease participation temporarily, depending on the severity of injury. - Women who sustain a musculoskeletal injury should allow sufficient recovery and rehabilitation time and take precautions to prevent reinjury. - Women who smoke should be informed that smoking might increase their risk for exercise-related injury. They should make every effort to stop smoking, not only to reduce their risk for injury, but also to enhance their long-term overall health. - Women should be realistic in setting their exercise goals by balancing the desire for measurable weight reduction, increases in endurance or strength, or other health-related fitness benefits with the risk for injury. # MMWR 29 RESEARCH AGENDA # Research Needs This report provides an overview of the relation between extrinsic training factors, selected intrinsic factors, and musculoskeletal injury risks during exercise. Some research exists regarding exercise-related injury risk factors among military or elite athletic populations; however, little research has been conducted among other physically active populations. Even less research specifically addresses the particular risks to women who exercise. These gaps in current knowledge limit the specificity with which recommendations can be made. Future research is needed to identify methods of promoting physical activity while preventing or reducing the risk for injury. As researchers continue to define the benefits of regular exercise, the following suggestions might help develop complementary research regarding injury risks: Surveillance systems need to be developed to monitor physical fitness, health, injury, and other medical outcomes of physical activity and exercise. Questions regarding exercise-related injuries need to be incorporated into existing surveillance instruments that monitor physical activity participation levels. Measures of exposure in physical activity (i.e., frequency, duration, and intensity) by sex, age, and activity should be incorporated into data-gathering systems to better characterize population-based injury risks. Research regarding the etiology of exercise-related injuries is needed to determine the incidence of and risk factors for injuries in common exercise activities (e.g., walking, hiking, bicycling, and aerobic dance) and active sports (e.g., tennis, racquetball, basketball, and soccer) for women. Identification of the amount (i.e., frequency, duration, and intensity), type (e.g., jogging, walking, biking, and dancing), and progression of exercise that is appropriate for women of differing physical fitness levels and body composition is needed to maximize fitness while minimizing injury risk. To prevent overuse injuries among women, the appropriate amounts and balance of training and recovery for different types of exercise and activity need to be determined. In addition, sex-specific exercise-related injury risks need to be determined to guide the choices women make regarding exercise. These risks include but are not limited to a) anterior cruciate ligament rupture, b) stress fractures, c) pregnancy and postpartum injury risks, and d) risks (and benefits) of exercise in older women and women with osteoporosis. Conducting longitudinal intervention trials to monitor injury occurrences while measuring changes in fitness is essential for developing and evaluating injury reduction measures. Determination of the long-term effects of exercise-related injuries on health outcomes (e.g., osteoarthritis, late or chronic sequelae, and disability) and future exercise participation is needed because a decrease in physical activity might increase the risk for chronic diseases. Finally, to document the impact of exercise-related injury and the importance of further research, the economic and social costs of exercise-related injury and any resultant nonadherence to exercise regimens need to be determined. # MMWR March 31, 2000 CONCLUSION Persons who participate in vigorous exercise might incur a higher number of musculoskeletal injuries than more sedentary persons. However, several intrinsic and extrinsic factors interact to modify the risk for incurring an exercise-related injury. For activities other than running and military training, little data are available regarding the incidence or risk factors for such injuries. The data suggest that a combination of factors (e.g., sex, current level of fitness, previous exercise experience, smoking, previous injury, and body composition) might affect the risk for exercise-related injury in women. However, how these factors act singly and in combination to influence injury risk is not well understood. The following conclusions might help in the development of further research regarding the relation between exercise and the risk for injury: - The most important risk factors for exercise-or training-related injuries are the frequency, duration, and intensity of the physical training activity. The total amount of exercise (e.g., the frequency, duration, and intensity) is the most consistently identified predictor for injury risk. - Physical fitness is inversely related to injury risk; as physical fitness level increases, risk for injury decreases. Men and women who participate in the same activities and have the same physical fitness levels generally have similar incidences of injury. Thus, physical fitness rather than female sex is the underlying risk factor. - A dose-response relation exists between the amount of weight-bearing exercise performed and the risk of injury for both women and men. - A training threshold exists, above which increased training does not appreciably increase fitness but will substantially increase risk for injury. This threshold might be different for each person. - Although higher current amounts of exercise or physical activity are risk factors for injury because of increased exposure, at any fixed amount of activity, men with a history of higher amounts of physical activity are at lower risk for injury. For women, the relation is unclear. - At any given amount of aerobic weight-bearing activity, women and men who have the highest aerobic fitness levels can be expected to have lower subsequent injury rates. - The combined findings of research regarding the association of training, previous physical activity, and current physical fitness levels suggest that tailoring exercise to accommodate a person's current level of fitness and previous physical activity reduces injury rates. Changes in frequency, duration, or intensity of exercise can have cumulative effects on injury risk. These findings are particularly important for persons who are the least fit or most sedentary because they are at the greatest risk for injury when initiating physical activity. - The protective effect against injury of higher levels of aerobic fitness provides an incentive to become more physically active. It suggests that incremental increases in fitness are beneficial in terms of increasing health benefits and decreasing injury risks. - The relation between previous injuries and higher risk for subsequent exerciserelated injuries provides some indication of the importance of a) recovery and rehabilitation and b) consideration of the history of previous injuries when planning exercise programs. - The association between smoking tobacco and higher exercise-related injury risks suggests another possible reason to discourage smoking, both for injury reduction in the short-term and increased overall health benefits in the longterm. - Although the association of body composition with exercise-related injury risks is not completely clear, the bimodal relation that exists suggests that proper maintenance of body weight in the normal range (i.e., BMI 18.5 kg/m 2 -24.9 kg/m 2 ) is important not only for health and appearance but also to reduce risks for injury. Further research is needed to answer many of the remaining epidemiologic questions and to help develop exercise programs for women that improve health while reducing the risk for injury. # Implementing Recommendations for the Early Detection of Breast and Cervical Cancer Among Low-Income Women Abstract Scope of the Problem: Among U.S. women, breast cancer is the most commonly diagnosed cancer and remains second only to lung cancer as a cause of cancer-related mortality. The American Cancer Society (ACS) estimates that 182,800 new cases of female breast cancer and 41,200 deaths from breast cancer will occur in 2000. Since the 1950s, the incidence of invasive cervical cancer and mortality from this disease have decreased substantially; much of the decline is attributed to widespread use of the Papanicolaou (Pap) test. ACS estimates that 12,800 new cases of invasive cervical cancer will be diagnosed, and 4,600 deaths from this disease will occur in the United States in 2000. Etiologic Factors: The risk for breast cancer increases with advancing age; other risk factors include personal or family history of breast cancer, certain benign breast diseases, early age at menarche, late age at menopause, white race, nulliparity, and higher socioeconomic status. Risk factors for cervical cancer include certain human papilloma virus infections, early age at first intercourse, multiple male sex partners, a history of sexually transmitted diseases, and low socioeconomic status. Black, Hispanic, or American Indian racial/ethnic background is considered a risk factor because cervical cancer detection and death rates are higher among these women. Recommendations for Prevention: Because studies of the etiology of breast cancer have failed to identify feasible primary prevention strategies suitable for use in the general population, reducing mortality from breast cancer through early detection has become a high priority. The potential for reducing death rates from breast cancer is contingent on increasing mammography screening rates and subsequently detecting the disease at an early stage -when more treatment options are available and survival rates are higher. Effective control of cervical cancer depends primarily on early detection of precancerous lesions through use of the Papanicolaou test, followed by timely evaluation and treatment. Thus, the intended outcome of cervical cancer screening differs from that of breast cancer screening. In 1991, the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was implemented to increase breast and cervical cancer screening among uninsured, low-income women. Research Agenda: To support recommended priority activities for NBCCEDP, CDC has developed a research agenda comprising six priorities. These six priorities are a) determining effective strategies to communicate changes in NBCCEDP policy to cancer screening providers and women enrolled in the program; b) identifying effective # INTRODUCTION Although the causes and natural histories of breast and cervical cancer are different, the public health responses to these diseases have been similar. Early detection of breast cancer and primary prevention of cervical cancer are possible through community-based screening programs; however, early detection of both breast and cervical cancer is less common among low-income- women (1 ). This report presents morbidity and mortality data regarding breast and cervical cancer, screening recommendations, an update on the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), and recommended priority activities for NBCCEDP. NBCCEDP is a major public health effort to increase breast and cervical cancer screening among uninsured, low-income women. # SCOPE OF THE PROBLEM Breast Cancer Among women in the United States, breast cancer is the most commonly diagnosed cancer and remains second only to lung cancer as a cause of cancer-related death. The American Cancer Society (ACS) estimates that 182,800 new cases of female breast cancer and 41,200 deaths from breast cancer will occur in 2000 (2 ). In 1996, data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program † indicated that the incidence of breast cancer increased 25.3% during 1973-1996 (Figure 1). Most of the increase occurred during 1973-1991; incidence rates remained stable during 1992-1996. In 1996, the incidence rate for breast cancer was 110.7 cases per 100,000 women, a 29.6% increase since 1980. In addition, in 1996, the case-fatality rate for breast cancer was 24.3 per 100,000 women, a 4.5% decrease since 1992, representing the first sustained decline in breast cancer-related mortality since 1973 (when SEER surveillance for breast cancer began). Although the percentage increases in incidence during 1973-1996 were similar among black and white women, the percentage decrease in mortality during 1992-1996 was substantially greater among white women than black women (3,4 ). Overall during 1992-1996, breast cancer incidence rates were higher among white women (113.1 per 100,000) than black women (100.3), but breast cancer death rates were lower among white women (25.1) than black women (32.0). Furthermore, these race-specific differences in rates varied by age. Among women aged <50 years, the incidence rate for black women (32.7) was higher than that for white women (31.1). Among women aged ³50 years, the rate was higher for white women (365.8) than for black women (308.7). The death rate among women aged <65 years was higher for black women (20.4) than for white women (14.3). Although the death rate among women aged ³65 years was higher for white women than for black women before 1987, recent data indicate that the death rate among this age group is higher for black women (130.9) than for white women (124.0) (4,5 ). On the basis of SEER data for 1988-1992 (most recent data available), incidence rates were highest for white (145.7), Hawaiian (105.6), and black women (95.4) and lowest for Korean (28.5), American Indian (31.6), and Vietnamese (37.5) women. Incidence rates among white, non-Hispanic women were four times higher than among Korean women (3 ). # MMWR March 31, 2000 Stage-specific survival rates among women with breast cancer have increased slightly since the 1970s (6 ). The overall 5-year survival rates for women during 1989-95 were 86% for white women and 71% for black women (4 ). Survival was greatest at the earliest stage of disease. Age-specific survival rates were similar for white and black women. One explanation for the disparity in race-specific survival rates is that white women, on average, seek medical care for tumors at an earlier stage of disease than black women. However, the interim between symptom recognition and medical consultation does not appear to account for these race-specific differences in survival rates or stage at diagnosis of breast cancer (6 ). Limited data are available regarding survival for other ethnic groups in the United States. In a study of stage at diagnosis and tumor histology among white and Asian women, the 5-year survival rate at all stages was higher among Asian women than among white women (7 ). In addition, based on data from another study, the survival rate among Hispanic women is similar to the rate among white women in the United States (8 ). # Cervical Cancer Since the 1950s, the incidence of invasive cervical cancer and mortality from this disease have decreased substantially. In large part, the decline has been attributed to widespread use of the Papanicolaou (Pap) test -a highly effective preventive measure. However, the rate of decline in invasive cervical cancer has slowed since the early 1980s and appears to have stabilized in recent years (Figure 2). ACS projects that approximately 12,800 cases of invasive cervical cancer will be diagnosed and that approxi- (2 ). During 1992-1996, the incidence rate at SEER sites was 7.9 cases per 100,000 women, and the death rate for cervical cancer was 2.8 per 100,000 women (4 ). On the basis of SEER data, both incidence and death rates for cervical cancer vary among racial/ethnic groups. The incidence rate for cervical cancer is highest among Vietnamese women (43.0), and the death rate for cervical cancer is highest among black women (6.7) (3 ). The incidence rate among black women (11.2 per 100,000) is approximately 50% higher than among white women (7.3) (3,4 ). Death rates among black women (5.9) are approximately twice as high as those among white women (2.4). Although the disparities in rates between blacks and whites have declined since 1990, differences in rates persist. This persistent disparity has been attributed to several factors, including differences in the prevalence of risk factors for cervical cancer; differences in screening, diagnostic evaluation, and treatment; and differences in the stage of disease at diagnosis (9 ). Race-specific differences in incidence and death rates for cervical cancer also varied by age (4 ). During 1992-1996, among women aged 40 years than for white women the same age. Regardless of race, most cervical cancer deaths occur among women aged ³50 years (4 ). For women in whom invasive but localized (i.e., Stage I) cervical cancer has been diagnosed, the 5-year relative survival rate is approximately 90% (4 ). In contrast, for women with advanced invasive cervical cancer (beyond the cervix and pelvis ), the 5-year relative survival rate is approximately 12%. As with breast cancer, diagnosis of invasive cervical cancer in black women usually occurs at a later stage of disease compared with white women. Moreover, 5-year relative survival rates for local and regional stages are lower for blacks than for whites. # ETIOLOGIC FACTORS # Breast Cancer The risk for breast cancer increases with advancing age. Other risk factors include personal or family history of breast cancer, history of certain benign breast diseases, early age at menarche, late age at menopause, exposure to ionizing radiation, obesity, white race, nulliparity, late age at first birth, nodular densities on mammogram, higher socioeconomic status, and residence in urban areas of the northern United States (6,10 ). Less clearly established risk factors include the duration between menstrual periods, use of oral contraceptives, use of replacement hormones (estrogen), height, alcohol consumption, and not breast-feeding. Studies of immigrants to the United States suggest that environmental factors rather than genetic factors are responsible for variations in breast cancer rates among countries. For example, the rate of breast cancer among first-generation Japanese-American women is only slightly higher than the rate among their mothers, but the rate among their daughters is considerably higher (6 ). No primary prevention measures suitable for use in the general population have been established for breast cancer. Preliminary results from clinical trials among highrisk women regarding the use of the drug tamoxifen indicate a 45% decline in incidence from its use (11 ). Although side effects and potential development of other neoplasms are associated with tamoxifen use, other medications in its class might offer even greater benefits in breast cancer treatment. The Study of Tamoxifen and Raloxifene (STAR) trial is under way to evaluate tamoxifen versus raloxifene and the potential for reducing the incidence of breast cancer in high-risk postmenopausal women. # Cervical Cancer The risk for cancer of the cervix has been associated with several factors, including infection with certain types of human papilloma virus (HPV), early age at first intercourse, multiple male sex partners, a history of sexually transmitted diseases, smoking, certain nutritional deficiencies, and low socioeconomic status (12 ). HPV is widely accepted as the cause of most squamous cell cervical cancers, and the sexual practices listed are well-established risk factors for the disease; however, the role of other demographic and behavioral factors is less clear. Black, Hispanic, or American Indian race/ ethnicity is considered a risk factor for cervical cancer because rates of detection and death from cervical cancer are higher among these women (13 ). However, some of the racial/ethnic differences in cervical cancer rates can be explained by the strong inverse association between socioeconomic indicators and the risk for invasive cervical cancer (13 ). This increased risk could be associated with differences in access to care and cultural behavior. # RECOMMENDATIONS FOR PREVENTION # Breast Cancer Studies of the etiology of breast cancer have failed to identify feasible primary prevention strategies suitable for use in the general population. Many established risk factors for the disease are neither environmental nor behavioral and, therefore, are not amenable to prevention. Most of the hypothesized behavioral factors are not fully accepted as risk factors and are typically difficult to alter at the individual level. For these reasons, reducing mortality from breast cancer through early detection has become a high priority. The potential for reducing death rates from breast cancer is contingent on increasing initial and repeat mammography screening rates and subsequently detecting the disease at an early stage -when more treatment options are available, and survival rates are higher. Mammography is the most effective method of detecting breast cancer in its earliest and most treatable stage (14 ). Mammography is a low-dose X-ray procedure that visualizes the internal structure of the breast to detect cancers too small to be palpated during a clinical breast examination (CBE) performed by a health-care provider. Mammography detects cancer before the woman can palpate the lump herself. Cancers detected at a small size are more likely to be localized (i.e., not spread to regional lymph nodes or distant body sites). The sensitivity of mammography (75%-94%) is higher than comparable values for CBE alone or breast self-examination (14,15 ). The specificity of mammography (i.e., the likelihood that a mammogram will correctly indicate that breast cancer is not present) is also high (83%-98%) (14,15 ). Widespread use of this procedure, alone or with a CBE performed by a trained health-care provider, can reduce overall mortality from breast cancer (14,16 ). Since the 1970s, scientific studies have demonstrated that regular screening mammograms among women aged 50-69 years can reduce mortality from breast cancer by 30% (14,(17)(18)(19). However, evidence is not as conclusive for women aged 40-49 years and ³70 years (14 ). The ability of mammography to identify breast cancer at an early stage improves the opportunity for effective treatment and survival. Women in whom localized/Stage I disease has been diagnosed have a 5-year relative survival rate of 94% (4 ). In comparison, women with disease spread beyond regional lymph nodes have a 5-year relative survival rate of only 18.2%. Treatment at this late stage is substantially less effective, as well as more debilitating. # Breast Cancer Screening Guidelines Recommended by Various Groups Annual breast cancer screening for women aged ³50 years is widely recommended. In addition, screening is recommended for women aged 40-49 years; however, consensus has not been reached regarding the effectiveness of screening or the optimal interval for screening in this age group (20 ). Several review groups have reached different conclusions about the efficacy of mammography among younger women because of the limitations of studies conducted among women in this age group. These limitations include small sample sizes and limited duration of follow-up after entry into the screening programs (21 ). In 1996, the U.S. Preventive Services Task Force (USPSTF) recommended that women aged 50-69 years receive routine breast cancer screening every 1-2 years using mammography alone or mammography combined with annual CBE (14 ). USPSTF noted that insufficient evidence exists to recommend or not recommend routine mammography or CBE for women aged 40-49 years and ³70 years. Moreover, insufficient evidence exists to recommend CBE alone or teaching breast self-examination. In addition, USPSTF noted that recommendations for mammography among high-risk women aged 40-49 years and among healthy women aged ³70 years might be made on other grounds. In 1997, a National Institutes of Health Consensus Development Conference panel reviewed new data not previously available to USPSTF, which documented mortality benefit from mammography among women aged 40-49 years (22 ). However, the panel concluded that these data did not warrant a universal recommendation for mammography for women aged 40-49 years. As a result, the panel encourages these women to determine for themselves whether to receive mammography on the basis of objective analysis of scientific evidence, individual health history, and perceived risks and benefits (20 ). Because mortality can be reduced among women aged 40-49 years, in 1997 the National Cancer Institute (NCI) accepted new guidelines for mammography screening recommended by the presidentially appointed National Cancer Advisory Board. These guidelines recommend that all women aged ³40 years receive mammography every 1-2 years to achieve the best possible outcome if breast cancer is detected (22 ). # Prevalence of Breast Cancer Screening Data collected through CDC's 1997 Behavioral Risk Factor Surveillance System (BRFSS) indicate that 85% of all interviewed women aged ³40 years had ever received a mammogram (23 ). The percentage of low-income women and women without health insurance who had ever received a mammogram was comparable (77% and 69%, respectively). The percentage of all interviewed women aged ³40 years who had received a mammogram within the preceding 2 years was 71%. Rates for low-income women and women without health insurance were substantially lower (58% and 50%, respectively). A Healthy People 2000 objective is to increase to at least 80% the proportion of women aged ³40 years who have ever received a CBE and a mammogram, and to at least 60% those aged ³50 years who have received them within the preceding 1-2 years (objective 16.11) (24 ). Although 1997 BRFSS data indicate the goal has been attained for all women interviewed aged ³40 years who had ever received a mammogram, progress is still needed to attain the goal for low-income women and women without health insurance. # Cervical Cancer Effective control of cervical cancer depends primarily on early detection of precancerous lesions through use of the Pap test, followed by timely evaluation and treatment. The Pap test is probably the most successful screening test ever developed to detect a cancer. Although the efficacy of cervical cancer screening using the Pap test has not been evaluated in clinical trials, at least two factors support the positive impact of this screening test: a) evidence from many observational studies and b) the marked decline in cervical cancer incidence and death rates in the United States and other countries since the introduction of the Pap test >40 years ago (14,25 ). In the United States, approximately 50 million Pap tests are performed annually (26 ). Approximately 10% of these tests indicate an abnormality requiring further testing. Detection and treatment of precancerous cervical intraepithelial neoplasia (CIN) lesions identified by the Pap test can prevent cervical cancer. Thus, the intended outcome of cervical cancer screening differs from breast cancer screening. The primary goal of cervical cancer screening is to detect and treat CIN to prevent the occurrence of invasive cancer. For women in whom CIN lesions have been detected, the likelihood of survival is nearly 100% with appropriate evaluation, treatment, and follow-up. # Cervical Cancer Screening Guidelines Recommended by Various Groups The American College of Obstetricians and Gynecologists (ACOG) and ACS recommend that women have a Pap test and pelvic examination when they become sexually active or at age 18 years, whichever occurs first (13 ). Annual Pap tests are recommended until three consecutive Pap tests are interpreted as being normal. Following this, the two groups recommend that Pap tests can be performed less frequently at the discretion of the provider (13 ). In 1996, USPSTF recommended routine screening for women who are or who have been sexually active and who have a uterine cervix (14 ). The task force recommends Pap tests with the onset of sexual activity and repeated screening every 3 years. A reduced interval between screenings can be recommended by the physician on the basis of a woman's risk factors for cervical cancer. In addition, USPSTF recommends that, on the basis of existing evidence, Pap screening might not be necessary for women after age 65 years. Moreover, USPSTF recommended not performing Pap tests on women who have undergone total hysterectomies for diseases unrelated to cervical cancer or its precursors (14 ). In recent years, several studies have been conducted to determine the value of expanding HPV testing from testing only women with abnormal Pap test results to routinely testing all women to detect those women at greatest risk for developing CIN or invasive cervical cancer. Evidence from these studies does not support routine HPV testing to screen for cervical cancer (26 ). Although new cervical cancer screening technologies have been approved for primary screening, professional organizations have not endorsed their widespread use because of concerns about cost effectiveness. An increasing concern is that rescreening the same women annually will not result in further reductions in cervical cancer mortality (27 ). Increased effort is needed to target groups with large proportions of unscreened or rarely screened women, including women residing in rural areas; minorities; and recent immigrants who have different attitudes, knowledge, and behaviors regarding disease prevention and health promotion. Screening for cervical cancer among these women could further reduce the burden of disease from cervical cancer. # Prevalence of Cervical Cancer Screening The 1997 BRFSS documented that 93% of women aged ³18 years with a uterine cervix reported ever having received a Pap test (23 ). Corresponding values for lowincome and uninsured women were 89% and 85%, respectively. Among all women with a uterine cervix, 80% had obtained a Pap test within the preceding 2 years. For low-income women and uninsured women, the proportion who had obtained a Pap test was substantially lower (69% and 65%, respectively). A Healthy People 2000 objective is to increase to at least 95% the proportion of women aged ³18 years with a uterine cervix who have ever received a Pap test, and to at least 85% those who have received a Pap test within the preceding 1-3 years (objective 16.12) (24 ). Although 1997 BRFSS data indicate the goal for women aged ³18 years with a uterine cervix who reported ever having received a Pap test is near attainment, progress is still needed, as with breast cancer screening, to attain the goal for lowincome women and women without health insurance. Low income and lack of health insurance are barriers to both cervical and breast cancer screening. These factors increase the likelihood that these diseases will be diagnosed at a later stage, when survival rates are lower (1 ). # Implementation of the National Breast and Cervical Cancer Early Detection Program In August 1990, Congress enacted the Breast and Cervical Cancer Mortality Prevention Act, thereby authorizing CDC to establish a national public health infrastructure to increase breast and cervical cancer screening among low-income women who are uninsured (28 ). Consequently, CDC established the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a comprehensive women's health initiative imple-mented through cooperative agreements with qualifying health agencies (including state and territorial health departments and American Indian/Alaska Native tribes and tribal organizations). In addition to providing breast and cervical cancer screening, participating programs provide diagnostic testing, surveillance and follow-up, case management, public education and outreach, professional education and training, quality assurance of screening tests, coalition and partnership development, and program evaluation. NBCCEDP-sponsored programs have initiated outreach efforts to serve women in high priority groups (e.g., women with increased risk for breast or cervical cancer and women who do not or rarely access breast and cervical cancer screening), including older women, racial/ethnic minorities, foreign-born women, women with disabilities, lesbians, and women residing in rural or other hard-to-reach areas. Fiscal year (FY) 2000 marked the 10th year of the NBCCEDP, with Congressional appropriations of $167 million. CDC provides funds to all 50 states, six U.S. territories, the District of Columbia, and 15 American Indian/Alaska Native tribes and tribal organizations to implement comprehensive screening programs for breast and cervical cancer (29 ). During the reporting period July 1991-March 1999, approximately 2.2 million screenings for breast and cervical cancer were provided to uninsured women. The program supported 1,049,752 mammograms: 64% of the mammograms were provided to women aged ³50 years; 48% were provided to racial/ethnic minorities (Figure 3). Breast cancer was diagnosed in 6,265 women aged ³40 years. Although the rate of abnormalities detected by a mammogram was highest for younger women, the rate of breast cancers detected per 100,000 mammograms increased directly with advancing age (Figure 4). A total of 1,192,346 Pap tests were performed: 72% of the tests were provided to women aged ³40 years; 47% were provided to racial/ethnic minorities (Figure 5). Cervical intraepithelial neoplasia was detected in 34,046 women. Invasive cervical cancer was diagnosed in 561 women. The rate of abnormal Pap tests varied inversely with age. # Policy of NBCCEDP As NBCCEDP has evolved, the program has addressed many challenges, especially regarding screening recommendations and treatment resources for women in whom precancerous cervical lesions or cancer of the breast or cervix has been diagnosed through NBCCEDP. FY 2000 Congressional appropriations will enable NBCCEDP to screen approximately 12%-15% of the eligible uninsured women aged 50-64 years in the United States (30 ). The remaining unmet need and the absence of funding to cover treatment expenses for women who have received a diagnosis of precancerous cervical lesions or breast or cervical cancer have been persistent challenges to the program. A key public health priority of NBCCEDP is to direct program resources to eligible women who have rarely or have never received breast or cervical cancer screening. To address this priority and maximize efficient use of limited resources, the program has developed cancercontrol policies on the basis of programmatic data, current scientific research, and availability of screening services through other government-supported programs (e.g., Medicare and Title X Family Planning programs). # Breast Cancer Screening Policies Following implementation of NBCCEDP in 1991, CDC encouraged NBCCEDPsponsored programs to place a high priority on screening women aged ³50 years. NBCCEDP data indicated that only 57% of their mammograms were provided to women aged ³50 years. In October 1994, CDC established the first age-specific targets for the breast cancer screening component of NBCCEDP. For 1995, 75% of the mammograms were to be provided to women aged ³50 years. The percentage was gradually increased to 90% by October 1998. A review of NBCCEDP mammography screening data in 12month intervals indicated that, since 1994, programs had screened increasing numbers of women aged ³50 years for breast cancer; however, the age-specific percentage goals had not been attained. For example, the percentage of initial mammograms provided to women aged ³50 years for the reporting period October 1996-September 1997 was 74%. In 1998, NBCCEDP mammogram screening policy was revised in response to new scientific research, recent changes in recommendations by NCI and ACS, changes in Medicare preventive services coverage, and the need to establish a more realistic national target based on historical programmatic screening data. The new NBCCEDP policy is to provide at least 75% of mammograms to women aged ³50 years who are not eligible to receive Medicare Part B benefits or are unable to pay the premium to enroll in Medicare Part B. Correspondingly, no more than 25% of mammograms should be provided to women aged <50 years. As a result of this new policy, some participating health agencies have developed strategies to cover breast cancer screening for women aged 40-49 years. Several programs have obtained breast cancer screening resources for these women from state appropriations or tobacco tax revenues and through collaborative efforts with foundations (e.g., the Susan G. Komen Breast Cancer Foundation). During October 1997-September 1998, 75% of NBCCEDP-sponsored mammograms were provided to women aged ³50 years. # Cervical Cancer Screening Policies The primary purpose of the cervical cancer component of NBCCEDP is to identify and treat precancerous cervical lesions and to detect and treat invasive cervical cancer at an early stage. When the program was established in 1991, CDC implemented program guidelines for cervical cancer screening that were consistent with ACS guidelines. Women enrolled in NBCCEDP who were aged ³18 years, with an intact uterine cervix, were eligible for an annual Pap test and pelvic examination. After a woman has had three consecutive annual examinations with normal findings, Pap tests could be performed less frequently at the discretion of the woman and her health-care provider. In 1999, CDC, in consultation with an external work group comprising clinical experts, epidemiologists, and public health practitioners, reexamined NBCCEDP's cervical cancer screening policy and other emerging issues related to Pap testing. One of the key issues addressed by this work group was recommendations for Pap screening intervals. ACOG's and ACS's recommendations regarding the frequency of screening are similar and advise that after a woman has had three consecutive annual examinations with normal findings, the Pap test can be performed less frequently at the discretion of the woman's provider. Scientific data suggest that once a woman has demonstrated no signs of CIN, as evidenced by three consecutive annual Pap tests with normal findings, her chance of developing CIN II or worse within a 3-year period is extremely low, regardless of other risk factors (31 ). Preliminary analysis of NBCCEDP data supports these findings (CDC, unpublished data, 2000). Beginning in March 2000, NBCCEDP-sponsored programs will be required to direct more cervical cancer screening resources to women who have never had a Pap test or who have not had a Pap test for at least 5 years. Among all women screened, at least 20% should be women who have either never been screened or have rarely been screened (i.e., not screened for ³5 years). Programs are also being required to reduce over-screening among program-enrolled women. Beginning in October 2001, programs will be required to document that at least 75% of women with three consecutive annual Pap tests with normal findings did not receive a fourth annual Pap test. Their screening interval will be changed to every 3 years. To successfully implement this policy change, CDC will assist NBCCEDP-sponsored programs in assessing current program provider practices, modifying patient recall systems, and developing professional and public education strategies. # Breast and Cervical Cancer Follow-Up and Treatment Policy The policy issue that has caused the greatest controversy in NBCCEDP concerns the availability of funds to pay for treatment of cancerous or precancerous lesions diagnosed in enrolled women (28 ). A crucial component of NBCCEDP is to ensure that all women with abnormal screening results, precancerous breast or cervical lesions, or a diagnosis of cancer receive timely and appropriate follow-up care. Program providers receive reimbursement for most diagnostic procedures, including diagnostic mammography, breast ultrasound, fine-needle aspiration of the breast, breast and cervical biopsies, and colposcopy of the cervix. However, the Breast and Cervical Cancer Mortality Prevention Act of 1990 prohibits use of federal program funds for any component of breast or cervical cancer treatment primarily because of a concern that such payment would rapidly deplete resources available for screening services. NBCCEDP-sponsored programs are required to identify and secure resources for treatment from other sources. # MMWR March 31, 2000 In 1996, CDC conducted in-depth case studies of seven state programs to determine how early detection programs identified and obtained resources for treatment. The results indicated that state health agencies and their partners had developed a wide range of strategies for procuring treatment services in the absence of program resources. However, the study respondents considered the strategies used to obtain these services as short-term solutions that were labor intensive and that diverted resources away from screening activities (32 ). NBCCEDP surveillance data for October 1991-September 1998 indicate that 92% of the clients in whom breast cancer had been diagnosed and 93% of the clients in whom invasive cervical cancer had been diagnosed initiated treatment. The remainder either refused treatment, were lost to follow-up, or had an outcome pending. In FY 1999, CDC received increased Congressional appropriations to expand case-management activities to assist women in overcoming financial, logistical, and other barriers to obtaining these services. # Recommended Priority Activities for CDC The Breast and Cervical Cancer Mortality Prevention Act of 1990 has played an important role in focusing public health efforts on cancer control in the United States. Since 1991, CDC has collaborated with a diverse group of public and private partners to build the public health infrastructure, implement screening services, and conduct research activities. CDC will continue to foster these relationships to achieve goals set in the following four priority areas of screening initiatives, case-management services, professional education and training, and partnerships: # Screening Initiatives - Collaborate with NBCCEDP-sponsored programs to increase public education and outreach strategies to reach women who have rarely or have never received breast or cervical cancer screening. - Collaborate with NBCCEDP-sponsored programs to implement strategies among health-care providers to address missed opportunities for enrolling women into screening. - Collaborate with NBCCEDP-sponsored programs to implement strategies through professional groups and public education to modify screening intervals for all program-enrolled women who have had three consecutive annual Pap tests with normal findings. - Continue to promote the need for routine rescreening for breast and cervical cancer at regular intervals to improve rescreening rates for women enrolled in NBCCEDP. # Case-Management Services - Expand case-management activities to ensure that women enrolled in NBCCEDP receive timely and appropriate rescreening and diagnostic services and treatment services, if indicated. - Increase case-management activities to sustain networks and partnerships to maximize access to and availability of diagnostic, treatment, and essential support services for women enrolled in NBCCEDP. efforts should be, and what proportion of screening resources should be allocated to case-management activities. - Priority: Conduct economic analyses to determine costs of providing screening services in NBCCEDP. Because the funds appropriated by Congress to NBCCEDP are not adequate to screen all eligible women who need breast and cervical cancer screening, economic analyses are necessary to enhance efficient use of the available resources. Important issues include the potential cost advantages of high-volume versus low-volume laboratories and mammography facilities, the sustainability of facilities that are providing program-funded screenings below their current cost levels, and the costs and benefits of mammography vans compared with standard facilities. # CONCLUSION Breast and cervical cancer continue to be major health problems in the United States. Preventive measures are available to reduce morbidity and mortality associated with these diseases. The NBCCEDP, through federal, state, territorial, and tribal governments, in collaboration with national and community-based organizations, has increased access to breast and cervical cancer screening among low-income and uninsured women. In addition, NBCCEDP-sponsored programs have increased the staff working in cancer control and the expertise of these persons, implemented professional education programs for health-care providers, and developed innovative public education and outreach strategies to encourage medically underserved women to seek screening services. This national effort enabled the United States to make substantial progress toward achieving the Healthy People 2000 objectives for breast and cervical cancer control, particularly among racial/ethnic minorities and the medically underserved. However, NBCCEDP still reaches only 12%-15% of uninsured women aged 50-64 years who are eligible for screening services. A continuing challenge for the future is to increase national commitment to providing screening services for all eligible uninsured women to ultimately reduce morbidity and mortality from breast and cervical cancer. # INTRODUCTION Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. In the United States, an estimated 23% of adolescents and adults have laboratory evidence of infection with T. gondii (1;CDC, unpublished data, 1994). Although these infections are usually either asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, and lymphadenopathy), infection in immunosuppressed persons (e.g., persons with acquired immunodeficiency syndrome ) can be severe. In addition, infections in pregnant women can cause serious health problems in the fetus if the parasites are transmitted (i.e., congenital toxoplasmosis) and cause severe sequelae in the infant (e.g., mental retardation, blindness, and epilepsy). Although congenital toxoplasmosis is not a nationally reportable disease and no national data are available regarding its occurrence, extrapolation from regional studies indicates that an estimated 400-4,000 cases occur in the United States each year. In addition, of the 750 deaths attributed to toxoplasmosis each year, 375 (50%) are believed to be foodborne, making toxoplasmosis the third leading cause of foodborne deaths in this country (2 ). In 1997, the U.S. Department of Health and Human Services, the U.S. Department of Agriculture (USDA), and the U.S. Environmental Protection Agency (EPA) collaborated to develop the National Food Safety Initiative (3 ). The project aims to reduce the incidence of foodborne illness by enhancing surveillance, improving risk assessment, developing new research methods, and furthering food-safety education. Because congenital toxoplasmosis poses a substantial public health problem, CDC has developed prevention recommendations to reduce the risk for congenital infections. In September 1998, CDC convened the National Workshop on Toxoplasmosis: Preventing Congenital Toxoplasmosis (NWTPCT) in Atlanta, Georgia, to discuss research priorities for preventing the disease. Approximately 30 international and national experts in toxoplasmosis participated, representing universities, practitioner associations, research institutions, health-care centers, and other federal agencies. Specific objectives of NWTPCT included defining approaches for reducing the prevalence of congenital toxoplasmosis, determining the data needed to evaluate and implement these strategies, and identifying critical research and prevention efforts for the future. This report summarizes the recommendations from this workshop and the activities that have been undertaken by CDC in response to these recommendations.* # SCOPE OF THE PROBLEM # Burden of Toxoplasmosis in the United States Toxoplasmosis is not a nationally reportable disease in the United States, and no reliable data are available at the national level about the number of cases diagnosed each year. The most reliable information about the burden of toxoplasmosis in the general population is derived from serosurveys, which determine the percentage of persons with elevated levels of Toxoplasma-specific IgG antibodies. Since the 1960s, rates of infection with Toxoplasma in the United States appear to be declining. In the 1960s, a study of U.S. military recruits indicated that the overall seroprevalence of Toxoplasma was 14% (5 ). In 1989, a second study of military recruits indicated a seroprevalence of 9.6% (6 ). Similar downward trends have been observed in France and Sweden (7,8 ). The most reliable estimate of Toxoplasma seroprevalence in the United States is derived from the third National Health and Nutrition Examination Survey (NHANES III) (1 ), which was conducted during 1988-1994. The survey design was a cluster sample of U.S. residents. Serum samples from 17,658 persons were tested at CDC for Toxoplasmaspecific IgG antibodies; 23% were positive. Of 5,988 women of childbearing age (i.e., age 12-49 years), 14% were seropositive (CDC, unpublished data, 1994). No recent U.S. studies of a large population of pregnant women have been conducted to determine the incidence of new infections during pregnancy. Although serosurveys of the general population help define temporal trends in Toxoplasma seropositivity rates and can be used to estimate the number of women of childbearing age who are at risk for acquiring Toxoplasma infections and potentially transmitting it to their fetuses, serosurveys are less helpful in estimating the number of cases of congenital toxoplasmosis. Three prospective studies provide useful information regarding the number of congenital toxoplasmosis cases in the United States. Two prospective studies in the 1970s both reported rates of congenital toxoplasmosis of approximately 10 per 10,000 live births. In one study in the early 1970s, 7,500 consecutive live births at a hospital in Birmingham, Alabama, were screened for Toxoplasma infection; of these, 10 (13 per 10,000 live births) were seropositive (9 ). In a study of acute Toxoplasma infection in 4,048 pregnant women in New York during 1967-1969, six (0.2%) women seroconverted during their pregnancies, and 17 others (0.4%) had at least an eightfold rise in antibody titers during pregnancy (10 ). Of the 23 infants born to these 23 women, three had congenital toxoplasmosis, representing an infection rate of 7 per 10,000 live births in the study population. More recent data regarding the rate of congenital toxoplasmosis are available from the New England Regional Newborn Screening Program (11 ). All infants born in the catchment area of this program are tested for evidence of congenital toxoplasmosis; infected infants undergo clinical evaluation and treatment for 1 year. During 1986-1992, of 635,000 infants who underwent serologic testing, 52 were infected, representing an infection rate of approximately 1 per 10,000 live births. Only two (4%) of these infants were recognized to have congenital toxoplasmosis before the screening results were known; however, follow-up examinations of 19 (40%) of the 48 infants evaluated revealed signs of disease (e.g., abnormal cerebrospinal fluid examinations, hydrocephalus, and retinal lesions). Whether the rates of congenital infection in these three studies are representative of the entire U.S. population is unknown. However, if these rates (i.e., 1 per 10,000 and 10 per 10,000 ) were extrapolated to the approximately 4 million live births in the United States each year, an estimated 400-4,000 infants would be born each year with congenital toxoplasmosis. Limited data are available to assist in estimating the portion of the disease burden of toxoplasmosis attributable to meat consumption. A recent study compared results from a cross-sectional seroprevalence study of Seventh Day Adventists, a religious group that follows a diet containing no meat, with serologic results from a control group of March 31, 2000 volunteers who were not Seventh Day Adventists (12 ). Results from this study documented a significantly lower rate of Toxoplasma infection in Seventh Day Adventists than the control group (24% versus 50%, respectively; p < 0.01). Thus, approximately one half of Toxoplasma exposure might be caused by eating contaminated meat. Furthermore, a statistically significant decrease in risk for infection was observed among nonmeat eaters even after the data were adjusted for age and sex (odds ratio = 0.2; 95% confidence interval = 0.1-0.5). Because this study was originally designed to evaluate the possible association between eating shellfish and Vibrio and Norwalk virus infections, important questions regarding toxoplasmosis (i.e., amount of meat consumed, contact with or ownership of cats, or history of outdoor activity) were not asked in the interview. A report conducted by USDA's Economic Research Service concluded that one half of the toxoplasmosis cases in the United States are caused by eating contaminated meat. The estimated economic burden of these infections is $7.7 billion each year, primarily from congenital toxoplasmosis (13 ). Pork has been implicated by some authorities as the meat most commonly associated with foodborne toxoplasmosis (14 ). In some areas, market pigs from small producers have had higher rates of Toxoplasma infections than pigs from larger producers (15 ); however, overall rates appear to be declining over time (16 ). In 1992, a large survey in Illinois documented that 3.1% of market pigs had serologic evidence of Toxoplasma infection (16 ). Toxoplasma infection has also been identified in other meats, but their contribution to the burden of disease is believed to be small (14 ). Although Toxoplasma infections are associated either with eating contaminated meat or with ingesting oocysts passed in the feces of cats, no laboratory test exists that can determine the origin of a Toxoplasma infection in a specific person and whether it was associated with foodborne, catborne, or soilborne transmission. Epidemiologic studies of the transmission of toxoplasmosis have been hindered by an inability to determine the origin of isolated infections. # Diagnosis and Treatment Acute toxoplasmosis is rarely diagnosed by detecting the parasite in body fluids, tissue, or secretions; the most common method of diagnosis is based on antibody detection. The presence of elevated levels of Toxoplasma-specific IgG antibodies indicates infection has occurred at some point but does not distinguish between an infection acquired recently and one acquired in the distant past. The presence of a high Toxoplasma-specific IgM antibody titer combined with a high IgG titer probably indicates an acute infection within the previous 3 months. A low-to-medium IgM titer and a high IgG titer might indicate an acute infection 3-6 months previously, but IgM antibodies have been detected as long as 18 months after initial infection (17 ). Determining when Toxoplasma infection occurred in a pregnant woman is particularly important because infection before conception poses no substantial risk for transmission of infection to the fetus; however, infection after conception does pose such risk. In the United States, commercial test kits for Toxoplasma-specific IgG and IgM antibodies are readily available. Some commercial IgM tests have had problems with specificity, resulting in unacceptably high rates of false-positive test results. In 1996, FDA and CDC conducted extensive evaluations of the six most commonly used commercial IgM kits in the United States to determine the extent of the problem with the specificity of these kits. Sensitivity and specificity rates for these six kits ranged from 93.3% to 100.0% and from 77.5% to 99.1%, respectively (18 ). As a result of these findings, in 1997 FDA distributed an advisory to physicians in the United States highlighting these test limitations. The agency provided a guide for interpreting test results and issued a recommendation to laboratory personnel and physicians advising them to be aware of the problems associated with the test kits before making decisions about the clinical management of their patients. In addition, IgM-positive results should be confirmed by a Toxoplasma reference laboratory (18 ). Treatment of toxoplasmosis in immunocompetent persons other than pregnant women is generally not indicated unless symptoms are severe or persistent (19)(20)(21). In immunocompromised persons, treatment usually consists of pyrimethamine and sulfadiazine. Depending on gestational age and whether the fetus is known to be infected, pregnant women have been treated with the antibiotic spiramycin or with sulfadiazine alone or the combination of pyrimethamine and sulfadiazine. Treatment of acute infection during pregnancy has been associated with an approximately 50% reduction in fetal infection (22 ). # ETIOLOGIC FACTORS T. gondii has a complex life cycle consisting of three stages: a) tachyzoite -during the acute stage of infection, this form of the parasite invades and replicates within cells; b) bradyzoite -during latent infections, this form of the parasite is present in tissue cysts; and c) sporozoite -this form of the parasite is found in oocysts, which are environmentally resistant. Members of the family Felidae (including domestic and feral cats) are the definitive hosts of Toxoplasma. During acute infections, cats excrete unsporulated (i.e., uninfectious) oocysts in their feces; after several days to several weeks, depending on environmental conditions, the oocysts sporulate and become infectious. Under favorable conditions (i.e., in warm, moist soil), oocysts can remain infectious for approximately 1 year. They do not survive in arid, cool climates and can be destroyed by heating (17,19,20,23,24 ). Toxoplasmosis can be transmitted to humans by three principal routes. First, humans can eat raw or inadequately cooked infected meat or eat uncooked foods that have come in contact with contaminated meat. Second, humans can inadvertently ingest oocysts that cats have passed in their feces, either in a cat litter box or outdoors in soil (e.g., soil from gardening or unwashed fruits or vegetables). Third, a woman can transmit the infection to her unborn fetus. Women infected with Toxoplasma before conception, with rare exceptions, do not transmit the infection to their fetuses. Women infected with Toxoplasma after conception (i.e., during pregnancy) can transmit the infection across the placenta to their fetuses. Maternal infections early in pregnancy are less likely to be transmitted to the fetus than infections later in pregnancy, but early fetal infections, when they do occur, are more likely than later infections to be severe (25 ). An estimated one half of untreated maternal infections are transmitted to the fetus. The classic triad of signs suggestive of congenital toxoplasmosis include chorioretinitis, intracranial calcifications, and hydrocephalus. However, most infants infected in utero are born with no obvious signs of toxoplasmosis on routine examination, but many develop learning and visual disabilities later in life (26,27 ). If untreated, congenital toxoplasmosis can be associated with severe and even fatal disease (28 ). The severity of Toxoplasma infections is correlated with the immune status of the infected person. Toxoplasmosis in immunocompetent adolescents or adults is generally mild or unapparent. Mild infections can result in lymphadenopathy, fever, fatigue, and malaise, all of which usually resolve within weeks to months without specific treatment. However, infection in immunocompromised persons can be severe. Immunosuppression caused by AIDS or therapies for malignancies, transplants, or lymphoproliferative disorders can result in reactivation of preexisting latent Toxoplasma infections. Reactivation most often involves the central nervous system, and symptoms can include meningoencephalitis or symptoms of a mass lesion. # RECOMMENDATIONS FOR PREVENTION - To prevent toxoplasmosis and other foodborne illnesses, food should be cooked to safe temperatures. A food thermometer should be used to measure the internal temperature of cooked meat to ensure that meat is cooked all the way through. Beef, lamb, and veal roasts and steaks should be cooked to at least 145 F, and pork, ground meat, and wild game should be cooked to 160 F before eating. Whole poultry should be cooked to 180 F in the thigh to ensure doneness. - Fruits and vegetables should be peeled or thoroughly washed before eating. - Cutting boards, dishes, counters, utensils, and hands should always be washed with hot soapy water after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables. - Pregnant women should wear gloves when gardening and during any contact with soil or sand because cat waste might be in soil or sand. After gardening or contact with soil or sand, wash hands thoroughly. - Health education for women of childbearing age should include information about meat-related and soilborne toxoplasmosis prevention. Health-care providers should educate pregnant women at their first prenatal visit about food hygiene and prevention of exposure to cat feces. - Health-care providers who care for pregnant women should be educated about two potential problems associated with Toxoplasma serology tests. First, no assay exists that can determine precisely when initial Toxoplasma infection occurred. Second, in populations with a low incidence of Toxoplasma infection, such as in the United States, a substantial proportion of the positive IgM test results will probably be false positive. - The government and the meat industry should continue efforts to reduce Toxoplasma in meat. # RESEARCH AGENDA NWTPCT Recommendations for Research Experts who participated in NWTPCT considered several issues regarding prevention of this disease. These issues included the need to improve estimates of the burden of toxoplasmosis and immunodiagnostics for the disease and to determine the applicability of national toxoplasmosis screening for newborns. Participants discussed current knowledge about these issues, gaps in current knowledge, and needs for future research. # Improving Estimates of the Burden of Toxoplasmosis In their recommendations, NWTPCT participants emphasized the importance of obtaining more complete and accurate data regarding the incidence of new infections and the number of cases by mode of transmission. Participants recommended that CDC obtain population-based data regarding the incidence of and risk factors for toxoplasmosis. In addition, participants recommended the use of existing private data systems (e.g., those of health-maintenance organizations and managed-care systems) for surveillance and research, and development of techniques that would enable tracing the source of individual infections to foodborne, catborne, or soilborne transmission. # Improving Immunodiagnostics for Toxoplasma NWTPCT participants recommended that additional efforts were needed to develop more accurate screening diagnostic tests and improved confirmatory tests. NWTPCT participants also emphasized that resources should be identified to increase current capacity to provide reference diagnostic services in the United States. # Determining the Applicability of National Toxoplasmosis Screening for Newborns Research is under way to determine the need for national toxoplasmosis screening of newborn infants in the United States (See Exhibit). NWTPCT participants identified the need for cost-effectiveness studies to enable comparison of the benefits of expanded testing in the United States and the costs of such testing. # CDC Priorities The Food Safety Initiative has enabled CDC to increase support for activities related to prevention of toxoplasmosis, with a special emphasis on preventing congenital toxoplasmosis. The NWTPCT has helped CDC to identify high-priority activities and to form important partnerships with other groups with similar goals. CDC is engaged in several activities to improve the ability to measure the burden of toxoplasmosis in the United States and to provide a baseline against which the impact of future prevention efforts can be measured. Epidemiologic staff are analyzing Toxoplasma IgG seroprevalence in samples collected in the nationally representative NHANES III (1 ) and preparing a document to disseminate the results. Plans are under way to conduct serologic testing of samples obtained as part of NHANES 2000 to evaluate trends in the prevalence of Toxoplasma infection and to assess the occurrence of acuteToxoplasma infections. In addition, CDC staff will examine national hospital discharge data and national death certificate data to monitor the annual number of cases of and deaths caused by toxoplasmosis, the proportion of toxoplasmosis associated with congenital infection, and the proportion associated with HIV infection. Other possible activities include a) examination of surveillance data (obtained from both educational and medical records) for multiple developmental disabilities (e.g., mental retardation, cerebral palsy, and hearing and vision impairment) and evidence of positive Toxoplasma tests and b) the designation by state health departments of congenital toxoplasmosis as a reportable infection. CDC is supporting a cost-effectiveness analysis of the New England Newborn Screening Program to provide background information for states considering newborn toxoplasmosis screening and reporting. One state has already received funding from CDC through the Emerging Infections Program and has begun toxoplasmosis-related activities. Minnesota is conducting active surveillance for toxoplasmosis using laboratories, ophthalmologists, infection-control practitioners, and other clinicians. CDC is conducting research on the genetic variation of Toxoplasma to develop tools that would enable molecular epidemiologic studies (e.g., to determine whether different strains have different characteristics and are more infectious or pathogenic for humans). The results of this research might help investigators describe the source and spread of Toxoplasma in outbreaks and differentiate between foodborne and cat feces or soilborne Toxoplasma infections. In addition, through FoodNet, CDC is querying laboratories in eight states about their diagnostic practices for toxoplasmosis. To help evaluate the accuracy of future commercial Toxoplasma antibody test kits, CDC created a Toxoplasma serum panel that contains known positive and negative sera. FDA now requires that any new commercial Toxoplasma test kit perform adequately based on results obtained using this panel. The panel is available for purchase through the CDC Technology Transfer Office. The American College of Obstetricians and Gynecologists, with assistance from CDC, is conducting a national survey of obstetricians to assess their knowledge about congenital toxoplasmosis and interpretation of related laboratory tests. The results of the survey will be used to identify ways to educate health-care providers about diagnosis and clinical management of pregnant women with suspected Toxoplasma infections. To # CONCLUSION Many cases of congenital toxoplasmosis in the United States can be prevented. Specific measures can be taken by women and their health-care providers to decrease the risk for infection during pregnancy and, if primary prevention fails and congenital infection occurs, to reduce the severity of infection in newborns. CDC is involved in efforts to improve measurement of the burden of toxoplasmosis in the United States, evaluate current prevention programs, train health-care providers, and educate women about toxoplasmosis. These efforts should allow CDC and state and local health departments to better monitor and reduce the impact of toxoplasmosis on pregnant women and their newborn infants. # MMWR March 31, 2000 # Exhibit Innovative and ambitious programs to prevent toxoplasmosis have been developed in the United States and in Europe, and the National Workshop on Toxoplasmosis: Preventing Congenital Toxoplasmosis (NWTPCT) provided a forum to compare current efforts. These programs involve three approaches: a) screening pregnant women (or all women of childbearing age) to detect as early as possible Toxoplasma infections (or susceptibility to such infections) that might indicate a risk for congenital infection, b) screening newborns to detect infections in infants as early as possible to enable early initiation of treatment, and c) educating women about preventing infection. # Screening Programs for Pregnant Women France In France, a screening program was implemented in 1976 to detect and treat Toxoplasma infection during pregnancy. The goal of this program is to institute preventive measures for seronegative women and to ensure early diagnosis and treatment of infection acquired during pregnancy. Since the beginning of the program, premarital and prenatal medical examinations for Toxoplasma antibodies have been performed. Premarital examinations are conducted to distinguish previously infected women from women who have not been previously infected. When a previously uninfected woman becomes pregnant, testing is conducted at her first prenatal examination during her first trimester and at six additional examinations conducted monthly during her second and third trimesters. In addition, women are educated about prevention methods during pregnancy (29 ). If these screening tests detect evidence of acute infection during pregnancy, treatment for the woman is initiated with spiramycin. If infection in the fetus is confirmed through fetal blood sampling and amniocentesis, pyrimethamine and sulfadiazine or sulfadoxine is added to the regimen (30)(31)(32). Even though coverage of the French program has been incomplete, the program has been associated with a decline in the incidence of congenital infection, as well as a decline in severe disease detected at birth. The proportion of the decline specifically attributable to the program or to the general decline in Europe in rates of seropositivity is difficult to determine because no unscreened group of women exists for comparison. # Austria Austria implemented a toxoplasmosis screening program in 1975. Nearly all women who become pregnant are serologically screened early in pregnancy and, if found to be negative initially, are tested again during the second and third trimesters. Women with Toxoplasma infections are treated as soon as infection is detected. Although seropositivity rates among pregnant Austrian women have declined from approximately 50.0% during the late 1970s to 36.7% during the early 1990s, the incidence of congenital Toxoplasma infection has declined even more, from 50-70 cases per 10,000 births before the program to 1 per 10,000 births during the early 1990s (33 ). As with the French program, the lack of an unscreened comparison group precludes determining the proportion of the decline attributable to the screening program, and lack of cost figures precludes costeffectiveness analyses. # European Research Network on Congenital Toxoplasmosis The European Research Network on Congenital Toxoplasmosis was established in 1993 and has sponsored several studies regarding public health interventions for congenital toxoplasmosis. Most recently, a multicenter study was conducted to evaluate the effectiveness of toxoplasmosis treatment administered during pregnancy in preventing transmission of maternal infection to the fetus. Pregnant women who visited one of five European university medical centers for prenatal care were screened for Toxoplasma antibodies at their first prenatal visit. Women who were seronegative were retested at least once every trimester in two centers and monthly in the other centers, until the birth of the infant. For women who seroconverted during pregnancy, prenatal antibiotic treatment was started, and their infants were followed for 1 year after birth. Treatment regimens consisted of spiramycin or a combination of pyrimethamine and sulfadiazine. If prenatal infection was confirmed with amniocentesis or cordocentesis, women were treated with pyrimethamine and sulfadiazine or sulfadoxine. Of women who screened positive and did not receive prenatal therapy, transmission from mother to infant occurred in 72% of the mother-infant pairs; of women who received prenatal therapy, transmission occurred in 39% of the mother-infant pairs. In addition, 20% of the untreated mothers gave birth to infants with severe sequelae, and 3.5% of the treated mothers gave birth to infants with severe sequelae. Furthermore, the earlier antibiotics were administered after infection, the less likely sequelae were detected in the infant (34 ). # Finland From January 1988 through June 1989, a cost-benefit analysis of Toxoplasma screening during pregnancy was conducted in a prospective study in Finland. The study compared costs of screening alternatives for primary infections during pregnancy with the costs of no screening. With screening, the annual costs of congenital toxoplasmosis were $95 US per pregnancy; without screening, annual costs were $128 US per pregnancy. Furthermore, screening along with health education was more beneficial than health education alone (35 ). The study findings suggest screening is beneficial in countries with low incidence of congenital toxoplasmosis, such as Finland. The findings of other studies suggest screening programs can also be beneficial in areas with high incidences of congenital toxoplasmosis (30,36,37 ). # NWTPCT's Assessment Although the findings of the European studies suggest Toxoplasma screening programs of women of childbearing age can prevent cases of congenital toxoplasmosis, several concerns could limit support for such programs in the United States. NWTPCT participants identified the need for cost-effectiveness studies to enable comparison of the benefits of expanded testing in the United States, the costs of such testing, and the unintended adverse consequences that might accompany such testing (e.g., inappropriately treating women with false-positive test results). # MMWR March 31, 2000 Screening Programs for Newborns # Denmark During June 1992-August 1996, researchers in Denmark conducted a newborn screening study for toxoplasmosis. The primary goal of this study was to determine the feasibility of screening newborn infants for congenital toxoplasmosis in an area with low prevalence; in Denmark, the seroprevalence of antibodies to Toxoplasma among women during this study was 28% (38,39 ). Approximately 90,000 infants were screened for Toxoplasma-specific IgG antibodies 5-10 days after birth. Infants born to mothers who seroconverted during pregnancy were subsequently examined physically and serologically for 1 year; for those with confirmed congenital infections, treatment was initiated with courses of pyrimethamine and sulfadiazine, alternating with spiramycin (38 ). During 1996, serum levels of Toxoplasma-specific IgM antibodies were also determined. The IgM test conducted within 10 days of birth resulted in a false-positive rate of 0.2 per 1,000 with no false-negatives. Results from this study indicated that a newborn screening program using a Toxoplasma-specific IgM antibody test exclusively could identify approximately 75% of infections in infants born to untreated mothers. In addition, the low rates of false-positives and false-negatives suggested this method would be feasible in large-scale newborn screening programs in areas with low seroprevalence rates of toxoplasmosis. # United States In the United States, the New England Newborn Screening Program tests newborn "filter-paper" specimens from all infants born in Massachusetts and New Hampshire for congenital toxoplasmosis by using a Toxoplasma-specific IgM antibody assay. If IgM antibodies are detected, an extensive clinical evaluation is performed, and a 1-year treatment regimen is initiated with a combination therapy of pyrimethamine and sulfadiazine (11 ). During 1986-1992, a total of 52 of the 635,000 infants screened had confirmed congenital infections; 50 appeared normal on routine neonatal examination and had toxoplasmosis diagnosed through screening alone. After more intensive examination, 19 (40%) of the 48 evaluated infants who appeared normal on routine examination had evidence of retinal or central nervous system disease. Treatment was provided for these infants, and compliance with therapy was observed. After 1 year of treatment, only one (2.2%) of 46 children had a neurologic deficit, and four (10.3%) of 39 had eye lesions that could have developed after birth. The findings of this program demonstrated that screening newborns for congenital toxoplasmosis is feasible in the United States. The laboratory and personnel costs of screening approximately 100,000 infants per year for Toxoplasma infection and following those who were infected totaled $220,000 or approximately $30,000 per infant identified. Costs were relatively low because the system used by the program to collect and process specimens was the same one already used for screening newborns for eight other diseases. On the basis of these preliminary cost estimates, this screening program appears to be a favorable alternative, considering the financial and social costs associated with raising a visually or mentally impaired child (40 ). # MMWR 73 NWTPCT's Assessment NWTPCT participants recognized the benefits of these newborn screening programs and discussed ways to evaluate the New England program to determine the benefit of using it as a model for developing additional programs in other areas of the United States. One specific recommendation was for CDC to support a detailed, costeffectiveness evaluation of the program. # Education Programs for Women The third approach to preventing toxoplasmosis focuses on educating women of childbearing age about minimizing their risk for infection with Toxoplasma. Education interventions assume that increased knowledge results in awareness, which consequently results in changes in risky behavior and declines in infection rates. Messages emphasize the importance of avoiding eating raw or undercooked meat, handling raw meat safely, and washing hands after gardening or changing cat litter boxes (37 ). # Canada A study conducted as part of prenatal classes at Canadian public health agencies evaluated the effect of a 10-minute teaching session on three behaviors: practices associated with cleaning the cat litter box and limiting the cat's diet to cooked food; safe food-handling practices; and handwashing after exposure to cat feces, garden soil, or raw meats. Among women in the classes, behavior improved regarding practices associated with cats; however, behavior regarding food-handling practices remained unchanged. In addition, improvement occurred in handwashing practices but only among professional women (41 ). # Belgium During 1979-1986, a Belgium study assessed the effectiveness of educational sessions held in hospital settings. Baseline data were collected during 1979-1982, when no education measures were in effect. During 1983-1986, education sessions were provided to pregnant women. Although the intervention was associated with a 34% decrease in seroconversion rates, the decrease was not statistically significant (42 ). # NWTPCT's Assessment NWTPCT participants considered education programs to be a potentially powerful intervention because of their low cost and because pregnant women were highly motivated to protect the health of their babies. However, participants emphasized that the impact of educational programs was difficult to evaluate because of the limited number of comparative studies a) conducted with rigorous scientific methodology and b) of sufficient size to enable calculation of the effectiveness of the intervention compared with its cost. # MMWR March 31,2000 The material in this report was prepared for publication by: National # Professional Education and Training - Increase collaboration with professional groups that provide continuing education for their constituents to address breast and cervical cancer control issues in standardized curricula and training. - Continue to advocate for incorporation of breast and cervical cancer education in curricula for health professionals to facilitate a long-term effect on provider practice. # Partnerships - Continue to build partnerships with public health departments, tribes and tribal organizations, national and voluntary organizations, academic centers, and health-care purchasers through the following activities: implementing strategies communitywide to promote awareness and screening practices among all women; replicating and disseminating programmatic approaches that are proven effective in providing screening to priority populations (e.g., racial/ethnic minorities and women residing in rural or other hard-to-reach areas); cosponsoring conferences, workshops, and training related to breast and cervical cancer issues; and advocating for breast and cervical cancer control priorities (e.g., policies and standards) to ensure the quality of mammography and Pap screening delivered by all providers. # RESEARCH AGENDA To support the recommended priority activities for NBCCEDP, CDC has developed a research agenda comprising six priorities. This research will assist in improving cancer screening services provided to women enrolled in NBCCEDP and in developing new methods to recruit eligible women who have rarely or have never received breast or cervical cancer screening. - Priority: Determine effective strategies to communicate changes in NBCCEDP policy to cancer screening providers and women enrolled in the program. Emerging developments in cancer prevention and control occasionally require substantial changes in program policy (e.g., changing from annual to triennial cervical cancer screening among women with three previous normal Pap tests). Changes in program policy might require adapting the practice patterns of providers and modifying the expectations and behaviors of enrolled women. Research is needed to develop and evaluate effective public and provider education and materials for dissemination that will help translate policy changes into practice as rapidly as possible. - Priority: Identify effective strategies to increase the proportion of enrolled women who complete routine breast and cervical cancer rescreening according to NBCCEDP policy. Available data submitted twice a year to CDC by participating programs suggest that many women enrolled in NBCCEDP, regardless of their race/ethnicity, do not complete routine rescreening on schedule. Some research is under way in this area, but more is needed. A multiethnic, multicultural focus group study of the barriers to mammography rescreening among NBCCEDP enrollees in Texas ( 33) resulted in development of an ongoing retrospective cohort investigation among 2,500 randomly selected enrollees in Maryland, New York, Ohio, and Texas. Findings from this research that identify risk factors for failure to rescreen on schedule will be used to develop and test new interventions to increase routine rescreening; however, additional research is needed in this area. - Priority: Identify effective strategies to increase NBCCEDP enrollment among eligible women who have never received breast or cervical cancer screening. Data from the 1997 BRFSS suggest that substantial numbers of age-eligible, lowincome women have never received mammography or Pap smear screening (23 ). To develop effective outreach and enrollment strategies for women who have rarely or have never received cancer screening, participatory research methods that involve unscreened women and members of their communities in all phases of the research process might be particularly valuable. In addition, quantitative research designs might be necessary to test proposed interventions. Research initiatives related to this priority topic must address both missed screening opportunities in diverse provider settings and various cultural, language, and institutional barriers that might influence a woman's willingness to accept free or low-cost cancer screening when offered. - Priority: Evaluate variations in clinical practice patterns among providers of NBCCEDP screening services. Analyses of data submitted every 6 months to CDC by participating programs have identified several practice patterns that differ markedly across these programs. These variations raise concern regarding quality assessment. For example, an analysis of mammography results for 1991-1996 reported through the Breast Imaging Reporting and Data System (BI-RADS ® ) lexicon developed by the American College of Radiology (34 ) documented that the proportion of mammograms coded "probably benign, shortterm follow-up recommended" varied substantially across the state, territorial, and tribal programs (35 ). To understand the reasons for such variations and to develop appropriate provider education materials, where necessary, case studies and record linkage investigations within collaborating programs might be necessary. Such studies must be conducted within participating programs because data submitted to CDC cannot be linked with medical records, pathology laboratory reports, or cancer registries. - Priority: Determine optimal models for providing case-management services to women in NBCCEDP who have an abnormal screening result or a diagnosis of cancer. Without effective case management, some low-income women who need additional cancer testing or treatment will not receive the necessary care or will not receive it as rapidly as possible. Diverse case-management models have been developed for other public health concerns including tuberculosis control, adolescent prenatal care, and human immunodeficiency virus infection/acquired immunodeficiency syndrome. Research is needed to evaluate the applicability of these and other models to low-income, medically uninsured women who need additional cancer testing and treatment. Critical issues include determining how women will be selected for case management, how extensive case-management # ACCREDITATION Continuing Medical Education (CME). CDC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 2.5 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. # Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training and awards 0.2 hour Continuing Education Units (CEUs). # Continuing Nursing Education (CNE). This activity for 2.9 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. # CE-2 # MMWR March 31, 2000 # GOALS AND OBJECTIVES This MMWR provides recommendations and other information to help health professionals improve skills in protecting the health of women. The articles in this MMWR were developed by CDC staff. This MMWR is intended to provide information to guide public health policy development, program management, and clinical care related to women's health. Upon completion of this educational activity, the reader should be able to develop strategies to reduce the risk for hip fractures, develop strategies to reduce the risk for exercise-related trauma, identify disease risk factors and prevention interventions for breast and cervical cancer, and develop strategies to reduce the risk for toxoplasmosis during pregnancy. To receive continuing education credit, please answer all of the following questions. # Detach or photocopy. Vol. 49 / No. RR-2 # MMWR 3 The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (888) 232-3228. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # IU.S. Government Printing Office: 2000-533-2206/08060 Region IV

Healthy eating patterns in childhood and adolescence promote optimal childhood health, growth, and intellectual development; prevent immediate health problems, such as iron deficiency anemia, obesity, eating disorders, and dental caries; and may prevent long-term health problems, such as coronary heart disease, cancer, and stroke. School health programs can help children and adolescents attain full educational potential and good health by providing them with the skills, social support, and environmental reinforcement they need to adopt long-term, healthy eating behaviors. This report summarizes strategies most likely to be effective in promoting healthy eating among school-age youths and provides nutrition education guidelines for a comprehensive school health program. These guidelines are based on a review of research, theory, and current practice, and they were developed by CDC in collaboration with experts from universities and from national, federal, and voluntary agencies. The guidelines include recommendations on seven aspects of a school-based program to promote healthy eating: school policy on nutrition, a sequential, coordinated curriculum, appropriate instruction for students, integration of school food service and nutrition education, staff training, family and community involvement, and program evaluation.# INTRODUCTION School-based programs can play an important role in promoting lifelong healthy eating. Because dietary factors "contribute substantially to the burden of preventable illness and premature death in the United States," the national health promotion and disease prevention objectives encourage schools to provide nutrition education from preschool through 12th grade (1 ). The U.S. Department of Agriculture's (USDA) Nutrition Education and Training (NET) Program urges "nutrition education be a major educational component of all child nutrition programs and offered in all schools, child care facilities, and summer sites" by the year 2000 (2 ). Because diet influences the potential for learning as well as health, an objective of the first national education goal is that children "receive the nutrition and health care needed to arrive at school with healthy minds and bodies" (3 ). The recommendations in this report are intended to help personnel and policymakers at the school, district, state, and national levels meet the national health objectives and education goals by implementing school-based nutrition education policies and programs. This report may also be useful to students, to parents, and to personnel in local and state health departments, community-based health and nutrition programs, pediatric clinics, and training institutions for teachers and public health professionals. These recommendations complement CDC guidelines for school health programs to prevent the spread of acquired immunodeficiency syndrome (AIDS) (4 ), to prevent tobacco use and addiction (5 ), and to promote physical activity (6 ). In this report, nutrition education refers to a broad range of activities that promote healthy eating behaviors. The nutrition education guidelines focus largely on classroom instruction, but they are relevant to all components of a comprehensive school health program-health education; a healthy environment; health services; counseling, psychological, and social services; integrated school and community efforts; physical education; nutrition services; and school-based health promotion for faculty and staff (7 ). Although the meals served by school food service programs are an important part of a school health program, this report does not provide specific recommendations related to purchasing and preparing food for school meals. Detailed information on this topic is available from many other publications (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and information sources (see Appendix A). These guidelines also do not address the specific nutrition education and counseling needs of pregnant adolescents (20,21 ) or young persons with special needs (22)(23)(24)(25)(26)(27)(28). These guidelines are based on a synthesis of research, theory, and current practice and are consistent with the principles of the national health education standards (29 ), the opportunity-to-learn standards for health education (29 ), the position papers of leading voluntary organizations involved in child nutrition (30 ), and the national action plan to improve the American diet (31 ). To develop these guidelines, CDC convened meetings of experts in nutrition education, reviewed published research, considered the recommendations of national policy documents (1,(32)(33)(34)(35), and consulted with experts from national, federal, and voluntary organizations. # EFFECTS OF DIET ON THE HEALTH, GROWTH, AND INTELLECTUAL DEVELOPMENT OF YOUNG PERSONS School-based nutrition education can improve dietary practices that affect young persons' health, growth, and intellectual development. Immediate effects of unhealthy eating patterns include undernutrition, iron deficiency anemia, and overweight and obesity. # Undernutrition Even moderate undernutrition can have lasting effects on children's cognitive development and school performance (36 ). Chronically undernourished children attain lower scores on standardized achievement tests, especially tests of language ability (37 ). When children are hungry or undernourished, they have difficulty resisting infection and therefore are more likely than other children to become sick, to miss school, and to fall behind in class (36,37 ); they are irritable and have difficulty concentrating, which can interfere with learning (38 ); and they have low energy, which can limit their physical activity (38 ). Some reports have estimated that millions of children in the United States experience hunger over the course of a year (39 ), but no scientific consensus currently exists on how to define or measure hunger (1 ). Skipping breakfast can adversely affect children's performance in problem-solving tasks (40)(41)(42). A study of low-income elementary school students indicated that those who participated in the School Breakfast Program had greater improvements in stand-ardized test scores and reduced rates of absence and tardiness than did children who qualified for the program but did not participate (43 ). Twelve percent of students reported skipping breakfast the day before one national survey was taken (44 ); 40% of 8th-and 10th-grade students in another study reported having eaten breakfast on ≤2 days the week before the survey (45 ). Strategies to encourage adequate nutrition among young persons include the following: - Promote participation in USDA food assistance programs (e.g., the School Breakfast Program and School Lunch Program, the Summer Food Service Program, and the Child and Adult Care Food Program). - Advise parents and guardians about community-based food supplementation programs (e.g., food stamps; local food pantries; and the Special Supplemental Nutrition Program for Women, Infants, and Children ). - Educate students and their families about the importance of eating breakfast. # Iron Deficiency Anemia Iron deficiency anemia is the most common cause of anemia in the United States (33 ). Iron deficiency hampers the body's ability to produce hemoglobin, which is needed to carry oxygen in the blood. This deficiency can increase fatigue, shorten attention span, decrease work capacity, reduce resistance to infection, and impair intellectual performance (33,46 ). Among school-age youths, female adolescents are at greatest risk for iron deficiency. Approximately 1% of elementary school-age children and 2%-4% of adolescent girls ages 12-19 years show evidence of iron deficiency anemia (47 ). To prevent iron deficiency, children and adolescents should eat adequate amounts of foods high in iron and in vitamin C, which helps the body absorb iron efficiently (33 ). # Overweight and Obesity* Overweight and obesity are increasing among children and adolescents in the United States (48)(49)(50)(51)(52). The prevalence of overweight among youths ages 6-17 years in the United States has more than doubled in the past 30 years; most of the increase has occurred since the late 1970s (52 ). Approximately 4.7 million, or 11%, of youths ages 6-17 years are seriously overweight (52 ). Obesity in young persons is related to elevated blood cholesterol levels (53)(54)(55)(56) and high blood pressure (57)(58)(59), and some very obese youths suffer from immediate health problems (e.g., respiratory disorders, orthopedic conditions, and hyperinsulinemia) (60 ). Being overweight during childhood and adolescence has been associated with increased adult mortality (61,62 ). Furthermore, obese children and adolescents are often excluded from peer groups and discriminated against by adults, experience psychological stress, and have a poor *Obesity refers to an excess of total body fat. Body fat content is usually estimated by one of two techniques, measuring skinfold thickness or computing the ratio of body weight to height. Researchers who use weight-to-height ratios tend to use the term "overweight" instead of "obesity." Although weight-to-height ratios correlate highly with body fat, they do not distinguish between body fat and lean body tissue: excess fat tissue is generally assumed to account for the additional weight, but excess weight can also include lean body mass or a large body frame (33 ). body image and low self-esteem (63,64 ). Increased physical activity and appropriate caloric intake are recommended for preventing and reducing obesity (35 ). CDC's guidelines for school and community health programs to promote physical activity among youths address strategies for increasing physical activity among young persons (6 ). # Unsafe Weight-Loss Methods Many young persons in the United States practice unsafe weight-loss methods. Deliberately restricting food intake over long periods can lead to poor growth and delayed sexual development (65 ). Data from one study indicated that the rate of smoking initiation is higher for adolescent girls who diet or who are concerned about their weight than for nondieters or girls having few weight concerns (66 ), and another study indicated that many white female high school students who smoke report using smoking to control their appetite and weight (67 ). Harmful weight loss practices have been reported among girls as young as 9 years old (68,69 ). Young persons involved in certain competitive sports and dancing are particularly at risk for unsafe weight control practices (70 ). A national survey of 8th-and 10th-grade students found that 32% skipped meals, 22% fasted, 7% used diet pills, 5% induced vomiting after meals, and 3% used laxatives to lose weight (45 ). Children and adolescents should learn about the dangers of unsafe weight-loss methods and about safe ways to maintain a healthy weight. The emphasis of society in the United States on thinness should be challenged, and young persons need to develop a healthy body image (71 ). # Eating Disorders Eating disorders (e.g., anorexia nervosa and bulimia nervosa) are psychological disorders characterized by severe disturbances in eating behavior. Anorexia nervosa is characterized by a refusal to maintain a minimally normal body weight, and bulimia nervosa is characterized by repeated episodes of binge eating followed by compensatory behaviors such as self-induced vomiting (72 ). Eating disorders often start in adolescence, and >90% of cases occur among females (72 ). Anorexia nervosa and bulimia nervosa affect as many as 3% of adolescent and young adult females, and the incidence of anorexia nervosa appears to have increased in recent decades (72 ). Compared with adolescents who have normal eating patterns, adolescents who have eating disorders tend to have lower self-esteem; a negative body image; and feelings of inadequacy, anxiety, social dysfunction, depression, and moodiness (73 ). Eating disorders can cause many severe complications, and mortality rates for these disorders are among the highest for any psychiatric disorder (74 ). Persons who have eating disorders should receive immediate medical and psychological treatment. # Dental Caries Dental caries is perhaps the most prevalent of all diseases (1 ). It affects 50.1% of youths ages 5-17 years and 84.4% of youths age 17 years (75 ). More than 50 million hours of school time are lost annually because of dental problems or dental visits (76 ) . Dental caries is a progressive disease, which, if left untreated, can result in acute infections, pain, costly treatment, and tooth loss. A strong link exists between sugar consumption and dental caries (33 ). To prevent dental caries, children and adolescents should drink fluoridated water, use fluoridated toothpaste, brush and floss their teeth regularly, have dental sealants applied to the pits and fissures of their teeth, and consume sugars in moderation (1 ). # EFFECTS OF CHILDHOOD EATING PATTERNS ON CHRONIC DISEASE RISKS OF ADULTS Nutrition education also should focus on preventing children and adolescents from developing chronic diseases during adulthood. Some of the physiological processes that lead to diet-related chronic disease begin in childhood. For example, autopsy studies have demonstrated that early indicators of atherosclerosis (the hardening of the arteries that is the most common cause of coronary heart disease ) begin in youth (77)(78)(79)(80)(81)(82)(83) and are related to blood cholesterol levels in young persons (79,(81)(82)(83). Unhealthy eating practices that contribute to chronic disease are established early in life; young persons having unhealthy eating habits tend to maintain these habits as they age (84 ). Thus, it is efficacious to teach persons healthy eating patterns when they are young; high-risk eating behaviors and physiological risk factors are difficult to change once they are established during youth. Diet-related risk factors for cardiovascular disease (e.g., high blood cholesterol level, high blood pressure, and overweight) are common in youths in the United States (34,52,(85)(86)(87)(88)(89)(90). Compared with their peers, children and adolescents who have high blood cholesterol (34,(91)(92)(93)(94)(95)(96), have high blood pressure (97,98 ), or are obese (91,(99)(100)(101)(102)(103) are more likely to have these risk factors during adulthood. Poor diet and inadequate physical activity together account for at least 300,000 deaths in the United States annually and are second only to tobacco use as the most prominent identifiable contributor to premature death (104 ). Interventions that promote healthy eating and physical activity behaviors during childhood and adolescence may not only prevent some of the leading causes of illness and death but also decrease direct health-care costs and improve quality of life. Diet is a known risk factor for the development of the nation's three leading causes of death: CHD, cancer, and stroke (33 ). Other health problems of adulthood associated with diet are diabetes, high blood pressure, overweight, and osteoporosis. # Coronary Heart Disease CHD kills more persons in the United States than any other disease does (1 ). Dietrelated risk factors for CHD include high blood cholesterol, high blood pressure, and obesity. These risk factors can be reduced by consuming less fat (particularly saturated fat) and cholesterol and by increasing physical activity (105 ). # Cancer One out of every five deaths in the United States is attributable to cancer (106 ). Dietary factors have been associated with several types of cancer, including colon, breast, and prostate (33 ). All cancer deaths in the United States might be reduced as much as 35% through dietary changes (107,108 ). The risk for some types of cancer may be reduced by maintaining a healthy weight; limiting consumption of fat, alcohol, and salt-cured, salt-pickled, or smoked foods; and eating more foods that protect the body against cancer (fruits, vegetables, whole grain cereals, and other high-fiber foods) (109 ). The National Cancer Institute advises eating at least five servings of fruits and vegetables each day (110 ). # Stroke Cerebrovascular disease, or stroke, is the third leading cause of death in the United States and a major cause of illness and disability (111 ). The most important risk factor for stroke is high blood pressure, which often can be controlled or prevented by adopting a healthy diet and maintaining a healthy weight (112 ). The risk for stroke can be reduced by consuming less sodium, increasing physical activity, and maintaining a healthy body weight. # Diabetes Diabetes is the seventh leading cause of death in the United States (104 ). CHD is two to four times more common and stroke is two to six times more common in persons who have diabetes than in persons who do not have diabetes (113 ). Diabetes can lead to blindness, kidney disease, and nerve damage (113 ). Non-insulin-dependent diabetes mellitus, which affects approximately 90% of persons who have diabetes, is often associated with obesity (114 ). Maintaining a desirable body weight through physical activity and modest caloric restriction is important in preventing diabetes and controlling its complications (114 ). # High Blood Pressure High blood pressure is a major cause of CHD, stroke, and kidney failure. About one in four adults in the United States has high blood pressure (115 ). Persons who have high blood pressure have three to four times the risk of developing CHD and as much as seven times the risk of stroke as do those who have normal blood pressure (116 ). Persons can reduce their risk for high blood pressure by consuming less sodium, increasing physical activity, and maintaining a healthy body weight. A diet high in potassium may help reduce the risk of high blood pressure (117 ). # Overweight In the United States, about one in three adults is overweight (118 ), and these persons are at increased risk for CHD, some types of cancer, stroke, diabetes mellitus, high blood pressure, and gallbladder disease (33 ). Overall risk for premature death is increased by excess weight; the risk increases as severity of overweight increases (33) . The best way to lose weight is to increase physical activity and control caloric intake, preferably by adopting a diet that is low in fat and high in vegetables, fruits, and grains (35 ). # Osteoporosis Osteoporosis is a decrease in the amount of bone so severe that the bone fractures easily. About 1.3 million bone fractures, including many fatal hip fractures, occur per year in persons ≥45 years of age (33 ). Low dietary calcium, a mineral essential for bone growth, may be associated with an increased risk for osteoporosis (33 ). For females especially, eating enough calcium is particularly important during childhood, adolescence, and young adulthood-when bones approach their maximum densityto reduce the risk for osteoporosis later in life (1,(119)(120)(121)(122). Regular weight-bearing exercises also can help prevent osteoporosis (33 ). # GUIDELINES FOR HEALTHY EATING To prevent certain diseases and to promote good health, persons >2 years of age should follow the seven recommendations that constitute the Dietary Guidelines for Americans (35 ). These guidelines are developed by the USDA and USDHHS and are published every 5 years. They are based on extensive reviews of hundreds of studies conducted over many years and represent the best current advice that nutrition scientists can give. The guidelines are consistent with dietary recommendations made by major health promotion organizations, including the National Research Council (32 ), the National Cholesterol Education Program of the National Institutes of Health (34,105 ), the National Cancer Institute (109 ), the American Cancer Society (123 ), and the American Heart Association (124 ). The principles contained in the Dietary Guidelines for Americans should be the primary focus of school-based nutrition education. By enabling young persons to adopt practices consistent with the guidelines, schools can help the nation meet its health objectives (1 ), which were designed to guide health promotion and disease prevention policy and programs at the federal, state, and local level throughout the 1990s. Objective 2.19 is to "increase to at least 75 percent the proportion of the Nation's schools that provide nutrition education from preschool through 12th grade, preferably as part of quality school health education" (1 ). The six relevant dietary guidelines are (a) eat a variety of foods; (b) balance the food you eat with physical activity-maintain or improve your weight; (c) choose a diet with plenty of grain products, vegetables, and fruits; (d) choose a diet low in fat, saturated fat, and cholesterol; (e) choose a diet moderate in sugars; and (f) choose a diet moderate in salt and sodium. (The seventh recommendation concerns adults and alcoholic beverages.) Enabling children and adolescents to follow these guidelines can help the nation achieve these national health objectives for the year 2000 (1 ): 2.3 Reduce overweight to a prevalence of ≤20% among people aged 20 and older and ≤15% among adolescents aged 12 through 19. Reduce average dietary fat intake to ≤30% of calories and average saturated fat intake to ≤10% of calories among people aged two and older. # Increase complex carbohydrates and fiber-containing foods in the diets of adults to five or more daily servings for vegetables (including legumes) and fruits and to six or more daily servings for grain products. Increase to ≥50% the proportion of overweight people aged 12 and older who have adopted sound dietary practices combined with regular physical activity to attain an appropriate body weight. 2.8 Increase calcium intake so ≥50% of youth aged 12 through 24 and ≥50% of pregnant and lactating women consume three or more servings daily of foods rich in calcium, and ≥50% of people aged ≥25 consume two or more servings daily. Decrease salt and sodium intake so that ≥65% of home meal preparers prepare foods without adding salt, ≥80% of people avoid using salt at the table, and ≥40% of adults regularly purchase foods modified or lower in sodium. The Food Guide Pyramid (Figure 1) was designed by the USDA and USDHHS to help persons follow the Dietary Guidelines for Americans. Schools can use the pyramid to illustrate the concepts of variety (eat different foods from among and within the food groups), moderation (limit the consumption of foods high in fat and added sugars), and proportionality (eat relatively greater amounts of foods from the groups that are lower in the pyramid: grains, vegetables, and fruits) (125 ). Other educational materials supplement the pyramid by listing low-fat choices within each food group (35 ). # EATING BEHAVIORS OF CHILDREN AND ADOLESCENTS IN THE UNITED STATES Many young persons in the United States do not follow the recommendations of the Dietary Guidelines for Americans or the Food Guide Pyramid. On average, children and adolescents consume too much fat, saturated fat, and sodium and not enough fruits, vegetables, or calcium (44,(126)(127)(128)(129) ; CDC, unpublished data). Children and adolescents obtain 33%-35% of their calories from fat and 12%-13% from saturated fat FIGURE 1. The Food Guide Pyramid -a guide to daily choices (above the recommended levels of 30% and 10%, respectively) (44,128,129 ). Only 16% of children ages 6-11 years and 15% of adolescents ages 12-19 years meet the recommendation for total fat intake; only 9% of children and 7% of adolescents meet the recommendation for saturated fat intake (130 ). Almost one-half of 8th-and 10thgrade students eat three or more snacks a day, and most of these snacks are high in fat, sugar, or sodium (45 ). Unpublished data from CDC's 1993 Youth Risk Behavior Survey indicated that, on the day before the survey, 41% of high school students in the United States ate no vegetables and 42% ate no fruits (127 ) (Appendix B). An analysis of a nationally representative sample of youths ages 2-18 years indicated that, over a 3-day period, the youths ate only 3.6 servings of fruits and vegetables daily and that fried potatoes accounted for a large proportion of the vegetables consumed, 20.4% of the youths ate the recommended five or more servings of fruits and vegetables daily, 50.8% ate fewer than one serving of fruit per day, and 29.3% ate fewer than one serving per day of vegetables that were not fried (131 ). Adolescent females eat considerably less calcium and iron than recommended by the Food and Nutrition Board of the National Research Council (126,129 ). Children and adolescents appear to be familiar with the general relationship between nutrition and health but are less aware of the relationship between specific foods and health. For example, young persons understand the importance of limiting fat, cholesterol, and sodium in one's diet, but they do not know which foods are high in fat, cholesterol, sodium, or fiber (45,132,133 ). One study indicated that adolescents were well-informed about good nutrition and health but did not use their knowledge to make healthy food choices (134 ). # THE NEED FOR SCHOOL-BASED NUTRITION EDUCATION Young persons need nutrition education to help them develop lifelong eating patterns consistent with the Dietary Guidelines for Americans and the Food Guide Pyramid. Schools are ideal settings for nutrition education for several reasons: - Schools can reach almost all children and adolescents. - Schools provide opportunities to practice healthy eating. More than one-half of youths in the United States eat one of their three major meals in school, and 1 in 10 children and adolescents eats two of three main meals in school (135 ). - Schools can teach students how to resist social pressures. Eating is a socially learned behavior that is influenced by social pressures. School-based programs can directly address peer pressure that discourages healthy eating and harness the power of peer pressure to reinforce healthy eating habits. - Skilled personnel are available. After appropriate training, teachers can use their instructional skills and food service personnel can contribute their expertise to nutrition education programs. - Evaluations suggest that school-based nutrition education can improve the eating behaviors of young persons (136)(137)(138). School-based nutrition education is particularly important because today's children and adolescents frequently decide what to eat with little adult supervision (139 ). The increase in one-parent families or families having two working parents and the availability of convenience foods and fast-food restaurants inhibit parents' monitoring of their children's eating habits. Young persons' food choices are influenced by television advertisements for lownutritive foods. Young persons see about one food advertisement for every 5 minutes of Saturday morning children's shows (140 ). Most of the foods advertised during children's programming are high in fat, sugar, or sodium; practically no advertisements are for healthy foods such as fruits and vegetables (140)(141)(142). Studies have indicated that, compared with those who watch little television, children and adolescents who watch more television are more likely to have unhealthy eating habits and unhealthy conceptions about food (143 ), ask their parents to buy foods advertised on television (144 ), and eat more fat (145 ). Some studies of young persons have found that television watching is directly associated with obesity (146)(147)(148)(149). Because youths in the United States spend, on average, more than 20 hours a week watching television (150 ) -more time over the course of the year than they are in school ( 141)-schoolbased programs should help counter the effect of television on young persons' eating habits. Schools are a critical part of the social environment that shapes young persons' eating behaviors and can therefore play a large role in helping improve their diet. However, schools cannot achieve this goal on their own when the cultural milieu has a large influence on food-related beliefs, values, and practices (30,138 ). Families, food stores, restaurants, the food industry, religious institutions, community centers, government programs, and the mass media must also support the principles of the Dietary Guidelines for Americans. The USDA's Team Nutrition (see Appendix A) seeks to gain the support of many sectors of society for improving the diet of young persons by creating innovative public and private partnerships that promote healthy food choices through the media, schools, families, and community (151 ). # PROMOTING HEALTHY EATING THROUGH A COMPREHENSIVE SCHOOL HEALTH PROGRAM In the school environment, classroom lessons alone might not be enough to effect lasting changes in students' eating behaviors (30 ); students also need access to healthy food and the support of persons around them (137 ). The influence of school goes beyond the classroom and includes normative messages from peers and adults regarding foods and eating patterns. Students are more likely to receive a strong, consistent message when healthy eating is promoted through a comprehensive school health program. A comprehensive school health program empowers students with not only the knowledge, attitudes, and skills required to make positive health decisions but also the environment, motivation, services, and support necessary to develop and maintain healthy behaviors (152 ). A comprehensive school health program includes health education; a healthy environment; health services; counseling, psychological, and social services; integrated school and community efforts; physical education; nutrition services; and a school-based health program for faculty and staff (7 ). Each compo-nent can contribute to integrated efforts that promote healthy eating. For example, classroom lessons on nutrition can be supported by - schools providing appealing, low-fat, low-sodium foods in vending machines and at school meetings and events; - school counselors and nurses providing guidance on health and, if necessary, referrals for nutritional problems; - community organizations providing counseling or nutrition education campaigns; - physical education instructors helping students understand the relationship between nutrition and physical activity; - school food service personnel serving healthy, well-balanced meals in the cafeteria; and - school personnel acting as role models for healthy eating (153 ). The USDA is promoting health-enhancing changes in the food service component of the school health program by requiring schools to serve meals that comply with the Dietary Guidelines for Americans (154 ) and by providing technical support to schools through Team Nutrition (151 ). # RECOMMENDATIONS FOR SCHOOL HEALTH PROGRAMS PROMOTING HEALTHY EATING Based on the available scientific literature, national nutrition policy documents, and current practice, these guidelines provide seven recommendations for ensuring a quality nutrition program within a comprehensive school health program. These recommendations address school policy on nutrition, a sequential, coordinated curriculum, appropriate and fun instruction for students, integration of school food service and nutrition education, staff training, family and community involvement, and program evaluation. Strategies that schools can use to achieve these recommendations are available (Appendix C). However, local school systems need to assess the nutrition needs and issues particular to their communities, and they need to work with key school-and community-based constituents, including students, to develop the most effective and relevant nutrition education plans for their communities. Vigorous, coordinated, and sustained support from communities, local and state education and health agencies, institutions of higher education, and national organizations also is necessary to ensure success (29 ). 1. Policy: Adopt a coordinated school nutrition policy that promotes healthy eating through classroom lessons and a supportive school environment. 2. Curriculum for nutrition education: Implement nutrition education from preschool through secondary school as part of a sequential, comprehensive school health education curriculum designed to help students adopt healthy eating behaviors. # Instruction for students: # Rationale for the Policy A coordinated school nutrition policy, particularly as part of an overall school health policy, provides the framework for implementing the other six recommendations and ensures that students receive nutrition education messages that are reinforced throughout the school environment. For example, such a policy would address nutrition education classes; school lunch and breakfast; classroom snacks and parties; use of food to reward or discipline; and food sold in vending machines, at school stores, snack bars, sporting events, and special activities, and as part of fundraising activities. The school environment can powerfully influence students' attitudes, preferences, and behaviors related to food (137 ). Without a coordinated nutrition policy, schools risk negating the health lessons delivered in the classroom and cafeteria by allowing actions that discourage healthy eating behaviors. # Developing the Policy A school nutrition policy should be a brief document that incorporates input from all relevant constituents of the school community: students, teachers, coaches, staff, administrators, food service personnel, nurses, counselors, public health professionals, and parents. The policy should meet local needs and be adapted to the health concerns, food preferences, and dietary practices of different ethnic and socioeconomic groups. Technical assistance for assessing nutrition education needs is available through the state NET Program (155 ). Schools might consider using one or more of the following techniques to assess their particular needs: - Interview nutrition professionals to learn more about local eating habits and to identify materials and services available for youths and adults. Schools might interview representatives from the school food service program; the state NET Program; the nutrition unit within the State Department of Health; the district or state school health coordinator; the local WIC program and Cooperative Extension nutrition education program; the state or local chapters of the American Cancer Society, American Dietetic Association, and the American Heart Association; nutrition councils or coalitions; university research programs; organizations with special insights into the particular nutrition education needs of cultural and ethnic minorities; or businesses that offer nutrition-related services or food products. - Interview food service staff about students' eating practices in the school cafeteria. - Observe the school cafeteria, the teachers' lunchroom, and other areas in the school where food is available. - Review nutrition curricula used by teachers. - Survey teachers to determine how nutrition is taught, whether teachers use food for reward or punishment, and the level of interest of teachers in nutrition or wellness programs for themselves. - Survey students to determine their dietary preferences and what types of healthy changes in school food they most want. The policy plan should include means of obtaining follow-up input from all parties and means of revising the plan as needed. Student involvement is critical to the success of a nutrition policy. A nutrition advisory committee or a nutrition subcommittee of the school health advisory council having student members can develop and promulgate a coordinated school nutrition policy. Technical assistance in forming a school nutrition advisory committee is available from the American School Food Service Association (Appendix A). Successful implementation of a nutrition policy also requires the active support of school and district educational leadership. # Content of the Policy The written policy should describe the importance of the nutrition component within the comprehensive school health program. This section can briefly describe the role of good nutrition in promoting childhood growth, health, and learning; discuss the role of child and adolescent nutrition in reducing the risk for chronic diseases of adulthood; identify the importance of establishing a school environment that supports healthy eating choices by young persons; and generate support for the policy by identifying how improvements in student nutrition can satisfy the needs of different constituents of the school community (e.g., students, teachers, and food service personnel). An optimal policy on nutrition should publicly commit the school to providing adequate time for a curriculum on nutrition, serving healthy and appealing foods at school, developing food-use guidelines for teachers, supporting healthy school meals, and establishing links with nutrition service providers. Curriculum. Adequate time should be allocated for nutrition education throughout the preschool, primary, and secondary school years as part of a sequential, comprehensive school health education program. In addition, teachers should be adequately trained to teach nutrition and be provided with ongoing in-service training. Healthy † and appealing foods. Healthy and appealing foods should be available in meals, a la carte items in the cafeteria, snack bars, and vending machines (Exhibit 1); as classroom snacks; and at special events, athletic competitions, staff meetings, and parents' association meetings. In addition, schools should discourage the sale of foods high in fat, sodium, and added sugars (e.g., candy, fried chips, and soda) on school grounds and as part of fundraising activities. Although selling low-nutritive foods may provide revenue for school programs, such sales tell students that it is acceptable to compromise health for financial reasons (158 ). The school thereby risks contradicting the messages on healthy eating given in class. If schools contract with food service management companies to supply meals, the contractors should be required to serve appealing, low-fat, low-sodium meals that comply with the standards of the Dietary Guidelines for Americans. † As defined by the U.S. Food and Drug Administration (156,157 ) in its food label regulations, a "healthy" food must be low in fat (≤3 g per serving), be low in saturated fat (≤1 g per serving), contain limited amounts of cholesterol (≤60 mg per serving for a single-item food), and contain limited amounts of salt (≤480 mg per serving until 1998, when the criterion for a single-item food will decrease to ≤360 mg per serving). In addition, single-item foods that are not raw fruits or vegetables must provide ≥10% of the daily value of one or more of the following nutrients: vitamin A, vitamin C, iron, calcium, protein, and fiber. Criteria for products that include more than one type of food (e.g., macaroni and cheese) vary depending on the food. *These foods are appropriate if the vending machine is refrigerated. † Some schools might not want to offer these items because these foods can contribute to dental caries. § Some schools might not want to offer peanut butter; although it is low in saturated fatty acids, peanut butter is high in total fat. Food use guidelines for teachers. Schools should discourage teachers from using food for disciplining or rewarding students. Some teachers give students low-nutritive foods, such as candy, as a reward for good behavior, and punish misbehaving students by denying a low-nutritive treat (159 ). These practices reinforce students' preferences for low-nutritive foods and contradict what is taught during nutrition education. Schools should recommend that both teachers and parents serve healthy party snacks and treats (160 ). Support for healthy school meals. Starting with the 1996-1997 school year, schools will be required to serve meals that comply with the standards of the Dietary Guidelines for Americans (154 ). To encourage students to participate in school meal programs and to make healthy choices in cafeterias, schools can use marketing-style incentives and promotions (13,14,135,161 ); use healthy school meals as examples in class; educate parents about the value of healthy school meals; involve students and parents in planning meals; and have teachers, administrators, and parents eat in the cafeteria and speak favorably about the healthy meals available there. Students should also be given adequate time and space to eat meals in a pleasant and safe environment (162 ). Links with nutrition service providers. Schools should establish links with qualified public health and nutrition professionals who can provide screening, referral, and counseling for nutritional problems (30,163 ); inform families about supplemental nutrition services available in the community, such as WIC ( 164), food stamps, local food pantries, the Summer Food Service Program, and the Child and Adult Care Food Program; and implement nutrition education and health promotion activities for school faculty, other staff, school board members, and parents. These links can help prevent and resolve nutritional problems that can impair a student's capacity to learn, demonstrate the value placed on good nutrition for the entire school community, and help adults serve as role models for school-age youths. # Recommendation 2. Curriculum for nutrition education: Implement nutrition education from preschool through secondary school as part of a sequential, comprehensive school health education curriculum designed to help students adopt healthy eating behaviors. Nutrition Education as Part of a Comprehensive School Health Education Program Nutrition education should be part of a comprehensive health education curriculum that focuses on understanding the relationship between personal behavior and health. This curriculum should give students the knowledge and skills they need to be "health literate," as delineated by the national health education standards (29 ) (Exhibit 2). The comprehensive health education approach is important to nutrition education because - unhealthy eating behaviors may be interrelated with other health risk factors (e.g., cigarette smoking and sedentary lifestyle) (165 ), - nutrition education shares many of the key goals of other health education content areas (e.g., raising the value placed on health, taking responsibility for one's health, and increasing confidence in one's ability to make health-enhancing behavioral changes), and - state-of-the-art nutrition education uses many of the social learning behavioral change techniques used in other health education domains. Therefore, nutrition education activities can reinforce, and be reinforced by, activities that address other health education topics as well as health in general. Linking nutrition and physical activity is particularly important because of the rising proportion of overweight youths in the United States. Nutrition education lessons should stress the importance of combining regular physical activity with sound nutrition as part of an overall healthy lifestyle. Physical education classes, in turn, should include guidance in food selection (6 ). # Sequential Lessons and Adequate Time Students who receive more lessons on nutrition have more positive behavioral changes than students who have fewer lessons (166,167 ). To achieve stable, positive changes in students' eating behaviors, adequate time should be allocated for nutrition education lessons. The curriculum should be sequential from preschool through secondary school; attention should be paid to scope and sequence. When designing the curriculum, schools should assess and address their students' needs and concerns. A curriculum targeted to a limited number of behaviors might make the most effective use of a scarce instructional time available for nutrition education (136 ). # EXHIBIT 2: National Health Education Standards (29 ) 1. Students will comprehend concepts related to health promotion and disease prevention. 2. Students will be able to access valid health information and healthpromoting products and services. 3. Students will be able to practice health-enhancing behaviors and reduce health risks. 4. Students will analyze the influence of culture, media, technology, and other factors on health. 5. Students will be able to use interpersonal communication skills to enhance health. 6. Students will be able to use goal-setting and decision-making skills to enhance health. 7. Students will be able to advocate for personal, family, and community health. To maximize classroom time, nutrition education can be integrated into the lesson plans of other school subjects; for example, math lessons could analyze nutrient intake or reading lessons could feature texts on nutrition (168 ). Little research on the integrated approach has been conducted ( 137), but embedding information on nutrition in other courses probably reinforces the goals of nutrition education. However, the exclusive use of an integrative approach might sacrifice key elements of an effective nutrition education program (e.g., adequate time, focusing on behaviors and skillbuilding, attention to scope and sequence, and adequate teacher preparation) (137 ). Therefore, integration into other courses can complement but should not replace sequential nutrition education lessons within a comprehensive school health education curriculum. Classroom time can be maximized also by having nutrition education lessons use skills learned in other classes (e.g., math or language arts) (169)(170)(171). Organizations and agencies can supply information on specific nutrition education curricula and materials (Appendix A). The USDA's NET Program provides technical assistance in school-based nutrition education (2,172 ). The Food and Nutrition Information Center of USDA's National Agricultural Library provides information on nutrition education evaluation and resources and serves as a national depository and lending library for NET materials. Nutritionists at some organizations can also answer specific nutrition content questions (Appendix A). # Focusing on Promoting Healthy Eating Behaviors The primary goal of nutrition education should be to help young persons adopt eating behaviors that will promote health and reduce risk for disease. Knowing how and why to eat healthily is important, but knowledge alone does not enable young persons to adopt healthy eating behaviors (137 ). Cognitive-focused curricula on nutrition education typically result in gains in knowledge but usually have little effect on behavior (173)(174)(175)(176)(177)(178). Behaviorally based education encourages specific healthy eating behaviors (e.g., eating less fat and sodium and eating more fruits and vegetables) (136,179 ); however, it does not detail the technical and scientific knowledge on which dietary recommendations are based and, therefore, might not fulfill science education requirements (180). The strategies listed in Appendix C can be used as central concepts in a behaviorally based nutrition education program. Several programs using a behavioral approach have achieved significant (p<0.05), positive changes in students' eating behaviors (167,(181)(182)(183)(184)(185)(186)(187)(188)(189)(190). Compared with students in control schools, students in some behaviorally based health and nutrition education programs had significant (p<0.05), favorable changes in serum cholesterol levels (167,188,191 ), blood pressure level (167,191 ), and body mass index (184 ). Although most of the behaviorally oriented programs did not achieve all their behavioral aims-perhaps because of the limited amount of curriculum time (136 )-current scientific knowledge indicates that a focus on behavior is a key determinant in the success of nutrition education programs (136)(137)(138). # Recommendation 3. Instruction for students: Provide nutrition education through developmentally appropriate, culturally relevant, fun, participatory activities that involve social learning strategies. Developmentally Appropriate and Culturally Relevant Activities Different educational strategies should be used for young persons at different stages of cognitive development. Regardless of the amount and quality of teaching they receive, young elementary schoolchildren might not fully understand abstract concepts (e.g., the nutrient content of foods or the classification of foods into groups) (192)(193)(194). Nutrition education for young children should focus on concrete experiences (e.g., increasing exposure to many healthy foods and building skills in choosing healthy foods) (169 ). More abstract associations between nutrition and health become appropriate as children approach middle school. By this age, children can understand and act on the connection between eating behaviors and health (137,194 ). Nutrition education for middle and high school students should focus on helping students assess their own eating behaviors and set goals for improving their food selection (138,195 ). Lessons for older children should emphasize personal responsibility, decision-making skills, and resisting negative social pressures (183,185,187,189 ). Nutrition education presents opportunities for young persons to learn about and experience cultural diversity related to food and eating. Students from different cultural groups have different health concerns, eating patterns, food preferences, and food-related habits and attitudes. These differences need to be considered when designing lesson plans or discussing food choices. Nutrition education can succeed only when students believe it is relevant to their lives. # Active Learning and an Emphasis on Fun The context in which students learn about healthy eating behaviors and the feelings students associate with healthy foods are key factors in determining their receptivity to nutrition education. Students are more likely to adopt healthy eating behaviors when - they learn about these behaviors through fun, participatory activities rather than through lectures (138,196,197 ); - lessons emphasize the positive, appealing aspects of healthy eating patterns rather than the negative consequences of unhealthy eating patterns; - the benefits of healthy eating behaviors are presented in the context of what is already important to the students; and - the students have repeated opportunities to taste foods that are low in fat, sodium, and added sugars and high in vitamins, minerals, and fiber during their lessons. § § When serving food, teachers must use hygienic food handling practices and consider possible food allergies and religious prohibitions; the food service director can help in this area. Computer-based lessons on nutrition can also be effective (198 ), especially when teacher time is limited or when student self-assessment is appropriate. Interactive, highly entertaining, and well-designed computer programs are now available to help young persons learn healthy food selection skills and assess their own diets (199,200). Computer-based lessons allow students to move at their own pace and can capture their attention. # Social Learning Techniques Most of the nutrition education programs that have resulted in behavioral change have used teaching strategies based on social learning theory (195,(201)(202)(203)(204)(205). In such lessons, increasing student knowledge is only one of many objectives. Social learning instruction also emphasizes - raising the value students place on good health and nutrition and identifying the benefits of adopting healthy eating patterns, including short-term benefits that are important to young persons (e.g., physical appearance, sense of personal control and independence, and capacity for physical activities); - giving students repeated opportunities to taste healthy foods, including foods they have not yet tasted; - working with parents, school personnel, public health professionals, and others to overcome barriers to healthy eating; - using influential role models, including peers, to demonstrate healthy eating practices; - providing incentives (e.g., verbal praise and small prizes) to reinforce messages; - helping students develop practical skills for and self-confidence in planning meals, preparing foods, reading food labels, and making healthy food choices through observation and hands-on practice; - enabling students to critically analyze sociocultural influences, including advertising, on food selection, to resist negative social pressures, and to develop social support for healthy eating; and - helping students analyze their own eating patterns, set realistic goals for changes in their eating behaviors, monitor their progress in reaching those goals, and reward themselves for achieving their goals. Nutrition education strategies include social learning techniques (Appendix C). # Recommendation 4. Integration of school food service and nutrition education: Coordinate school food service with nutrition education and with other components of the comprehensive school health program to reinforce messages on healthy eating. The school cafeteria provides a place for students to practice healthy eating. This experience should be coordinated with classroom lessons to allow students to apply critical thinking skills taught in the classroom (2,8,9,(11)(12)(13)(14)(15)18,169,178,206 ). School food service personnel can - visit classrooms and explain how they make sure meals meet the standards of the Dietary Guidelines for Americans, - invite classes to visit the cafeteria kitchen and learn how to prepare healthy foods, - involve students in planning the school menu and preparing recipes, - offer foods that reinforce classroom lessons (e.g., whole wheat rolls to reinforce a lesson on dietary fiber), - post in the cafeteria posters and fliers on nutrition, and - display nutrition information about available foods and give students opportunities to practice food analysis and selection skills learned in the classroom. In addition, classroom teaching can complement the goals of the school food service. For example, teachers can help food service managers by teaching students about the importance of nutritious school meals and getting feedback from students on new menu items developed to meet the goals set by USDA's School Meals Initiatives for Healthy Children (154 ). To ensure consistent nutrition messages from the school, food service personnel should work closely with those responsible for other components of the school health program. For example, the personnel can - help develop and implement school policies that make healthful foods available; - educate parents about the value of school meals (e.g., put health messages in monthly menus sent home to parents or make periodic presentations at parents' association meetings) (11,13 ); - help schools access and assess community public health and nutrition services; and - keep classroom teachers, physical education teachers, coaches, counselors, health-service providers, and other staff informed about the importance of healthy school meals. # Recommendation 5. Training for school staff: Provide staff involved in nutrition education with adequate preservice and ongoing in-service training that focuses on teaching strategies for behavioral change. Training in nutrition and health education can increase the extent to which teachers implement a curriculum (207)(208)(209), which in turn affects the likelihood that students' eating behaviors will change (167,207 ). All elementary school teachers as well as secondary school teachers in disciplines such as home economics, family and consumer sciences, language arts, physical education, and science should receive nutrition education training. State NET Programs can provide technical assistance for training teachers in nutrition education (Appendix A). Training should address content and teaching strategies. Because classroom teachers often need more help with innovative nutrition teaching techniques than with content (195,210 ), training should focus on giving teachers the skills they need to use the nonlecture, active learning methods discussed previously (195 ). Training programs are most effective if they - are designed to meet the specific needs of the teachers and are based on the teachers' level of nutrition knowledge and experience with the suggested teaching strategies, - model behavioral change techniques and give teachers practice in using them, - involve multiple sessions spaced across time so that teachers can try out the newly learned techniques in their classrooms and report on their experiences to the training group, and - provide posttraining sessions so that teachers can share experiences with their peers (211,212 ). Teachers should understand the importance of fully implementing the selected curriculum and become familiar with its underlying theory and concepts. Training should also help teachers assess and improve their own eating practices and make them aware of the behavioral messages they give as role models (213 ). Continuing education activities in nutrition education should be offered to food service personnel so this staff can reinforce classroom instruction through the school meal program and help shape the school's nutrition policy. State NET Programs and the National Food Service Management Institute provide technical assistance and training seminars for school nutrition professionals (see Appendix A). Administrative support is also critical to implementing a new program (214 ). Training for school administrators can help gain their support for nutrition education. Health promotion services for all school staff can positively affect their eating behaviors and their effectiveness in teaching healthy eating behaviors (180,215,216 ). # Recommendation 6. Family and community involvement: Involve family members and the community in supporting and reinforcing nutrition education. The attitudes and behaviors of parents and caretakers directly influence children's and adolescents' choice of foods (217,218 ). Parents control most of the food choices available at home, so changing parents' eating behaviors may be one of the most effective ways to change their children's eating behaviors. Involving parents in a nutrition education curriculum at the elementary school level can enhance the eating behaviors of both the students (181,(219)(220)(221) and the parents (181,219,222 ). Although parental involvement can enhance the effects of nutrition education programs at the elementary school level, it is not known whether involving parents at the secondary school level helps improve the students' eating behaviors. For older youths, self-assessment (185,189,198 ) and peer educators (187 ) might be more influential than parental involvement (137 ). Parents are usually more receptive to activities that can be done at home than to those that require their attendance at the school (223,224 ). To involve parents and other family members in nutrition education, schools can - send nutrition education materials and cafeteria menus home with students, - ask parents to send healthy snacks to school, - invite parents and other family members to periodically eat with their children in the cafeteria, - invite families to attend exhibitions of student nutrition projects or health fairs (217 ), - offer nutrition education workshops and screening services, and - assign nutrition education homework that students can do with their families (e.g., reading and interpreting food labels, reading nutrition-related newsletters, and preparing healthy recipes). Through school health advisory councils or through direct contact with community organizations, schools can engage community resources and services to respond to the nutritional needs of students (225,226 ). Schools can also participate in community-based nutrition education campaigns sponsored by public health agencies or voluntary organizations. Students are most likely to adopt healthy eating behaviors if they receive consistent messages through multiple channels (e.g., home, school, community, and the media) and from multiple sources (e.g., parents, peers, teachers, health professionals, and the media) (225 ). # Recommendation 7. Program evaluation: Regularly evaluate the effectiveness of the school health program in promoting healthy eating, and change the program as appropriate to increase its effectiveness. Policymakers should regularly review the effectiveness of the school nutrition program. All groups affected by the program should have the opportunity to provide input. Assessment of nutrition programs and policies should include whether - a comprehensive school nutrition policy exists and is implemented as written; - nutrition education is provided throughout the preschool, primary, and secondary school years as part of comprehensive school health education; - teachers deliver nutrition education through developmentally appropriate, culturally relevant, fun, participatory activities that involve social learning strategies; - teachers and school food service personnel have undertaken joint project planning and action; - teachers have received curriculum-specific training; and - families and community organizations are involved in nutrition education. Schools might also consider measuring the effects of their programs and policies on self-reported eating behaviors; key variables that influence behavior, such as knowledge, attitudes, self-confidence, and behavioral intentions; and in-school eating behaviors that are easy to assess, such as participation in school food service programs and the number of students choosing healthy alternatives in the cafeteria (e.g., salad bars or low-fat milk). Schools can consult with the state NET Program or with evaluation specialists at universities, school districts, or the state departments of education or health to identify methods and materials for evaluating the effectiveness of their program (227,228). Valid evaluations can increase parent and community support for school programs, help schools reward teachers for exceptional work, and support grant applications for enhancing school health programs. # CONCLUSION To ensure a healthy future for our children, school-based nutrition education programs must become a national priority. These programs should be part of comprehensive school health programs and reach students from preschool through secondary school. School leaders, community leaders, and parents must commit to implementing and sustaining nutrition education programs within the schools. Such support is crucial to promoting healthy eating behaviors. The seven recommendations for school-based nutrition education presented in this report provide the framework for establishing such programs. By adopting these recommendations, schools can help ensure that all school-age youths attain their full educational potential and good health. # APPENDIX B: YOUTH RISK BEHAVIOR SURVEILLANCE SYSTEM AND SCHOOL HEALTH POLICIES AND PROGRAMS STUDY In 1990, CDC established the Youth Risk Behavior Surveillance System to help monitor progress in attaining national health and education objectives by periodically measuring the prevalence of behaviors in six health risk categories. These behaviors, which are usually established during youth, contribute to the leading causes of death and disease in the United States. Dietary behaviors are one of the six health risk categories. CDC conducts the Youth Risk Behavior Survey (YRBS) biennially in a national probability sample of high school students and enables interested state and local education agencies to conduct the survey in comparable probability samples in states and cities (127 ). The specific dietary behaviors and attitudes monitored by the YRBS include consumption of fruits and vegetables, consumption of foods high in fat, perceptions of body weight, and attempted weight loss and weight-loss techniques used. The YRBS also obtains information about specific physical activity behaviors. In 1994, CDC conducted the School Health Policies and Programs Study (SHPPS), which is a national study of school policies and programs at the school, district, and state levels that support comprehensive school health programs. The study also provides baseline data on national health and education objectives that can be attained through school health and physical education, school food service, and school health services and policies (229 ). SHPPS included a mail survey of local and state education agencies' policies related to school health in grades kindergarten through 12. The survey was conducted in all states and in a nationally representative sample of districts. The study also included on-site, structured interviews with school principals, health education teachers, physical education teachers, school food service directors, school nurses, counselors, and other personnel in a nationally representative sample of middle schools and high schools. The questionnaire included the following: school nutrition education requirements for students; the content of nutrition education curricula; training and joint activities of food service staff and teachers responsible for nutrition education; school policies related to foods sold in vending machines and for fundraising; food service practices related to purchasing and preparing food; involvement of parents, staff, and students in planning food service meals; and involvement of fast-food or food service management companies in school meals. - Teach the importance of balancing food intake and physical activity. - Identify healthy snacks (e.g., fruits, vegetables, and low-fat milk). - Increase students' confidence in their ability to make healthy eating choices by gradually building up their food selection and preparation skills and giving them practice. # Strategies to enhance behavioral capabilities that will support healthy eating - Provide many healthy foods for students to taste in an enjoyable social context. - Let students prepare simple snacks. - Have students try unfamiliar and culturally diverse foods that are low in fat, sodium, and added sugars. # For upper elementary students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Involve parents in nutrition education through homework. - Provide role models (e.g., teachers, parents, other adults, adolescents, and celebrities or fictional characters) for healthy eating. - Through class discussions and small-group exercises, provide social support for making healthy changes in eating and physical activity. - Provide cues, through posters and marketing-style incentives that students design, that encourage students to make healthy choices about eating and physical activity. - Use incentives, such as verbal praise or token gifts, to reinforce healthy eating and physical activity. Do not use food as a reward or punishment of any behavior. # Strategies to enhance personal characteristics that will support healthy eating - Explain the effects that diet and physical activity have on future health as well as on immediate concerns (e.g., current health, physical appearance, obesity, sense of well-being, and capacity for physical activity). - Teach the principles of the Dietary Guidelines for Americans and the Food Guide Pyramid. Instill pride in choosing to eat meals and snacks that comply with these principles. - Help students identify foods high and low in fat, saturated fat, cholesterol, sodium, added sugars, and fiber. - Teach the importance of balancing food intake and physical activity. - Teach the importance of eating adequate amounts of fruits, vegetables, and whole grains. - Help students increase the value they place on health and their sense of control over food selection and preparation. - Increase students' confidence in their ability to make healthy eating choices by gradually building up their food selection and preparation skills and giving them practice. - Have students analyze food preferences and factors that trigger eating behaviors. # Strategies to enhance behavioral capabilities that will support healthy eating - Provide opportunities for students to taste many healthy foods in an enjoyable social context. - Let students prepare healthy snacks or simple meals. - Encourage students to try unfamiliar and culturally diverse foods that are low in fat, sodium, and added sugars and that are high in fiber. - Have students select healthy foods from a fast-food restaurant menu. - Teach students how to recognize the fat, sodium, and fiber contents of foods by reading nutrition labels. - Help students record and assess their food intake. - Teach students how to use the Food Guide Pyramid to assess their diet for variety, moderation, and proportionality. - Have students set simple goals for changes in eating and physical activity, and devise strategies for implementing these changes and monitoring progress in reaching their goals. - When appropriate, let students practice (through role plays) encouraging parents to make healthy choices about eating and physical activity at home. - Have students examine media and social influences on eating and physical activity; teach students how to respond to these pressures. # Strategies to enhance behavioral capabilities that will support healthy eating - Let students plan and prepare healthy meals. - Have students select healthy foods from restaurant and cafeteria menus. - Teach students how to use nutrition labels to make healthy food choices. - Teach students ways to modify recipes and prepare foods to reduce fat and sodium content and to increase fiber content. - Help students identify incentives and reinforcements for their current eating and physical activity behaviors. - Have students examine media and social inducements to adopt unhealthy eating and physical activity patterns, teach them how to respond to these pressures, and let them use their new knowledge to identify their own resistance strategies. - Have students analyze environmental barriers to healthy eating and physical activity; explore strategies for overcoming these barriers. - When appropriate, give students practice in encouraging parents to make healthy choices about eating and physical activity at home. - Teach students to record their food intake, then have them assess and compare their diets with the standards set forth in the Dietary Guidelines for Americans and the Food Guide Pyramid. Have them assess and compare their intake of key nutrients (e.g., calcium and iron) with the intake recommended by the Public Health Service. - Have students set goals for healthy changes in eating and physical activity, identify barriers and incentives, and assess alternative strategies for reaching their goals and decide which to follow. Show students how to monitor their progress, revise their goals if necessary, and reward themselves for successfully attaining their goals. - Teach students how to evaluate nutrition claims from advertisements and nutrition-related news stories. The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to lists@list.cdc.gov. The body content should read subscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800. Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555. All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. # 6U.S. Government Printing Office: 1996-733-175/47007 Region IV # APPENDIX A: NUTRITION EDUCATION RESOURCE LIST Nutrition education curricula and print, audiovisual, and computer-based materials are available from government agencies, voluntary organizations, corporations, and commodity organizations. State Nutrition Education and Training Program coordinators can help schools identify the most appropriate nutrition education curricula and materials. National clearinghouses that can help schools identify a wide range of nutrition education and school food service resources are sponsored by the U.S. Department of Agriculture's Food and Nutrition Information Center and the National Food Service Management Institute; the former also serves as a lending library. # APPENDIX C: SELECTED SCHOOL-BASED STRATEGIES TO PROMOTE HEALTHY EATING Different, developmentally appropriate activities are listed for lower elementary school, upper elementary school, and middle and high school students (194 ). This list is not intended to be comprehensive. However, it does include many of the concepts critical to improving the diet and health of young persons in this country. Schools should review these educational activities in relation to their students' needs and abilities to determine which activities are appropriate at each grade level. Interventions that promote healthy changes in eating behaviors need to target three interacting spheres of influence: (a) the environment, which influences the likelihood that healthy eating behaviors will be adopted through social norms, influential role models, cues to action, reinforcements, and opportunities for action; (b) personal characteristics (e.g., knowledge, attitudes, beliefs, values, confidence in one's ability to change eating behaviors, and expectations about the consequences of making those changes); and (c) behavioral skills and experience, which are related to selecting or preparing specific foods, dietary self-assessment, and decision-making (186,194,203,204 ). The strategies listed here require the involvement of teachers, administrators, food service personnel, other school staff, and parents (194 ). Classroom teachers play the lead role in most of these activities, but many activities would be most effective if they were reinforced by other persons; all adults in the school community can help by serving as role models. Each school or district should determine the policies it needs to guide its nutrition-related activities and who is responsible for the tasks. # For lower elementary students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Involve parents in nutrition education through homework. - Provide role models (e.g., teachers, parents, other adults, older children, and celebrities or fictional characters) for healthy eating. - Provide cues, through posters and marketing-style incentives, that encourage students to make healthy choices about eating and physical activity. - Use incentives, such as verbal praise or token gifts, to reinforce healthy eating and physical activity. Do not use food for reward or punishment of any behavior. # Strategies to enhance personal characteristics that will support healthy eating - Make basic connections between food and health (e.g., "You need food to feel good and to grow"). # For middle and high school students Strategies to make the food environment more health-enhancing - Make healthy foods (e.g., fruits, vegetables, and whole grains) widely available at school, and discourage the availability of foods high in fat, sodium, and added sugars. - Provide role models (e.g., teachers, parents, other adults, and celebrities) for healthy eating. - Use peers as role models, and use peer-led nutrition education activities. - Through class discussions and small-group exercises, provide social support for making healthy changes in eating and physical activity. - Provide cues, through posters and marketing-style incentives that students design, that encourage students to make healthy choices about eating and physical activity. # Strategies to enhance personal characteristics that will support healthy eating - Explain the effects that diet and physical activity have on future health as well as on immediate concerns (e.g., current health, physical appearance, obesity, eating disorders, sense of well-being, and capacity for physical activity). - Have students identify reasons to adopt healthy eating and physical activity patterns. - Teach the principles of the Dietary Guidelines for Americans. Instill in the students pride in choosing to eat meals and snacks that comply with these principles. - Teach students how to identify foods high and low in fat, saturated fat, cholesterol, sodium, and added sugars. - Teach students how to identify foods that are excellent sources of fiber, complex carbohydrates, calcium, iron, vitamin A, vitamin C, and folate. - Teach the importance of balancing food intake and physical activity. - Teach the effects of unsafe weight-loss methods and the characteristics of a safe weight-loss program. - Help students increase the value they place on health and their sense of control over food selection and preparation. - Increase students' confidence in their ability to eat healthily by gradually building up their skills and giving them practice. - Help students examine what motivates persons to adopt particular eating habits. Have students keep a food diary noting what cues their own eating behavior (e.g., mood, hunger, stress, or other persons).