October 2015 placed Evidence-based Series (EBS) 2-12 Version 2 in the EDUCATION AND INFORMATION section. This means that the recommendations will no longer be maintained but may still be useful for academic or other information purposes. The PEBC has a formal and standardize process to ensure the currency of each document (PEBC Assessment & Review Protocol) Evidence-based Series (EBS) 2-12 Version 2, the full review report, consists of the following 4 parts: 1. Guideline Overview 2. Summary 3. Full Report 4. Document Assessment and Review Tool# 
FULL REPORT I. QUESTION Does combined modality radiotherapy and chemotherapy improve survival compared with radiotherapy alone in patients with localized carcinoma of the esophagus for whom a non-surgical approach is used?

# II. CHOICE OF TOPIC AND RATIONALE
Carcinoma of the esophagus has a poor overall prognosis. The extent of disease at the time of presentation and a patient's performance status are the most powerful predictors of the potential for cure (1,2). The opportunity exists to eradicate the disease that is localized at presentation through therapy given with curative intent. The current TNM (Tumour Node Metastases) staging system (6 th edition 2002) (3) incorporated major prognostic factors, including the extent of esophageal wall involvement (T1-4) and whether local regional nodes are involved (N1). The extent of disease that oncologists consider amenable to curative intent is evolving. The changes in the precision and accuracy of diagnostic modalities, including the use of tools such as minimally invasive staging techniques, are improving the accuracy of clinical staging. Within this context, most would consider patients with T4 disease and extensive nodal involvement incurable. There is increasing evidence that patients with less than five nodes involved may have a better outcome than those with more extensive disease (4). Furthermore, the definition of nodal stations that are considered regional and still amenable to potentially curative therapies is also evolving. For the purpose of this guideline, patients with T1-3, small volume N1, M0 are considered potential candidates for curative therapy.
Both primary surgery and radiotherapy (RT) are offered as treatment options to suitable candidates. In cervical tumours, the desire to avoid a laryngoesophagectomy, together with the retrospective data supporting a better prognosis with cervical esophageal tumours, has resulted in the general acceptance of an organ-preserving approach for these patients. For patients with thoracic esophageal tumours, the recommendation for a primary surgical approach versus a primary radiotherapy approach had predominantly been based on the patient's medical operability, the patient's preference, and the treating physician's estimation of the relative morbidity of the outcomes. A well-known attempt in the United Kingdom to compare surgery and radiotherapy through a randomized study failed through the inability to accrue patients (5). Two randomized studies compared surgery alone versus radiotherapy alone (6,7). In 1994, Fok et al (6) reported a four-arm study comparing surgery alone, preoperative radiotherapy and surgery, postoperative radiotherapy and surgery, and radiotherapy alone. The study was conducted in Hong Kong and included 156 patients. Median survival for surgery versus radiotherapy was 21.6 months versus 8.2 months (p<0.001). Similarly, in 1999 Badwe et al (7) reported a randomized study comparing surgery alone versus radiotherapy alone. A total of 99 patients participated in this study. Overall survival was significantly superior in the surgery arm versus the radiotherapy arm (p=0.002). The generalizability of these results to contemporary surgical and radiotherapy techniques and practices and the selection factors that need to be considered when choosing between these two treatment modalities will be discussed in a separate guideline for the overall management of esophageal cancer that would be produced in due course.
Studies of the patterns of care of esophageal cancer in North America have shown an increase in the use of combined chemoradiotherapy (RTCT). Daly et al (8) analyzed patterns of care using the U.S. National Cancer Database and found that the treatment modality most commonly employed for esophageal cancer is combined radiotherapy and chemotherapy (30.2%), followed by surgery alone (18%). The most common chemotherapy regimen used in combination with radiation is 5-fluorouracil (5FU) and cisplatin. In the Patterns of Care Study (9), the chemotherapy agents most frequently used were 5FU (84%), cisplatin (64%), and mitomycin (9%). Youssef et al (10) compared management and outcome of carcinoma of the esophagus in Ontario and the United States. Controlling for age, sex, histology, and sub-site, the rate of esophagectomy was similar, but the rate of primary RT was lower in Ontario. Practice patterns for the use of RT versus combined RTCT, and the types of chemotherapy that are being used, have not been described for Ontario or Canada.
This practice guideline report addresses the question of whether the addition of chemotherapy to a primary radiotherapy approach improves patient outcomes. A separate guideline is being prepared on the use of neoadjuvant or adjuvant therapy for resectable esophageal cancer when surgery is the primary modality (PG2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer). Eventually, the Gastrointestinal Cancer Disease Site Group (DSG) will consolidate both guidelines to produce a comprehensive recommendation for patients with localized carcinoma of the esophagus who are treated with curative intent.

# III. METHODS Guideline Development
This practice guideline report was developed by the Practice Guidelines Initiative (PGI) of Cancer Care Ontario's Program in Evidence-based Care (PEBC), using the methods of the Practice Guidelines Development Cycle (11). Evidence was selected and reviewed by two members of the PGI's Gastrointestinal Cancer Disease Site Group and methodologists. Members of the Gastrointestinal Cancer DSG disclosed potential conflict of interest information.
The practice guideline report is a convenient and up-to-date source of the best available evidence on combined modality radiotherapy and chemotherapy in the non-surgical management of localized esophageal cancer, developed through systematic reviews, evidence synthesis, and input from practitioners in Ontario. The body of evidence in this report is primarily comprised of mature randomized controlled trial data; therefore, recommendations by the DSG are offered. The report is intended to promote evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations, and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee.
The PGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original guideline information.
The systematic review component of this guideline report has been published as a Cochrane Review (12). MEDLINE (1966to December 2001, CANCERLIT (1983to October 2001, and the Cochrane Library (2001, Issue 4) were searched with no language restrictions. Medical subject heading (MeSH) terms employed included "esophageal neoplasms" with subheadings "drug therapy", "radiotherapy", or "therapy". The terms used to capture randomized trials included the use of "randomized controlled trials", "controlled clinical trials", "random allocation", "exp clinical trials", and the text word "random". The proceedings of the 1999, 2000, and 2001 annual meetings of the American Society of Clinical Oncology (ASCO) and the American Society for Therapeutic Radiology and Oncology (ASTRO) were also searched. Ongoing trials were identified through the Physician Data Query (PDQ) database (/).

# Literature Search Strategy
The literature search was updated on February 10, 2005 using the following databases: MEDLINE (through February week 1, 2005), EMBASE (through week 6, 2005), and the Cochrane Library's dB of Systematic Reviews (through Issue 4, 2004). Abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology through 2004 were also searched for relevant evidence. The National Cancer Institute's (NCI) clinical trials database was also searched on February 10, 2005 for listings of ongoing clinical trials.

# Inclusion Criteria
Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma.

# Exclusion Criteria
- Esophagectomy as a planned intervention 2. Use of pure radiosensitizer (e.g. misonidazole) with radiotherapy

# Study Endpoints
The primary endpoint of interest was overall survival. Data were examined for one-to five-year overall mortality rates. Secondary endpoints included local recurrence and adverse effects. While disease-specific survival and quality-of-life data would be useful endpoints to consider, they were not reported by the primary authors of the eligible trials and could not be evaluated. The data in this report are based on the intention-to-treat (ITT) principle unless data for only evaluable patients were reported and there was insufficient information to allow for an ITT analysis.

# Synthesizing the Evidence
Studies of combined modality radiotherapy and chemotherapy can generally be categorized as using a concomitant or sequential approach based on the relative timing of the radiotherapy and chemotherapy, with different biological bases behind their designs. In this report, the trials that used a concomitant approach were described and analyzed separately from trials using a sequential approach. When data from trials of sequential and concomitant approaches were examined together, the pooled data were heterogeneous, suggesting that the studies are different in nature. Thus, a combined analysis of both approaches was rejected.
Data on survival and local recurrence were pooled and the results were examined for statistical heterogeneity. For each meta-analysis, data were pooled at a common time-point (e.g., mortality at one-year). The time point selected for meta-analyses must be clinically credible and relevant but not so far along the survival curve that wide confidence intervals result from fewer patients contributing to the estimate. Since time points prior to the median will generally ensure that there is sufficient data to be credible, the median survival times, weighted by the size of the treatment arms, were calculated to determine an appropriate time point for each meta-analysis. Pooling was conducted using one-year mortality data for all meta-analyses because the weighted median survival time was less than one year for both the concomitant and sequential groups (13).
The study results were pooled using Review Manager 4.0.3 (Metaview Update Software), which is available through the Cochrane Collaboration. The random effects model was used as the more conservative estimate of effect (14). Results were expressed as odds ratios (OR) with 95% confidence intervals (CI). An OR less than 1.0 favours the experimental treatment (i.e., RTCT) and an OR greater than 1.0 favours the control (i.e., RT alone). In addition, the absolute difference is presented as percent difference in outcome, calculated from the pooled event rates. The number of patients that need to be treated with RTCT for one additional patient to benefit (NNT) was also calculated.
Results for adverse effects were not pooled because the primary authors of eligible trials reported data on adverse effects using different scoring systems and symptom categories. The presentation of the incidence of adverse effects (as opposed to the numbers of patients affected within each toxicity grade) makes a quantitative summary statistic difficult. The results were summarized in a descriptive fashion for this review based on the incidence of grade of toxicity for acute and late adverse effects, where available across the studies, to allow for a qualitative comparison.
Data extraction was performed independently by two members of the Gastrointestinal Cancer DSG. Discrepancies were resolved through consensus.

# Subgroup Analysis
It was hypothesized a priori that the use of cisplatin versus non-cisplatin chemotherapy would have an impact on the effectiveness of treatment, and a subgroup analysis was planned to examine this hypothesis. The two most commonly employed chemotherapy regimens in Canada are 5FU/mitomycin and 5FU/cisplatin, and one of the major decisions facing clinicians is what type of chemotherapy to use if the combined modality approach is adopted. Furthermore, cisplatin-based chemotherapy has been used in combination with radiotherapy in many other disease systems resulting in significant improvement in outcome (15)(16)(17)(18)(19)(20). It is, therefore, important to explore the impact of cisplatin versus non-cisplatin chemotherapy within the context of combined modality.

# Potential Sources of Heterogeneity and Sensitivity Analysis
The following factors were postulated a priori to be potential sources of heterogeneity: study quality using scores on the Jadad scale (21) (>2 versus 2); dose of radiotherapy (BED 2 >60 versus BED 60); and type of chemotherapy (cisplatin-containing versus others). These factors were used to explore any significant heterogeneity of results across the trials. Heterogeneity of study results was assessed using a visual plot (22) and by calculating the Breslow-Day statistic using a planned cut-off for significance of p<0.05. The robustness of our conclusions was examined through subsequent sensitivity analyses using these factors.

# IV. RESULTS

# Literature Search Results
No fully published reports of meta-analyses were identified, although the pooling of data presented in this guideline report was published in abstract form in 1999 (23). This abstract will not be discussed further because the meta-analysis has been updated for this guideline report. A related study by Smith et al (24) was excluded due to surgery being a planned option within the study design.
Ten randomized trials of concomitant RTCT met the inclusion criteria (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). After a careful evaluation of the methodology, it was decided to include only eight of these trials (25)(26)(27)(28)(29)(30)(31)(32) in the analysis. The trial by Hukku et al (33) was excluded because of concerns about the adequacy of the randomization procedure. Between 1990 and 1992, Kolaric et al reported five identical abstracts (34)(35)(36)(37)(38) for the same trial. This trial was excluded because there is sufficient uncertainty and absence of appropriate data for the clinical question we were trying to answer. Of the eight trials of concomitant RTCT that were included in the analysis, all but one trial (29) have been fully published. In addition to the report of long-term follow-up of the trial by the Radiation Therapy Oncology Group (RTOG) (32), five prior reports of this trial were identified and reviewed for data extraction (39)(40)(41)(42)(43). Five fully published, randomized trials of sequential RTCT met the inclusion criteria and were included in this review (44)(45)(46)(47)(48). Update Updating activities found an RCT by Savani and Jani reported in abstract form (1u). This trial compared RTCT to RT alone in a sample of 48 patients diagnosed with squamous cell carcinoma. There were insufficient details in the abstract regarding the intervention (dose regimen of chemotherapy and radiotherapy employed, timing of radiotherapy and chemotherapy), adequacy of the randomization process, and outcomes of interest (duration of follow up, overall survival, local recurrence rates, or late toxicities). Available study characteristics are included in Table 1-2. The investigators provided information on complete response post treatment, dysphagia relief, and acute toxicities in the abstract. The authors concluded that multimodal therapy with RTCT is a better therapeutic option, with acceptable (acute) toxicity profile and good response rate. Due to insufficient detail to permit optimal assessment of the study, the available outcome data (response rate, dysphagia relief, or acute toxicities) were NOT incorporated into the current review. Additional data from this trial will be incorporated in this review as full results become available.

# Outcomes Study Characteristics
Tables 1 and 2 outline the pertinent study characteristics and the treatment regimens. Patients with squamous cell carcinoma were included in all trials, with six trials devoted exclusively to this pathology (25,27,28,31,44,46). All of the other trials included both squamous cell carcinoma and adenocarcinomas. The extent of the primary disease was variable, with the majority of patients suffering from locally advanced disease. All trials excluded patients with distant metastases although this was done without the benefit of any abdominal imaging in all but three trials (31,32,44). It is highly probable that a substantial proportion of included patients had nonlocalized disease. Patients with disease spread to the supraclavicular lymph nodes were accepted in three trials (26,32,44). The presence or absence of disease spread to the mediastinal lymph nodes was not specified in any of the published eligibility criteria. Most trials used specified criteria to exclude patients in poor general condition. The chemotherapy regimens varied across the trials and included methotrexate (44), bleomycin (25)(26)(27), cisplatin (29,30), cisplatin and bleomycin (47), 5FU, mitomycin and bleomycin (28), 5FU and cisplatin (31,32,45), oral futrafur (46), and intraarterial adriamycin, 5FU and cisplatin (48). In general, the duration of follow up was short with only one-and two-year mortality data available for comparison. Table 3 provides survival data for the randomized trials. Five-year survival data were available for only three trials (28,32,44).  
For trials of concomitant RTCT, data on mortality were available at one year for seven trials (25,26,(28)(29)(30)(31)(32). There was no statistically significant heterogeneity among the trials of concomitant RTCT when one-year mortality data was considered (p=0.49). Pooling across the seven trials involving 687 patients at one year resulted in an OR of 0.61 (95% CI, 0.44 to 0.84; p<0.00001) in favour of concomitant RTCT (Figure 1). When expressed as an absolute mortality rate, the one-year mortality rate for RTCT versus RT alone was 56% versus 67%. This is an absolute difference of 11% and a NNT of 9.
The pooled analysis of five trials involving 440 patients of sequential RTCT versus RT (44-48) revealed no significant difference in survival between the treatment groups at one year (Figure 2). There was significant heterogeneity across the trials (p=0.03), but there were too few studies to allow for a meaningful exploration of the potential sources of heterogeneity.

# Subgroup analysis
It was hypothesized a priori that the use of cisplatin versus non-cisplatin chemotherapy would have an impact on the effectiveness of treatment. When only concomitant RTCT trials using cisplatin-containing chemotherapy were included (29)(30)(31)(32), a statistically significant survival benefit was detected at one year (OR, 0.54; 95% CI, 0.36 to 0.82; p=0.003) (Figure 3).

# Sensitivity analysis
Sensitivity analyses were conducted to test the robustness of the results of the pooled analyses. The two variables that were examined by additional analyses were study quality and radiation dose in combined RTCT.
The exclusion of lower quality studies and studies reported only in abstract form did not have a significant impact on the conclusion.
The radiotherapy dose fractionation employed, especially as it was used in the control arm, has important implications on whether the study was optimally designed to evaluate the use of combined concomitant RTCT as a potentially curative therapy. Sensitivity analysis using one-year mortality data (Figure 4) was performed for studies using a BED of  60Gy-1 and <60Gy-1. In this analysis, no statistically significant survival benefit was detected for studies using BED  60Gy-1 (OR, 0.76; 95% CI, 0.46 to1.25; p=0.3), and significant benefits were observed in only the two studies that employed BED of <60Gy-1 (OR, 0.54; 95% CI, 0.32 to 0.90; p=0.02). This observation infers that the survival benefit observed may be due to chemotherapy compensating for suboptimal radiotherapy dosing rather than augmenting survival beyond what optimal radiotherapy alone could provide. 

# Local recurrence
Data on local recurrence were available for only three trials of concomitant RTCT (28,29,32). The trial by the RTOG (32) was the only one for which local recurrence rates for years one to three was reported. Pooling of the data detected a significant reduction in local recurrence in patients treated with concomitant RTCT compared with RT alone (OR, 0.52; 95% CI, 0.31 to 0.89; p=0.004) and no statistically significant heterogeneity (p=0.23) (Figure 5). When expressed as probabilities, the recurrence rates were 55% versus 69%, with an absolute difference of 14% and a NNT of 7.
There was also no significant heterogeneity among results for trials of sequential RTCT (p=0.26). The pooled OR was 1.05 (95% CI, 0.59 to 1.87; p=0.20), indicating no significant difference in local recurrence for sequential RTCT compared with RT alone (Figure 6).

# Adverse Effects
The adverse effects experienced by patients in trials of concomitant RTCT are summarized in Table 4. No information on adverse effects was available for the trial reported by Andersen et al (27). In four trials, acute adverse effects were reported using a grading system (29-32) while a narrative description of the intensity of the severity was provided instead of grading toxicity in three trials (25,26,28). Earle et al (25) described one patient with severe nausea and vomiting, one with severe stomatitis, one with severe dermatitis requiring discontinuation of chemotherapy, and one patient with white cell counts less than 2.9X10 9 /l in the combined modality arm. In the radiotherapy alone arm, two patients had leucopenia with white cell counts less than 2.9 X10 9 /l. Araujo et al (28) described three patients with severe esophagitis in the combined modality arm and no adverse effects corresponding to grade 3-4 criteria in the radiotherapy alone arm. These descriptions of toxicity intensity correspond to grade 3-4 toxicity (according to RTOG toxicity criteria). In order to facilitate presentation of the data, they are included in Table 4 under the column for acute grade 3-4 toxicity. As grade 1-2 adverse effects were not reported consistently, only grade 3-4 and toxic deaths (acute and late) are presented for comparison.
Acute adverse effects, particularly gastrointestinal and hematological toxicities, were more frequent among patients treated with concomitant RTCT compared with RT alone (Table 4). Concomitant RTCT was associated with more grade 3-4 acute adverse effects compared with RT alone. There was no difference in late toxicity between the two treatment groups. Toxic deaths were rare. Zhang (26) reported that 3/48 patients in the RTCT arm died with extensive pulmonary infiltrate which was attributed to the combination of high dose RT and bleomycin compared to 0/51 in the radiotherapy alone arm. Slabber et al (31) described 2/34 versus 2/36 patients in the RTCT versus RT who died following perforation after dilatation. In the trial by the RTOG (32), there was 1/61 deaths in the RTCT arm secondary to renal and bone marrow failure compared to 0/62 in the radiotherapy alone arm.
In the two trials of sequential RTCT for which data on adverse effects were reported (44,45), no toxicity grading system for intensity of adverse effects was used (Table 5). Roussel et al (44) observed more adverse effects with sequential RTCT, with predominantly hematological toxicity and mucositis. In addition, there was one death with myelopathy occurring in the RT alone arm, and one from severe pancytopenia in the RTCT arm. Nausea and vomiting and hematological toxicities were more common among patients in the sequential RTCT arm of the study by Zhou (45).  

# V. INTERPRETIVE SUMMARY
Based on the pooled analyses, concomitant RTCT compared with RT alone was associated with an absolute reduction of one-year mortality from 67% to 56%, with a NNT of 9. The recurrence rate was reduced from 69% with RT alone to 55% with concomitant RTCT, with a NNT of 7. These benefits, while relatively modest, are not trivial considering the generally poor survival rates and the morbidity associated with an uncontrolled primary tumour. However, these advantages are associated with a significant increase in potentially life-threatening and severe adverse effects (grade 3-4). While quality of life was not evaluated in any of these trials, this aspect also demands consideration within the context of the magnitude of the survival advantage and expected survival rate based on disease and patient status. An appreciation of the primary conclusions of the studies and their impact on clinical practice patterns over time would help to put the current review in perspective. All of the published studies, with the exception of Zhang (26) (which was published only in the Chinese literature, and therefore has received very little attention), have suggested that RTCT is ineffective, until the results published by the RTOG (32). Despite the long history of negative studies, this one positive RTOG study has, for several reasons, resulted in substantial changes to clinical practice since its publication. The RTOG study supports the findings of many phase II studies suggesting a favourable outcome, but perhaps more importantly, the results are consistent with similar benefits observed in other solid tumours, such as head and neck, lung, and cervical cancer, when concomitant cisplatin was used with radical radiotherapy (15)(16)(17)(18)(19)(20). In a disease where the general outcome is uniformly poor, a single positive study conducted by a large collaborative group was sufficient to motivate the adoption of this approach in standard clinical practice.
How strong is the evidence in support of combined modality? Given the methods employed to evaluate the literature, this quantitative review represents a comprehensive search of the existing data from randomized studies, and as such, represents the best available data for any evidence-based conclusions. However, three major factors will continue to limit the strength of our conclusions. First, many different types of chemotherapy regimen were tested among the studies identified. Second, long-term data are lacking for many of the included studies. Third, the sensitivity analysis raised the possibility that the observed survival benefit at one year may be explained by chemotherapy compensating for suboptimal radiotherapy doses in some studies, rather than combined chemotherapy/radiotherapy being able to improve outcome beyond what could be achieved by optimal radiotherapy alone. Despite these limitations, it is unlikely that further clinical trials using radiotherapy alone as a control arm will be undertaken to provide additional evidence to address this question, given the current practice patterns in North America.
The current review illustrates a benefit in local control and survival with the use of concomitant RTCT. This result in turn supports the common clinical practice of employing combined RTCT when offering a non-surgical approach with a curative intent for the management of esophageal cancer. In patients with favourable performance status and who have a reasonable chance of completing concomitant RTCT, this approach is a reasonable option compared with radiotherapy alone. Participation in clinical trials is strongly encouraged to further define the optimal strategy needed to minimize adverse effects and further enhance treatment outcomes within the context of combined RTCT.
There was no evidence to suggest any survival or local control benefit using sequential RTCT compared with RT alone. Given these results and the increased adverse effects associated with sequential RTCT, this approach should not be recommended in standard practice.

# VI. ONGOING TRIALS
No ongoing trials were found that addressed the guideline question and met the inclusion criteria for this review of the evidence. Clinical trials designed to reduce toxicity and further augment the outcome of this approach are ongoing, and participation in these trials should be encouraged.

# VII. DISEASE SITE GROUP CONSENSUS PROCESS
The Gastrointestinal Cancer DSG readily agreed upon and approved the contents of the practice guideline report. The committee felt, however, that it was important to highlight the following issues.
The meta-analysis of survival benefit was based on one-year data only; therefore, caution must be used when interpreting the results, especially when long-term survival benefit is considered.
The Gastrointestinal Cancer DSG members debated how to address the issue of what type of chemotherapy to recommend in the context of a combined radiotherapy and chemotherapy approach. The current review was undertaken to address the general question of whether a combined approach is superior to radiotherapy alone and, therefore, was not designed to answer the question of what specific type of chemotherapy-radiotherapy regimen is superior to others. To address the latter question, we would need to review randomized studies comparing a standard type of combined radiotherapy and chemotherapy versus an experimental one, but these studies are not available. In the current review, it was hypothesized that whether or not cisplatin-based chemotherapy was used would have an impact on the conclusion of the review, and the subgroup analysis in fact did support this. The current clinical practice in North America in this area has been heavily shaped by the results of the RTOG study (32). There has been a substantial increase in the use of combined radiotherapy and chemotherapy in recent years (8), and when it is used, 5FU and cisplatin are the chemotherapy agents most commonly employed (9). The DSG felt that given the results of the meta-analysis and the current practice pattern, the use of a cisplatin-containing regimen should be the treatment of choice when concomitant radiotherapy and chemotherapy is used. For patients with poor performance status, radiotherapy alone or optimal palliative therapy should be considered.
The DSG also felt that it is important to point out the significant risk of toxicity associated with concomitant radiotherapy and chemotherapy. This fact may indeed outweigh the potential benefits in survival and local control, depending on the patient's general condition. The decision to adopt a combined radiotherapy and chemotherapy approach over radiotherapy alone for the curative management of carcinoma of the esophagus should be undertaken only after due consideration of these factors and in consultation with the patient.
The group also felt it should be made clear that there are no randomized trials of chemoradiation alone versus surgery alone as the primary modality for patients with curable esophageal cancer who are suitable for both (surgical and non-surgical) approaches.

# VIII. EXTERNAL REVIEW OF THE PRACTICE GUIDELINE REPORT
This section describes the external review activities undertaken for the original guideline report.

# Draft Recommendations
Based on the evidence described in the original report above 3 the Gastrointestinal Cancer DSG drafted the following recommendations:

# Target Population
These recommendations apply to adult patients with localized carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist.

# Draft Recommendations
- Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, the use of a cisplatin-based chemotherapy regimen is recommended when concomitant radiotherapy and chemotherapy is used.
- Patients should be aware of the increased acute toxicity associated with this approach. The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits and the patient's general condition.  Sequential radiotherapy and chemotherapy should not be recommended as standard practice.

# Qualifying Statements
- Localized esophageal cancer has been managed surgically or with radiotherapy. There are no randomized trials comparing these treatments, so it is unclear whether a surgical or a nonsurgical approach is superior in patients who are suitable for both approaches.

# Related Guideline
Practice Guideline Initiative's Practice Guideline #2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer.

# Practitioner Feedback
Based on the evidence contained in the original report and the draft recommendations presented above, feedback was sought from Ontario clinicians.
Practitioner feedback was obtained through a mailed survey of 163 practitioners in Ontario (28 medical oncologists, 21 radiation oncologists, 111 surgeons and three gastroenterologists). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations outlined and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer DSG reviewed the results of the survey.
Key results of the practitioner feedback survey are summarized in Table 6. Seventy-nine surveys (53%) were returned. Twenty-nine respondents (37%) (10 medical oncologists, seven radiation oncologists, and 12 surgeons) indicated that the practice-guideline-in-progress report was relevant to their clinical practice and completed the survey. 

# Strongly disagree or disagree
The rationale for developing a clinical practice guideline, as stated in the "Choice of Topic" section of the report, is clear.
There is a need for a clinical practice guideline on this topic.
The literature search is relevant and complete. 25 (86%) 2 (7%) 2 (7%) The results of the trials described in the report are interpreted according to my understanding of the data.
The draft recommendations in this report are clear. 27 (93%) 1 (3%) 1 (3%) I agree with the draft recommendations as stated.
27 (93%) 1 (3%) 1 (3%) This report should be approved as a practice guideline. 21 (72%) 5 (17%) 1 (3%)
If this report were to become a practice guideline, how likely would you be to make use of it in your own practice?

# Very likely or likely
Unsure Not at all likely or unlikely 21 (72%) 7 (24%) 0 Percentages may not total 100% due to missing data.

# Summary of Written Comments
Eight respondents (28%) provided written comments. Five of the eight respondents expressed concern that the recommendation for cisplatin-based chemotherapy versus non-cisplatin-based chemotherapy goes beyond that suggested by the available evidence. A medical oncologist who disagreed with the recommendations indicated that it would be imprudent to advise concomitant radiotherapy and cisplatin-based chemotherapy for all patients until it is determined that patients with adenocarcinoma do better with radiotherapy plus cisplatin-based chemotherapy and patients with squamous cell carcinoma do better with COP (cyclophosphamide, vincristine, prednisone). This practitioner also questioned the use of odds ratios rather than absolute risk reduction and number needed to treat. Another respondent requested an algorithm to help in deciding between surgical and non-surgical treatment. The same respondent commented on the limited discussion on quality of life. One respondent wondered why a European Cooperative Oncology Group (ECOG) study of chemoradiation was not included, although this respondent also acknowledged that surgery was a planned intervention for some patients in this ECOG study.
The Gastrointestinal Cancer DSG acknowledged the comments from the practitioner feedback survey that highlighted the limitations of the evidence in support of a cisplatin-containing regimen. These comments were forthcoming despite the fact that the limitations of the data were already discussed in the interpretive summary in the original draft. The DSG, therefore, felt it was appropriate to reword the recommendation to read "a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used." Instead of the original wording of "a cisplatin-based chemotherapy regimen is recommended when concomitant radiotherapy and chemotherapy is used."
The utility of other novel regimens will be incorporated into the guideline report through our guideline update process when relevant studies are completed and reported.
Two respondents felt that the literature identified was incomplete, although only one additional reference was cited, i.e. the ECOG study reported by Smith et al (24). This study did not satisfy our inclusion criteria because surgery was an optional but planned intervention.

# Practice Guidelines Coordinating Committee Approval Process
The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval. All 11 members of the PGCC returned ballots. Ten PGCC members approved the practice guideline report as written and one member approved the guideline conditional on the GI DSG addressing specific concerns. The PGCC member requested that the following issues be addressed prior to the approval of the guideline report:
One member thought that the first bullet under key evidence should end with, "at conventional radiation dose fractionation schedules", or "at the doses and fractionation of radiation used in the control arms of trials" because increasing the radiation dose or fractionation schedule could achieve improved results (but which would also increase radiation toxicity). For this reason, the same member thought there should have been an exclusion criterion for trials that used inadequate doses of radiotherapy because they give a false impression of the value of the experimental arm.
Another member stated that there should be a recommendation regarding placing patients on trials to better define concurrent chemoradiotherapy combinations that will improve outcomes with less toxicity, as this item appeared in the guideline text.
Modifications/Actions 1. Sensitivity analysis using one-year mortality data (Figure 4) was performed for studies using a BED of  60Gy-1 and <60Gy-1. In this analysis, no statistically significant survival benefit was detected for studies using BED  60Gy-1 (OR, 0.76; 95% CI, 0.46 to1.25; p=0.3); and significant benefits were observed in only the two studies that employed BED of <60Gy-1 (OR, 0.54; 95% CI, 0.32 to 0.90; p=0.02). This observation infers that the survival benefit observed may be due to chemotherapy compensating for suboptimal radiotherapy dosing rather than augmenting survival beyond what optimal radiotherapy alone could provide. Although the meta-analysis detected an outcome that was not as strong as expected, supporting the use of combined RTCT in non-surgical therapy for esophageal cancer is still a reasonable recommendation. 2. A bullet providing suggestions for future clinical trials was added to the recommendations. 3. All necessary editing changes were also made.

# Approved Practice Guideline Recommendations
These practice guideline recommendations reflect the integration of the draft recommendations with feedback obtained from the external review process. They have been approved by the Gastrointestinal Cancer DSG and the Practice Guidelines Coordinating Committee.
- Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used.  Patients should be made aware of the increased acute toxicity associated with this approach.
The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits, and the patient's general condition.  Sequential radiotherapy and chemotherapy is not recommended as standard practice.  Future clinical trials to better define the optimal chemoradiotherapy combination that would improve outcomes while limiting toxicities are strongly encouraged.

# IX. PRACTICE GUIDELINE
This practice guideline reflects the most current information reviewed by the Gastrointestinal Cancer DSG.

# Target Population
These recommendations apply to adult patients with localized (T1-3, small volume N1, M0) carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist.    patients with localized carcinoma of the esophagus for whom a non-surgical approach is used?

# Target Population:
These recommendations apply to adult patients with localized (T1-3, small volume N1, M0) carcinoma of the esophagus and good performance status who are considering a non-surgical approach and for whom combined radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist.
5b. List below any changes to the selection criteria in the original version made necessary by new questions, changes to existing questions, or changes in available evidence (e.g., limit a search to randomized trials that originally included non-randomized evidence).
- Both phase 2 and 3 RCTs are of interest.  No changes to the inclusion or exclusion criteria, or study endpoints

# Inclusion Criteria:
Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma.
- Esophagectomy as a planned intervention 2. Use of pure radiosensitizer (e.g., misonidazole) with radiotherapy

# Study Endpoints:
The primary endpoint of interest was overall survival. Data were examined for one-to five-year overall mortality rates. Secondary endpoints included local recurrence and adverse effects. While disease-specific survival and quality-of-life data would be useful endpoints to consider, they were not reported by the primary authors of the eligible trials and could not be evaluated. The data in this report are based on the intention-to-treat (ITT) principle unless data for only evaluable patients were reported and there was insufficient information to allow for an ITT analysis.
5c. Conduct an updated literature search based on that done for the current version and modified by 5a and 5b above. Report the results below.
Full Selection Criteria, including types of evidence (e.g., randomized, non-randomized, etc.):
Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized trials of combination chemotherapy and radiotherapy compared with radiotherapy alone in adult patients with primary esophageal carcinoma.   
- Concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on considerations of the current clinical practice pattern and the currently available research evidence, a cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when concomitant radiotherapy and chemotherapy is used.  Patients should be made aware of the increased acute toxicity associated with this approach.
The decision to use concomitant radiotherapy and chemotherapy should only be made after careful consideration of the potential risks, benefits, and the patient's general condition.  Sequential radiotherapy and chemotherapy is not recommended as standard practice.  Future clinical trials to better define the optimal chemoradiotherapy combination that would improve outcomes while limiting toxicities are strongly encouraged.

# Related Guidelines
Practice Guideline Initiative's Practice Guideline #2-11: Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer. We also don't expect that stronger evidence will be published in the near future that would change the current recommendations  Therefore, guideline 2-12 can be ENDORSED. If Yes, the document can be ENDORSED. If No, go to 8.

# X. JOURNAL REFERENCE
- Does any of the newly identified evidence, on initial review, contradict the current recommendations, such that the current recommendations may cause harm or lead to unnecessary or improper treatment if followed? Answer Yes or No, and explain if necessary, citing newly identified references:

# not applicable
If Yes, a WARNING note will be placed on the web site. If No, go to 9. 9. Is there a good reason (e.g., new stronger evidence will be published soon, changes to current recommendations are trivial or address very limited situations) to postpone updating the guideline? Answer Yes or No, and explain if necessary:

# not applicable
If Yes, the document update will be DEFERRED, indicating that the document can be used for decision making and the update will be deferred until the expected evidence becomes available. If No, go to 10.
- An update should be initiated as soon as possible. List the expected date of completion of the update:

# not applicable
An UPDATE 4  subject area so fully that it would be very surprising to identify any contradictory or clarifying evidence.  SUFFICIENT RECOMMENDATIONS -Sufficient means that the current recommendations are based on consensus, opinion and/or limited evidence, and the likelihood of finding any further evidence of any variety is very small (e.g., in rare or poorly studied disease).  WARNING -A warning indicates that, although the topic is still relevant, there may be, or is, new evidence that may contradict the guideline recommendations or otherwise make the document suspect as a guide to clinical decision making. The document is removed from the Web site, and a warning is put in its place. A new literature search may be needed, depending on the clinical priority and resources.

# Document Assessment and Review Outcomes
- ARCHIVED -An archived document is a document that will no longer be tracked or updated but may still be useful for academic or other informational purposes. The document is moved to a separate section of the Web site and each page is watermarked with the phrase "ARCHIVED".
- ENDORSED -An endorsed document is a document that the DSG/GDG has reviewed for currency and relevance and determined to be still useful as guidance for clinical decision making. A document may be endorsed because the DSG/GDG feels the current recommendations and evidence are sufficient, or it may be endorsed after a literature search uncovers no evidence that would alter the recommendations in any important way.
- DEFERRAL -A Deferral means that the clinical reviewers feel that the document is still useful and the decision has been made to postpone further action for a number of reasons. The reasons for the deferral are in the Document Assessment and Review Tool.
- UPDATE -An Update means that the DSG/GDG recognizes that there is new evidence that makes changes to the existing recommendations in the guideline necessary but these changes are more involved and significant than can be accomplished through the Document Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest opportunity to reflect this new evidence. Until that time, the document will still be available as its existing recommendations are still of some use in clinical decision making.