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7a73f9287841533eeb11c025026322a23d519f2c | cco | None | # 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.(...TRUNCATED) | # 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?
# Recurrence/Restaging
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.
# Diagnosis/Staging
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):
o 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.
o PET can detect some synchronous primaries that may be missed by other modalities. With respect to regional nodes (N):
o
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):
o 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.
# Recurrence/Restaging
# 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.
o 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.(...TRUNCATED) | None | None |
0ca6b1adf1e6c001dc70cd13be35a1e8a4c14839 | cco | None | # 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.(...TRUNCATED) | This report is copyrighted by Ontario Health (Cancer Care Ontario); the report and the illustrations herein may not be reproduced without the express written permission of Ontario Health (Cancer Care Ontario). Ontario Health (Cancer Care Ontario) reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. 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. Ontario Health (Cancer Care Ontario) 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.# Clinical Utility of Multigene Profiling Assays in Early-Stage Invasive Breast 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 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.
# PREAMBLE
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.(...TRUNCATED) | None | None |
68984194848f42b555d2a3c9077ac7a1e53f976b | cco | None | # 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(...TRUNCATED) | 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. Disclaimer Care has been taken in the preparation of the information contained in this report. 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. Cancer Care Ontario 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.# Magnetic Resonance Imaging for Pre-Treatment Local Staging of Prostate Cancer Section 1: Recommendations
This section 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 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.
# Note:
• 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(...TRUNCATED) | None | None |
c80ad0d5ba1eee75e1702847d361abd6ce4bc7b0 | cco | None | 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.(...TRUNCATED) | 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.
# Recommendations
• 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
# Methods
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 https://www.cancercareontario.ca for all additional Practice Guidelines Initiative reports.(...TRUNCATED) | None | None |
7a09ab0610ecc9990db3362ca0b00a37a016acb4 | cco | None | # 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.(...TRUNCATED) | # 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.
# RECOMMENDATIONS
# 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.(...TRUNCATED) | None | None |
8dc99ba0e643ca9733145769790691870c07fb3b | cco | None | # 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(...TRUNCATED) | # 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 http://www.cancercare.on.ca 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(...TRUNCATED) | None | None |
3fc88a47cdb08da328a10eddd380c8ffc6415303 | cco | None | 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.(...TRUNCATED) | 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.
# RECOMMENDATIONS
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.
# ALGORITHM
# POST-ENDORSEMENT:
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 <7 and PSA ≤10 ng/ml), intermediate risk (cT2b, Gleason = 7 or or high risk (cT2c or PSA >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.
# Nomograms
Prostate Risk Calculator developed by Nam et al 2011 is available here: http://sunnybrook.ca/content/?page=OCC_prostateCalc (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.
- 2.
# LUTS
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.
- 3.
# 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.(...TRUNCATED) | None | None |
5b1aedafa44e59813f737012f097d77bc96dd71b | cco | None | 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(...TRUNCATED) | 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.
# Methods
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).
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
# 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 http://www. 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.
# RESULTS
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.
# jco.org
# 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.
# Acknowledgment
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(...TRUNCATED) | None | None |
2f0b7d32a0fed28287602ada73d594179dd16882 | cco | None | "In Canada in 2010, an estimated 2600 new cases of ovarian cancer will be diagnosed and, of those ca(...TRUNCATED) | "A\n\n# INTRODUCTION\nIn Canada in 2010, an estimated 2600 new cases of ovarian cancer will be diagn(...TRUNCATED) | None | None |
43f3fad5ab04c54218779ea3e2a205987f8f58e1 | cco | None | "To determine the risk of cutaneous malignant melanoma (herein referred to as melanoma) associated w(...TRUNCATED) | "An assessment conducted in November 2022 deferred the review of Evidencebased Series (EBS) 8-8. Thi(...TRUNCATED) | None | None |
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🎉 NEW DROP 🎉 PubMed Guidelines
We just added 1627 clinical guidelines found in PubMed and PubMed Central to the dataset on December 23rd, 2023. Merry Christmas!
Clinical Guidelines
The Clinical Guidelines corpus is a new dataset of 47K clinical practice guidelines from 17 high-quality online medical sources. This dataset serves as a crucial component of the original training corpus of the Meditron Large Language Model (LLM). We publicly release a subset of 37K articles from our Guidelines corpus, extracted from 9 of 17 sources that allow content redistribution, namely CCO, CDC, CMA, ICRC, NICE, PubMed, SPOR, WHO and WikiDoc.
You can scrape and clean all 17 guideline sources using our code in epfLLM/meditron.
Dataset Details
- Curated by: EPFL LLM Team
- Language(s): English only
- License: Common Crawl Foundation Terms of Use
- Repository: epfLLM/meditron
- Paper: MediTron-70B: Scaling Medical Pretraining for Large Language Models
- Knowledge Cutoff: August 2023
Dataset Creation
Curation Rationale
The dataset was curated to provide a high-quality collection of clinical practice guidelines (CPGs) for the medical training of LLMs. Our Clinical Guidelines corpus comprises 48,096 articles from 17 globally recognized sources for clinician and patient-directed guidance across high and low-resource settings, multiple medical domains (internal medicine, pediatrics, oncology, infectious disease, etc.) and multiple geographical locations.
Source Data
Clinical practice guidelines are rigorously researched frameworks designed to guide healthcare practitioners and patients in making evidence-based decisions regarding diagnosis, treatment, and management. They are compiled through a systematic process of collaborative consensus between experts to establish recommendations from the latest evidence on best practices that would maximize benefit in light of practical concerns such as available resources and context. As a super-synthesis of meta-analyses, they sit atop the evidence pyramid and form the basis of actionable evidence-based practice.
Clinical guidelines differ based on several factors:
- Organizational level: CPGs are produced at various organizational granularities, ranging from global to hospital-level initiatives directed by international professional medical associations to informal consortia, regional or national governmental bodies to individual NGOs and hospitals.
- Geographic scope: The geographic scope ranges from global (WHO) to national (CDC, NICE) and regional (Ontario, Melbourne) to institutional (ICRC, Mayo Clinic). This corpus is biased towards English-speaking regions due to its exclusive focus on English content.
- Resource level: The corpus also represents health care concerns from high- (Ontario, Melbourne), low- (WHO), and volatile- (ICRC) resource settings.
- Audience level: Guidelines also contains a range of technical and conversational vocabulary with target audiences of clinicians or patients (or both), and is sometimes highly specialized within a theme (cancer, pediatrics, infectious disease).
- Peer-review: The peer review processes also ranged from UN bodies (WHO), institutional review boards (ICRC), professional associations (AAFP) to publicly crowdsourced knowledge bases (WikiDoc).
- Document size: Article length varies widely from very short statements to 100+ page guides.
Who are the source data producers?
The dataset is sourced from 17 globally recognized medical entities, covering a wide range of healthcare contexts and audiences.
We employed pragmatic selection criteria over medical sources, seeking CPGs that were:
- (1) open-access
- (2) systematically formatted with homogenous textual structure (i.e., in a format in which automated processes could be deployed without excessive risk of misaligning textual sequences)
- (3) in the language predominantly represented by the pre-training corpus of Llama (i.e., English)
- (4) covering a breadth of medical sub-domains, audiences (clinician, nurse, patient), and resource settings (high, low, and humanitarian response settings)
| Source | Full Name | Tag | Guidelines | Words | Audience | Country | Released |
|---|---|---|---|---|---|---|---|
| AAFP | American Academy of Family Physicians | aafp |
50 | 9.4K | Doctor | USA | No |
| CCO | Cancer Care Ontario | cco |
87 | 199K | Doctor | Canada | Yes |
| CDC | Center for Disease Control and Prevention | cdc |
621 | 6.7M | Doctor | USA | Yes |
| CMA | Canadian Medical Association | cma |
431 | 1.7M | Doctor | Canada | Yes |
| CPS | Canadian Paediatric Society | cps |
54 | 133K | Doctor | Canada | No |
| drugs.com | Drugs.com | drugs |
6548 | 4.1M | Both | International | No |
| GuidelineCentral | GuidelineCentral | gc |
1029 | 1M | Doctor | Mix | No |
| ICRC | International Committee of the Red Cross | icrc |
49 | 1.2M | Doctor | International | Yes |
| IDSA | Infectious Diseases Society of America | idsa |
47 | 646K | Doctor | USA | No |
| MAGIC | Making GRADE The Irresistible Choice | magic |
52 | 415K | Doctor | Mix | No |
| MayoClinic | MayoClinic | mayo |
1100 | 2.2M | Patient | USA | No |
| NICE | National Institute for Health and Care Excellence | nice |
1656 | 8.1M | Doctor | UK | Yes |
| PubMed | PubMed | pubmed |
1627 | 10.8M | Doctor | Mix | Yes |
| RCH | Royal Children's Hospital Melbourne | rch |
384 | 410K | Doctor | Australia | No |
| SPOR | Strategy for Patient-Oriented Research | spor |
217 | 1.1M | Doctor | Canada | Yes |
| WHO | World Health Organization | who |
223 | 3.1M | Both | International | Yes |
| WikiDoc | WikiDoc | wikidoc |
33058 | 34M | Both | International | Yes |
Data Collection and Processing
PDF documents were converted to text using GROBID.
After extracting the raw text from each source, we cleaned data with an ad-hoc process to exclude irrelevant or repetitive content that did not contribute to the textual content, such as URLs, references, figures, table delimiters, and ill-formatted characters.
This filtering procedure was performed differently for each source using a sample of 50 articles. Please note that this procedure is not perfect, as it may have removed useful information or kept superfluous content. We provide the raw_text for each article if you would like to perform your own cleaning step.
Additionally, the text was standardized to a unified format with hierarchical section headers indicated by '#', homogenous spacing '\n\n' separating paragraphs, and normalized lists formatted with '- ' bullet points.
Finally, all samples were deduplicated using title matching, and articles that were too short or not English were filtered out.
Personal and Sensitive Information
As the articles are publicly accessible, no personal or sensitive information is included.
Dataset Structure
Each row of the dataset represents one clinical practice guideline article, and consists of the following dataset fields (all strings):
| Field | Description | Sources with field |
|---|---|---|
id |
Unique identifier for each article | All |
source |
Source tag (cco, cdc, cma, icrc, nice, spor, who or wikidoc) |
All |
title |
Title of the article | CMA, NICE & WikiDoc |
url |
URL of the article | NICE, WikiDoc & PubMed |
raw_text |
Unprocessed scraped article text | All |
clean_text |
Cleaned and formatted article text | All |
overview |
Short summary or abstract of the article | NICE & Pubmed |
Uses
The dataset is intended for use in tasks related to text generation, specifically in the context of clinical practice guidelines. It can be employed for training language models and other natural language processing applications within the healthcare domain.
Out-of-Scope Use
- Redistribution: Please always check redistribution licenses before using the content as these may also evolve over time. To the best of our knowledge, we are following the redistribution licensing of each source and we invite users to inform us if that is not the case.
- Malicious use: We do not support any use of this corpus that may be harmful. Creating tools that provide clinical advice is commendable, but extremely dangerous if not done with the appropriate care. Such tools need to be validated for safety and utility by medical professionals in randomized controlled trials. i.e. please do not create cowboy health apps that fool vulnerable users into thinking they are receiving validated advice.
Bias, Risks, and Limitations
- Peer-Review Quality: It is important to understand that while most sources are validated by internationally endorsed professional associations, a large proportion of articles are from Wikidoc which contains crowdsourced content. While edits in Wikidoc are generally restricted to expert review, the process of consensus and oversight is different from the traditional rigor of clinical guidelines.
- Representation: This corpus is in English, and over-represents English-speaking regions. While we have included WHO and ICRC guidelines for low-resource settings, further work needs to be done to scrape sources from diverse contexts.
- Temporal scope: Guidelines are constantly updated and these represent a snapshot of each in August 2023. Please re-scrape for updated content.
Recommendations
We warmly invite users to help us build a more representative corpus with high-quality peer-reviewed clinical practice guidelines in various languages and representing the full scope of clinical specialties and geographic regions. We encourage users of this content to be mindful of its current limitations in temporal and geographic scope and we repeat our warning: creating tools that provide clinical advice is commendable, but extremely dangerous if not done with the appropriate care. Such tools need to be validated for safety and utility by medical professionals in randomized controlled trials. i.e. Please don’t create cowboy health apps that fool vulnerable users into thinking they are receiving validated advice.
Acknowledgments
The availability of open-access clinical practice guidelines (CPG) was critical to this work, and we thank all the societies listed above. A broader representation of geography, medical specialties, and contexts (especially low-resource settings) could be achieved through more standardized CPG formatting practices to ensure reliable textual extraction (e.g., releasing .txt or .html versions with structured content). We encourage the CPG community to continue to make these documents available (open-access with permissive licenses for incorporation into large language models) and easily usable.
Authors
- Curation: Mary-Anne Hartley
- Scraping: Antoine Bonnet, Alexandre Sallinen, Igor Krawczuk, Kyle Matoba
- Cleaning: Antoine Bonnet, Alexandre Sallinen
Citation
If you use the Clinical Guidelines corpus, please cite out work:
@misc{chen2023meditron70b,
title={MEDITRON-70B: Scaling Medical Pretraining for Large Language Models},
author={Zeming Chen and Alejandro Hernández-Cano and Angelika Romanou and Antoine Bonnet and Kyle Matoba and Francesco Salvi and Matteo Pagliardini and Simin Fan and Andreas Köpf and Amirkeivan Mohtashami and Alexandre Sallinen and Alireza Sakhaeirad and Vinitra Swamy and Igor Krawczuk and Deniz Bayazit and Axel Marmet and Syrielle Montariol and Mary-Anne Hartley and Martin Jaggi and Antoine Bosselut},
year={2023},
eprint={2311.16079},
archivePrefix={arXiv},
primaryClass={cs.CL}
}
@software{epfmedtrn,
author = {Zeming Chen and Alejandro Hernández-Cano and Angelika Romanou and Antoine Bonnet and Kyle Matoba and Francesco Salvi and Matteo Pagliardini and Simin Fan and Andreas Köpf and Amirkeivan Mohtashami and Alexandre Sallinen and Alireza Sakhaeirad and Vinitra Swamy and Igor Krawczuk and Deniz Bayazit and Axel Marmet and Syrielle Montariol and Mary-Anne Hartley and Martin Jaggi and Antoine Bosselut},
title = {MediTron-70B: Scaling Medical Pretraining for Large Language Models},
month = November,
year = 2023,
url = {https://github.com/epfLLM/meditron}
}
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