Preoperative or Postoperative Therapy for Stage II or III Rectal Cancer: An Updated Practice Guideline

Clinical Oncology 22 (2010) 265–271 Contents lists available at ScienceDirect

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Guidelines

Preoperative or Postoperative Therapy for Stage II or III Rectal Cancer: An Updated Practice Guideline R.K.S. Wong *, S. Berry y, K. Spithoff z, M. Simunovic x, K. Chan y, O. Agboola k, B. Dingle { on behalf of the Gastrointestinal Cancer Disease Site Group * Princess

Margaret Hospital, University Health Network, Radiation Medicine Program, Toronto, Ontario, Canada Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada z Cancer Care Ontario’s Program in Evidence-based Care, McMaster University, Hamilton, Ontario, Canada x Juravinski Cancer Centre, Department of Surgical Oncology, Hamilton, Ontario, Canada k The Ottawa Hospital Regional Cancer Centre, Ottawa, Ontario, Canada { London Regional Cancer Centre, London, Ontario, Canada y

Received 15 June 2009; received in revised form 19 February 2010; accepted 4 March 2010

Abstract Aims: Uncertainty remains regarding the optimal therapy for patients with stage II or III rectal cancer. Systematic reviews and practice guidelines on preoperative and postoperative therapy for rectal cancer were published by the Gastrointestinal Cancer Disease Site Group in 2003 and 2000, respectively. The systematic reviews were updated and revised and new recommendations for preoperative and postoperative therapy were developed based on the updated body of evidence. The following research questions were addressed: After appropriate preoperative staging tests, should patients with resectable clinical stage II or III rectal cancer be offered preoperative radiotherapy (with or without chemotherapy)? What is the role of postoperative radiotherapy and/or chemotherapy for patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy, in terms of improving survival and delaying local recurrence? Materials and methods: The MEDLINE, EMBASE and Cochrane Library databases, as well as meeting proceedings from the American Society of Clinical Oncology, were searched for reports of randomised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy for stage II or III rectal cancer. The draft practice guideline and systematic reviews were distributed through a mailed survey to 129 health care providers in Ontario for review. Results: Systematic reviews on preoperative and postoperative therapy for rectal cancer were developed. On the basis of the evidence contained in these reviews, the Gastrointestinal Cancer Disease Site Group drafted recommendations. Of the 33 practitioners who responded to the mailed survey, 97% agreed with the draft recommendations as stated, 88% agreed that the report should be approved as a practice guideline and 94% indicated that they were likely to use the guideline in their own practice. Conclusions: Preoperative chemoradiotherapy is preferred, compared with standard fractionation preoperative radiotherapy alone, to decrease local recurrence. Preoperative chemoradiotherapy is also preferred, compared with a postoperative approach, to decrease local recurrence and adverse effects. For patients with relative contraindications to chemotherapy in the preoperative period, an acceptable alternative is preoperative radiotherapy alone followed by surgery. Patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy should be offered postoperative therapy with concurrent chemoradiotherapy plus fluoropyrimidine-based chemotherapy. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Adjuvant chemotherapy; adjuvant radiotherapy; chemoradiotherapy; neoadjuvant therapy; practice guideline; rectal neoplasms

Introduction

Author for correspondence: R.K.S. Wong, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada, M5G 2M9. Tel: þ1-416-9462126; Fax: þ1-416-946-6561. E-mail address: [email protected] (R.K.S. Wong).

Adenocarcinoma of the rectum is a prevalent malignancy for which the mainstay of therapy is surgical resection. Despite evidence that an improved surgical technique for rectal cancer, referred to as total mesorectal excision (TME), dramatically improves disease control [1–5], many patients continue to experience local and distant recurrence.

0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2010.03.002

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Preoperative and postoperative radiotherapy and/or chemotherapy have been investigated in numerous randomised trials to further improve outcome. Since the early 1990s, patients in Ontario with stage II and III rectal tumours have been advised to receive postoperative chemoradiotherapy, in an effort to avoid local tumour recurrence and to improve survival [6,7]. However, there is an increasing body of evidence that preoperative therapy results in lower rates of recurrence and a better toxicity profile than a postoperative approach for certain patient groups. Two relevant practice guidelines developed by the Gastrointestinal Cancer Disease Site Group (DSG) have been previously published. A guideline on postoperative radiotherapy and/or chemotherapy for resected stage II or III rectal cancer was published in 2000 [7] and a preoperative radiotherapy guideline for clinically resectable rectal cancer was published in 2003 [8]. In order to integrate important new evidence, the Gastrointestinal Cancer DSG updated and revised the systematic reviews for preoperative and postoperative therapy and developed new recommendations for stage II and III rectal cancer based on that evidence.

Materials and Methods This practice guideline was developed by Cancer Care Ontario’s Program in Evidence-based Care (PEBC) Gastrointestinal Cancer DSG using the methods of the Practice Guidelines Development Cycle [9]. The systematic reviews and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care. Questions After appropriate preoperative staging tests, should patients with resectable clinical stage II or III rectal cancer be offered preoperative radiotherapy (with or without chemotherapy)? What is the optimal preoperative radiotherapy fractionation scheme? What is the role of postoperative radiotherapy and/or chemotherapy for patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy, in terms of improving survival and delaying local recurrence?

American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology, were searched to 2007 for reports of randomised controlled trials (RCTs), meta-analyses or systematic reviews comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy. Evidence was selected by two members of the PEBC’s Gastrointestinal Cancer DSG and a methodologist. Data were extracted by one reviewer and verified through a data-auditing procedure. The systematic reviews of preoperative and postoperative therapy on which the recommendations are based are available from the Cancer Care Ontario website [10]. Gastrointestinal Cancer Disease Site Group Consensus The Gastrointestinal Cancer DSG reviewed the evidence contained in the systematic reviews. Recommendations were drafted based on that evidence and the consensus of the Gastrointestinal Cancer DSG. Internal Review Before distributing the draft report for external review, the practice guideline and systematic reviews were reviewed by the PEBC Report Approval Panel, which consists of two members, including an oncologist with expertise in clinical and methodology issues. External Review After approval of the draft systematic review and practice guideline by the Gastrointestinal Cancer DSG and the Report Approval Panel, the document was distributed through a mailed survey to health care providers in Ontario, Canada for review and feedback. A sample of 129 practitioners (27 medical oncologists, 19 radiation oncologists and 84 surgeons) received the survey, which consisted of items evaluating the methods, results and interpretation of the evidence used to inform the draft recommendations and of questions about whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed and follow-up reminders were sent to non-responders at 2 and 4 weeks. The Gastrointestinal Cancer DSG reviewed the results of the survey.

Results Target Population Literature Search Results These recommendations apply to adult patients with clinically resectable or resected stage II or III rectal cancer. Systematic Review The core methodology used to develop the evidentiary base for this practice guideline was two systematic reviews on preoperative and postoperative therapy for stage II or III rectal cancer. The MEDLINE, EMBASE and Cochrane Library databases, as well as meeting proceedings from the

Six RCTs [11–16] were identified that reported data for patients with stage II or III resectable rectal cancer comparing preoperative radiotherapy or chemoradiotherapy with surgery alone or other preoperative or postoperative approaches (Table 1). A Cochrane review on preoperative therapy for all resectable rectal cancer was also reviewed [17]. In addition, 29 RCTs and six meta-analyses were identified that compared postoperative radiotherapy and/or chemotherapy with other postoperative approaches

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Table 1 Summary of randomised controlled trials of preoperative therapy for stage II or III rectal cancer patients [10] Treatment

Control

Number of trials in Cochrane review [17]

Trials reporting data for stage II/III patients

Preoperative radiotherapy versus surgery alone Preoperative radiotherapy

Surgery alone

19

[11] [12]

Preoperative radiotherapy versus other Preoperative chemoradiotherapy Selective postoperative chemoradiotherapy Preoperative radiotherapy (long interval to surgery) Preoperative radiotherapy (lower dose) Preoperative chemoradiotherapy versus postoperative chemoradiotherapy Preoperative chemoradiotherapy

Preoperative radiotherapy Preoperative radiotherapy (short course) Preoperative radiotherapy (short interval to surgery) Preoperative radiotherapy (higher dose)

Postoperative chemoradiotherapy

5 2

[13–15] –

1

–

1

–

NA

[16]

NA, not applicable.

[10]. The results from individual trials can be found in the full guideline report on the Cancer Care Ontario website [10]. Preoperative Therapy Recommendations  Preoperative chemoradiotherapy is preferred, compared with preoperative radiotherapy (standard fractionation: longer course 45–50.4 Gy in 25–28 fractions) alone, to decrease local recurrence.  Preoperative chemoradiotherapy is preferred, compared with a postoperative approach, to decrease local recurrence and adverse effects.  For patients with relative contraindications to chemotherapy in the preoperative period, acceptable alternatives are preoperative standard fractionation (longer course 45–50.4 Gy in 25–28 fractions) or hypofractionation (short course 25 Gy in five fractions) radiotherapy alone followed by surgery, guided by the risk of adverse effects.  Patients eligible for preoperative radiotherapy with or without chemotherapy should also be considered for adjuvant chemotherapy. Qualifying statements  Recommendations for preoperative therapy presuppose adequate preoperative staging investigations, including transrectal ultrasound and/or magnetic resonance imaging (MRI) with surface or endorectal coil to assess the T category, MRI with surface or endorectal coil to assess the N category, a digital rectal examination, computerised axial tomography scan or MRI to assess the mesorectal margin, computerised axial tomography scan or MRI of the abdomen to assess for potential metastatic or stage IV disease, and chest X-ray for pulmonary imaging.  Potential inaccuracies of preoperative testing on tumour staging should be discussed with patients to allow them to make informed decisions [18].

 The eventual rectal surgery is expected to include TME principles. The quality of surgery greatly influences the potential benefits of preoperative treatments. A substantial number of trials included in the evidentiary base did not use currently recommended standards of surgery, including TME.  In most instances, there should be a 4–6-week delay from the completion of radiotherapy to surgery, to allow patients to recover to an optimal preoperative physiological state. The exception is the use of short-course radiotherapy where, in relatively healthy patients, surgery can occur immediately after radiotherapy, and ideally within 10 days of the initiation of radiotherapy. Key evidence Two RCTs comparing preoperative radiotherapy versus surgery alone for patients with resectable rectal cancer, including stage I–IV patients, presented outcomes separately for stage II and III patients [11,12]. Subgroup analyses showed a significant local control benefit for preoperative radiotherapy in these patients. This is consistent with the local control benefit for all resectable rectal cancer patients reported in a Cochrane review [17] (hazard ratio 0.71; 95% confidence interval 0.64–0.78; number needed to treat 22; 95% confidence interval 17–29, assuming a control group local recurrence rate of 17% at 5 years). Two RCTs comparing preoperative chemoradiotherapy with standard fractionation longer course radiotherapy for patients with stage II and III rectal cancer found a local recurrence benefit and an improved complete pathological response rate for patients who received chemoradiotherapy [13,14]. A RCT comparing preoperative short-course radiotherapy alone versus preoperative standard fractionation chemoradiotherapy did not demonstrate a difference in survival, local control or late toxicity between groups [15]. One RCT [16] comparing preoperative versus postoperative chemoradiotherapy (with four cycles of postoperative 5-fluorouracil chemotherapy) for patients with clinical stage II and III rectal cancer showed a lower local

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recurrence rate (relative risk 0.46; 95% confidence interval 0.26–0.82; from 6 to 13%) and lower acute and late toxicities in favour of preoperative chemoradiotherapy. Postoperative Therapy Recommendations  Patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy should be offered postoperative therapy with concurrent chemoradiotherapy in addition to fluoropyrimidine-based chemotherapy. The evidence reviewed shows that this treatment improves survival and reduces local recurrence rates compared with observation alone or radiotherapy alone after surgery.  For patients receiving postoperative chemoradiotherapy, the optimal way of administering 5-fluorouracil during chemoradiotherapy d via continuous infusion or bolus 5-fluorouracil d is not clear, as neither method is definitively superior in terms of efficacy or toxicity. Either method of administration can be considered appropriate, and treatments for individual patients should be based on an informed discussion of the potential risks and benefits of each mode of delivery.  Informed discussions regarding the potential advantages of adjuvant therapy also need to address the significant acute and long-term toxicity that can potentially occur with combined treatment with radiotherapy and chemotherapy.  It is the expert opinion of the Gastrointestinal Cancer DSG that patients who have received preoperative chemoradiotherapy or radiotherapy should receive postoperative chemotherapy.

postoperative adjuvant therapy of high-risk colon cancer. Patients with resected rectal cancer at similarly high risk of systemic recurrence should be offered the same systemic adjuvant therapy as their counterparts with resected colon cancer, based on the recommendations of the PEBC’s guideline on adjuvant systemic chemotherapy for stage II or III colon cancer [19].  Enteritis, diarrhoea, bowel obstruction or perforation, and fibrosis within the pelvis are associated with radiotherapy. Delayed adverse effects from radiotherapy include radiation enteritis (4%), small bowel obstruction (5%), rectal stricture (5%), pelvic fracture and worsening sexual and bowel function. A greater number of haematological and non-haematological adverse effects are associated with chemotherapy plus radiotherapy than with chemotherapy alone or radiotherapy alone. Combined chemotherapy plus radiotherapy is associated with acute gastrointestinal and haematological adverse effects that may be severe or life-threatening.

Key evidence Twenty-nine RCTs, six meta-analyses of postoperative radiotherapy and/or chemotherapy in stage II and III resected rectal cancer, and a review of the adverse effects of adjuvant radiotherapy and chemotherapy were reviewed [10]. Meta-analyses of overall survival and local failure data were conducted for the following comparisons: radiotherapy versus observation alone, chemotherapy versus observation alone (systemic and oral), combined chemoradiotherapy versus observation, chemotherapy versus radiotherapy, chemoradiotherapy versus radiotherapy alone, and chemoradiotherapy versus chemotherapy alone [10]. The results are summarised in Table 2.

Review and Update

Qualifying statements  Oxaliplatin-based chemotherapy and capecitabine have emerged as recommended treatments for the

Practice guidelines developed by the PEBC are reviewed and updated regularly. The full evidence-based series report

Table 2 Meta-analyses of randomised controlled trials of postoperative therapy for stage II or III rectal cancer patients [10] Comparison

Number of trials

Comparisons examined

Number of trials in meta-analysis

Meta-analysis results Relative risk (95% confidence interval)

Radiotherapy versus observation

7

Chemotherapy versus observation

6

Survival Local failure Survival (intravenous þ oral) Local failure (intravenous þ oral) Survival Local failure Survival Local failure Survival Local failure Survival Local failure

7 7 6

0.98 (0.90, 1.07; P ¼ 0.65) 0.78 (0.65, 0.95; P ¼ 0.01) 0.75 (0.65, 0.88; P ¼ 0.0003)

4

0.74 (0.55, 0.98; P ¼ 0.04)

2 2 3 2 3 2 3 2

0.74 0.42 0.85 1.32 0.81 0.54 0.96 0.58

Chemoradiotherapy versus observation

2

Chemotherapy versus radiotherapy

3

Chemoradiotherapy versus radiotherapy

3

Chemoradiotherapy versus chemotherapy

3

(0.55, (0.23, (0.73, (0.92, (0.67, (0.32, (0.82, (0.38,

0.98; 0.75; 0.99; 1.91; 0.99; 0.90; 1.13; 0.87;

P ¼ 0.04) P ¼ 0.004) P ¼ 0.03) P ¼ 0.14) P ¼ 0.04) P ¼ 0.02) P ¼ 0.64) P ¼ 0.008)

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and subsequent updates can be found on the Cancer Care Ontario website [10].

Discussion and Consensus of the Gastrointestinal Cancer Disease Site Group The limited evidence available specifically for clinical stage II and III rectal cancer suggests that the best evidence for the role of preoperative therapy has to be inferred from the data for all stages. Data for all patients with resectable rectal cancer indicate that preoperative radiotherapy results in a marginal survival benefit of 2% (assuming an expected survival rate of 60%) and a significant improvement in local control compared with surgery alone, but no significant benefit was detected for resectability or sphincter-preserving surgery [17]. It should be noted that most of the trials on preoperative radiotherapy predate the use of TME-type surgery, and thus it cannot be concluded that, if optimal surgery is provided, radiotherapy will confer even this marginal survival benefit. Although the Dutch TME trial did go to some lengths to promote proper surgical technique, not all patients received high-quality TME surgery [20]. An analysis of data specifically for patients with stage II and III disease confirmed that the use of preoperative radiotherapy decreases the risk of local recurrence in patients with stage II and III disease [11,12]; however, no benefit in overall survival or cause-specific survival was shown in the limited data available. Potential improvements in local control with preoperative radiotherapy must be balanced against a greater risk for both acute adverse effects, including pelvic or perineal wound infection, enteritis, diarrhoea, bowel obstruction, and perforation, and late adverse effects, including stool frequency and incontinence problems, pelvic fractures, and worsening sexual function. What is the relative merit of shorter course (25 Gy in five fractions) versus longer course (standard fractionation) preoperative radiotherapy? In addition to differences in overall treatment time, the larger dose per fraction predicts for a higher risk of late toxicities. The shorter fractionation is typically followed by surgery within 10 days of the initiation of radiotherapy, whereas the longer course of treatment is typically delivered with chemotherapy followed by surgery about 4–6 weeks after the completion of radiotherapy or chemoradiotherapy. No trial has explored combining chemotherapy with the shorter fractionation radiotherapy. Shorter versus longer fractionations of radiotherapy alone have not been compared directly. The RCT of 312 patients by Bujko et al. [15] compared short-course radiotherapy versus long-course chemoradiotherapy (two cycles). There were no significant differences in key outcomes, including overall survival, relapse-free survival, local recurrence rates or late toxicities. There were more acute toxicities when using chemoradiotherapy, but a higher risk of a positive circumferential margin in the radiotherapy-alone arm, although this was not paralleled by an increase in local recurrence rates. Despite the similar results on major outcomes, there remains some rationale in favour of the longer course, used in combination with chemotherapy, that requires

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consideration until further evidence is available. It should be noted that, in this trial, there was a relatively small number of patients with tethered tumours (19%) and low lying rectal lesions (abdominoperineal resection rate 35%). The limited generalisability of the trial results to patients where positive margins and risk of local recurrence is of greatest concern cannot be ignored. With the superior outcome shown by incorporating chemotherapy in the treatment, the use of preoperative long-course chemoradiotherapy represents an approach that can derive the maximal relative benefit. However, for patients where acute toxicities are a major concern, the option of the shorter fractionation should be considered as a reasonable alternative. The most powerful evidence guiding the choice between a preoperative versus a postoperative approach comes from the direct comparison between preoperative and postoperative chemoradiotherapy by Sauer et al. [16]. The existing evidence would support a preoperative chemoradiotherapy approach. This approach is expected to provide superior local control benefit, as well as a higher pathological complete response rate, with significantly lower acute and late toxicities, within the context of TME surgery. In other words, the preoperative approach provides the greatest relative benefit for the same modalities (chemotherapy, radiotherapy and surgery) and dose intensity, but with less toxicity. Could selective postoperative radiotherapy (with or without chemotherapy) be superior to preoperative radiotherapy for higher risk patients? The results of the MRC 07 trial [21] suggest that preoperative radiotherapy for higher risk patients is superior to selective postoperative radiotherapy (with or without chemotherapy) in terms of local control and disease-free survival. Existing evidence therefore supports the use of preoperative chemoradiotherapy over postoperative chemoradiotherapy when both options are feasible. For patients who are found to have higher risk disease postoperatively, postoperative chemoradiotherapy should be recommended. Should postoperative chemotherapy be given after preoperative radiotherapy with or without chemotherapy? There is an obvious paucity of research efforts directed specifically towards answering this question. Bosset et al. [14] conducted the only trial identified that included a comparison of preoperative chemoradiotherapy versus preoperative chemoradiotherapy with postoperative chemotherapy (two cycles of 5-fluorouracil plus folinic acid [FA]). No significant difference between the outcomes of these two treatment arms could be observed. Sauer et al. [16] used four cycles of 5-fluorouracil/FA in both treatment arms comparing preoperative versus postoperative chemoradiotherapy. Despite the lack of direct evidence, offering postoperative chemotherapy after preoperative radiotherapy or chemoradiotherapy is common practice, with the rationale based on indirect evidence. Because the benefit of radiotherapy, given either preoperatively or postoperatively, is primarily on local control, the survival benefit that is observed with combination postoperative chemoradiotherapy is predominantly attributed to the systemic effect of chemotherapy [22]. In fact, the next generation of trials assumes the therapeutic benefit of

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postoperative systemic therapy and focuses on asking the question whether novel postoperative chemotherapy regimens are superior to ‘standard’ regimens. Despite the absence of direct evidence, given the above consideration, the expert opinion of the Gastrointestinal Cancer DSG supports the use of postoperative chemotherapy in stage II and III rectal cancer after preoperative radiotherapy or chemoradiotherapy. Given the potential downstaging effect of standard fractionation preoperative chemoradiotherapy or radiotherapy, the decision to use adjuvant chemotherapy after surgery and standard fractionation radiotherapy or chemoradiotherapy should be based on clinical staging. The role of post-treatment pathological staging or primary tumour response to therapy deserves further study [23]. Pathological stage should be used to guide the need for adjuvant therapy in patients receiving hypofractionation (short-course) preoperative radiotherapy. The optimal choice of chemotherapy should be based on the assessment of the risk of recurrence. Newer agents, such as capecitabine and oxaliplatin, have not been thoroughly studied in randomised trials of rectal cancer patients. Oxaliplatin is emerging as a standard of care with no additional studies in the postoperative setting anticipated, bypassing the traditional evidentiary development path. Although the DSG would normally be reluctant to recommend a therapy in the absence of definitive evidence, it is reasonable to consider oxaliplatin and capecitabine here. Specifically, despite the fact that there is currently no direct randomised evidence for these newer agents in rectal cancer, there is evidence for the benefits of capecitabine and oxaliplatin in the adjuvant therapy of resected colon cancer [24,25]. Given the biological similarity between colon and rectal cancer in terms of their histology, tissue of origin, patterns and risk of systemic recurrence, and the fact that these two diseases are treated the same when they metastasise, the adjuvant systemic therapy of rectal cancer has been led by advances in the adjuvant therapy of colon cancer. In North America, oxaliplatin-based postoperative therapy has been accepted as a standard, based on the extrapolation of data from adjuvant colon trials. In an ongoing Intergroup trial for

rectal cancer, ECOG-E5204, patients in both arms receive oxaliplatin-based adjuvant therapy. Given the benefits observed with capecitabine- and oxaliplatin-based therapy in the adjuvant treatment of colon cancer, most Gastrointestinal Cancer DSG members felt that it is reasonable and appropriate to offer patients with resected rectal cancer at high risk of systemic recurrence the same adjuvant systemic therapy as their counterparts with colon cancer. Early attempts to enhance the effect of preoperative chemoradiotherapy by adding newer chemotherapy agents active in rectal cancer have not yet translated into superior outcomes. However, longer term results and randomised trial data are pending. Until a superior regimen is identified, 5-fluorouracil infusion with radiotherapy, approximately 50 Gy in 25 fractions, remains the standard approach. In most instances, there should be a 4–6-week delay from the completion of radiotherapy to surgery, to allow patients to recover to an optimal preoperative physiological state. The exception is the use of short-course radiotherapy, where, in relatively healthy patients, surgery can occur immediately after radiotherapy, and ideally within 10 days of the initiation of radiotherapy. Considering all the above evidence, it can be concluded that there is no significant overall survival or relapse-free survival benefit with the use of preoperative radiotherapy and different ways of delivering the radiotherapy in patients with stage II or III rectal cancer. The reason for considering the use of preoperative radiotherapy lies exclusively with the desire to reduce local recurrence rates, which is accomplished at the expense of greater acute and late toxicities. The addition of chemotherapy with the longer standard fractionation courses provides a further reduction in local recurrence rates, again at the expense of incremental acute toxicities. For the subgroup of patients who are at higher risk for local recurrence (e.g. where TME with a negative circumferential margin may be difficult to accomplish), the use of preoperative chemoradiotherapy has the additional benefit of a greater likelihood of tumour response, a higher pathological complete response rate and a lower positive circumferential margin. In these patients, the rationale for the use of preoperative longer course

Table 3 Responses to eight items on the external review survey Survey item

The rationale for developing a guideline, as stated in the introduction section of the report, is clear. There is a need for a guideline on this topic. The literature search is relevant and complete. The results of the trials described in the draft report are interpreted according to my understanding of the data. The draft recommendations in the report are clear. I agree with the draft recommendations as stated. This report should be approved as a practice guideline. If this report were to become a practice guideline, how likely would you be to make use of it in your own practice?

Number (%) Strongly agree or agree

Neither agree nor disagree

Strongly disagree or disagree

32 (97)

1 (3)

0 (0)

31 (94) 31 (94) 31 (94)

1 (3) 2 (6) 2 (6)

1 (3) 0 (0) 0 (0)

31 (94) 31 (97) 29 (88) Very likely or likely 31 (94)

2 (6) 1 (3) 1 (3) Unsure 1 (3)

0 (0) 0 (0) 3 (9) Not at all likely or unlikely 1 (3)

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chemoradiotherapy is even stronger. For the same intensity of chemoradiotherapy, the effect is greatest, and with the least acute and late toxicities, when the delivery is carried out preoperatively. Data from ongoing trials, as outlined in the full report of this guideline [10], may help to further clarify optimal therapy for patients with stage II and III rectal cancer. Internal and External Review of the Practice Guideline The PEBC Report Approval Panel and external clinical experts reviewed the draft systematic reviews and practice guideline and provided feedback. See Table 3 for a summary of key results of the external review survey. The main comments and responses of the authors are summarised in the full report of this guideline on the Cancer Care Ontario website [10].

Acknowledgements The authors would like to thank the members of the PEBC’s Gastrointestinal Cancer DSG for their contributions to the development of this practice guideline. The Cancer Care Ontario PEBC is sponsored by Cancer Care Ontario and the Ministry of Health and Long-term Care.

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