Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection

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1 Evidencebased Series 229 IN REVIEW A Quality Initiative of the Program in Evidencebased Care (PEBC), Cancer Care Ontario (CCO) Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection D. Jonker, K. Spithoff, J. Maroun, and the Gastrointestinal Cancer Disease Site Group Report Date: April 17, 2008 Evidence Based Series 229 was reviewed in January 2014 and the Gastrointestinal Cancer Disease Site Group (DSG) made the decision to UPDATE IT. The NEW version is expected to be publicly available in September Users are advised that the recommendations for Stage II patients may no longer be valid for some groups of patients in which treatment is ineffective and toxicity from treatment may be unnecessarily harmful. The PEBC has a formal and standardized process to ensure the currency of each document (PEBC Assessment & Review Protocol) The full Evidencebased Series 229 is comprised of 3 sections and is available on the CCO website on the PEBC Gastrointestinal Cancer DSG page Section 1: Guideline Recommendations Section 2: Evidentiary Base Section 3: EBS Development Methods and External Review Process 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: ext Fax: [email protected] Guideline Citation (Vancouver Style): Jonker D, Spithoff K, Maroun J; Gastrointestinal Cancer Disease Site Group. Adjuvant systemic chemotherapy for stage II and III colon cancer following complete resection. Toronto (ON): Cancer Care Ontario; 2008 Apr 17 [In review 2011 Sep]. Program in Evidencebased Care Evidencebased Series No.: 229 IN REVIEW.

2 EBS 229 IN REVIEW Evidencebased Series #229: Section 1 Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection: Guideline Recommendations D. Jonker, K. Spithoff, J. Maroun, and the Gastrointestinal Cancer Disease Site Group. A Quality Initiative of the Program in Evidencebased Care (PEBC), Cancer Care Ontario (CCO) Report Date: April 17, 2008 Evidencebased Series (EBS) #229 replaces Practice Guidelines #21 and #22 QUESTIONS Should patients with stage II or III colon cancer receive adjuvant systemic chemotherapy? What are the preferred adjuvant systemic chemotherapy options for patients with completely resected stage II or III colon cancer? Outcomes of interest were diseasefree survival (DFS), overall survival (OS), adverse effects, and quality of life. Comparisons of interest were: 1. Fluoropyrimidinebased systemic chemotherapy versus observation. 2. Intravenous (IV) 5fluorouracil (FU) versus oral fluoropyrimidines. 3. Fluoropyrimidines versus fluoropyrimidines plus oxaliplatin. 4. Fluoropyrimidines versus fluoropyrimidines plus irinotecan. TARGET POPULATION These recommendations apply to adult patients with stage II or III colon cancer who have undergone resection with curative intent as primary therapy. RECOMMENDATIONS Stage II Colon Cancer These recommendations are under review. Users are advised that the recommendations for Stage II patients may no longer be valid for some groups of patients in which treatment is ineffective and toxicity from treatment may be unnecessarily harmful. The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, the subset of patients with highrisk stage II disease who should be considered for adjuvant therapy includes patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of highrisk prognostic features on individual prognosis, and patient preferences. RECOMMENDATIONS page 1

3 EBS 229 IN REVIEW When treated with adjuvant therapy, highrisk stage II patients should receive similar regimens to those recommended for stage III patients. The enrolment of resected highrisk 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. Stage III Colon Cancer The Gastrointestinal Cancer Disease Site Group (DSG) recommends that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within eight weeks of surgery. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment. The recommended treatment option is: 5FU given intravenously in combination with leucovorin (LV) and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5FU/LV/oxaliplatin regimens have demonstrated superior DFS when compared with 5FU plus LV and are the recommended regimens. Oxaliplatin administration is associated with a 1% risk of persistent grade 3 neuropathy that needs to be considered in conjunction with expected benefits of therapy. Some patients would not be considered appropriate for oxaliplatin regimens. Examples include patients with underlying neurologic 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: Oral capecitabine administered for six months, which has equivalent efficacy to intravenous 5FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more handfoot syndrome when compared with 5FU/LV. 5FU in combination with LV administered for six months using either the weekly or monthly schedule. Suitable patients should be offered entry into clinical trials testing new adjuvant treatments for resected stage III colon cancer. KEY EVIDENCE Published metaanalyses of randomized controlled trials (RCTs) comparing adjuvant chemotherapy with observation alone generally demonstrated superior DFS and OS, particularly for stage III patients. Although hazard ratios (HRs) also favoured chemotherapy for stage II patients, these were not statistically significant. Two RCTs reported at least equivalent DFS and OS results for oral fluoropyrimidines (capecitabine and oral UFT) compared with intravenous 5FU/LV (15). In the XACT study, patients in the capecitabine arm experienced significantly less grade 3/4 stomatitis, grade 3/4 neutropenia requiring intervention, febrile neutropenia/sepsis, diarrhea, nausea and vomiting, and alopecia than did patients in the 5FU/LV arm, but more handfoot syndrome. Quality of life did not differ significantly between treatment arms in either RCT. Two RCTs compared 5FU/LV plus oxaliplatin with 5FU/LV alone in patients with resected stage II and III colon cancer (69) For the abbreviations of clinical trial group names, please see Section 2: Appendix 2. MOSAIC: o The MOSAIC RCT reported a significant benefit in DFS after five years of followup for stage II and III patients who received FOLFOX4 compared with patients who received 5FU/LV (HR, 0.80; p=0.003). Fiveyear DFS was 73.3% in the FOLFOX4 group and 67.4% in the 5FU/LV group. A subgroup analysis by disease stage RECOMMENDATIONS page 2

4 EBS 229 IN REVIEW demonstrated a significant benefit in DFS for FOLFOX4 compared with 5FU/LV in stage III patients (HR, 0.78; p=0.005; 5year DFS, 66.4% versus [vs] 58.9%) but not in stage II patients (HR, 0.84; p=0.258; 5year DFS, 83.7% vs 79.9%). In an exploratory analysis, HRs suggested a possible benefit in DFS for oxaliplatin in patients with highrisk stage II disease (HR, 0.74; p>0.05) but not for lowrisk stage II patients (HR, 1.22; p>0.05). These data are available only in abstract form and as a publicly available online presentation (7). o After six years of followup, overall survival was not significantly different between treatment arms in the overall analysis of stage II and III patients (HR 0.85; p=0.057) or in the subgroup analysis of stage II patients (HR, 1.00; p=0.996; 6year OS, 86.9% vs 86.8%); however, analysis of stage III patients demonstrated a significant benefit for the addition of oxaliplatin (HR, 0.80; p=0.029; 6year OS, 73.0% vs 68.6%) (7). NSABP C07: o The NSABP C07 RCT demonstrated a significant benefit in DFS for the overall analysis of stage II and III patients (HR, 0.80; p=0.0034; 4year DFS, 73.2% vs 67.0%) (8). None of the four RCTs comparing fluoropyrimidines with irinotecan to fluoropyrimidines alone (1013) detected a significant benefit in DFS for the addition of irinotecan. Two RCTs reported no significant difference in OS between treatment groups, although one was small and underpowered. Three of the four RCTs are available as abstracts and publicly available online presentations only (1113). Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and LongTerm Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. Contact Information For further information about this report, please contact: Dr. Jim Biagi, CoChair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W, Kingston, ON, K7L 5P9 TEL ext. 4502; FAX 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: ext Fax: [email protected] RECOMMENDATIONS page 3

5 EBS 229 IN REVIEW REFERENCES 1. Twelves C, Wong A, Nowacki MP, Abt M, Burris III H, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352: Twelves C, Wong A, Nowacki M, McKendrick J, van Hazel G, Douillard J, et al. Updated efficacy findings from the XACT phase III trial of capecitabine (X) vs. bolus 5FU/LV as adjuvant therapy for patients (pts) with Dukes C colon cancer. Proc Annu Meet Soc Clin Oncol. 2005;23(16S):A Scheithauer W, McKendrick J, Begbie S, Borner M, Burns WI, Burris HA, et al. Oral capecitabine as an alternative to i.v. 5fluorouracilbased adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol. 2003;14: Lembersky BC, Wieand HS, Petrelli NJ, O Connell MJ, Colangelo LH, Smith RE, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C06. J Clin Oncol. 2006;24: Kopec JA, Yothers G, Ganz PA, Land SR, Cecchini RS, Wieand HS, et al. Quality of life in operable colon cancer patients receiving oral compared with intravenous chemotherapy: results from National Surgical Adjuvant Breast and Bowel Project Trial C06. J Clin Oncol. 2007;25: Andre T, Boni C, MounedjiBoudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350: de Gramont A, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: updated efficacy results of the MOSAIC trial, including survival, with a median followup of six years. Proc Annu Meet Soc Clin Oncol. 2007;25(18S):A Kuebler JP, Wieand HS, O Connell MJ, Smith RE, Colangelo LH, Yothers G, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C07. J Clin Oncol. 2007;25: Land SR, Kopec JA, Cecchini RS, Ganz PA, Wieand HS, Colangelo LH, et al. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C07. J Clin Oncol. 2007;25: Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB J Clin Oncol. 2007;25: Ychou M, Raoul J, Douillard J, Bugat R, Mineur L, Viret F, et al. A phase III randomized trial of LV5FU2+CPT11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). Proc Annu Meet Soc Clin Oncol. 2005;23(16S)A Van Cutsem E, Labianca R, Hossfeld D, Bodoky G, Roth A, Aranda E, et al. Randomized phase III trial comparing infused irinotecan / 5fluorouracil (5FU)/folinic acid (IF) versus 5 FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3). Proc Annu Meet Soc Clin Oncol. 2005; 23(16S):A Sasaki K, Takasaka H, Kiriyama K, Inafuku Y, Yabana T, Furuhata T, et al. Adjuvant postoperative chemotherapy for Dukes C colorectal cancer; weekly lowdose Irinotecan (CPT11) plus oral 5FU versus oral 5FU only. Proc Annu Meet Soc Clin Oncol. 2004;22(14S):A3735. RECOMMENDATIONS page 4

6 Evidencebased Series #229: Section 2 Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection: Evidentiary Base D. Jonker, K. Spithoff, J. Maroun, and the Gastrointestinal Cancer Disease Site Group. A Quality Initiative of the Program in Evidencebased Care (PEBC), Cancer Care Ontario (CCO) Report Date: April 17, 2008 Evidencebased Series (EBS) #229 replaces Practice Guidelines #21 and #22 QUESTIONS Should patients with stage II or III colon cancer receive adjuvant systemic chemotherapy? What are the preferred adjuvant systemic chemotherapy options for patients with completely resected stage II or III colon cancer? Outcomes of interest were diseasefree survival (DFS), overall survival (OS), adverse effects, and quality of life. Comparisons of interest were: 1. Fluoropyrimidinebased systemic chemotherapy versus observation. 2. Intravenous (IV) 5fluorouracil (FU) versus oral fluoropyrimidines. 3. Fluoropyrimidines versus fluoropyrimidines plus oxaliplatin. 4. Fluoropyrimidines versus fluoropyrimidines plus irinotecan. INTRODUCTION In Ontario, colorectal cancer is second only to lung cancer as a cause of cancer death, with an estimated 3,250 deaths per year. Colorectal cancer is the fourth most common cancer site when both sexes are combined, representing 13.1% of all new cancer cases, with approximately 7,800 new cases per year (1). In males, colorectal cancer is the second most common site, and, in females, colorectal cancer is the third most common site (1). The prognosis of the newly diagnosed colon cancer patient is determined by the clinicopathologic stage of the disease. In stage II disease, there is tumour penetration through the bowel wall beyond the submucosa, but there is no involvement of the regional lymph nodes or distant sites. Stage III disease involves metastases to regional lymph nodes. The overall survival of patients with stage II disease is 70% to 80% five years after surgery (2). More than a third of patients with colon carcinoma present with lymph node metastases (stage III), and more than half of those patients, initially treated for cure, relapse and later die of the disease. Highrisk stage II disease is associated with an outcome similar to that of patients with stage III disease, with a fiveyear overall survival of 40% to 50%. The definition of high risk is a subject of considerable debate and research, and remains inadequately described in current TNM staging (see Appendix 1 for a comparison of staging systems). Possible prognostic factors that EVIDENTIARY BASE page 1

7 may indicate a higher risk of recurrence include T4 stage, presence of vascular invasion, perforation, inadequately sampled lymph nodes, poor differentiation, bowel obstruction, and molecular markers such as 18q allelic loss or microsatellite stability (MSS); however, these risk factors have not been confirmed in prospective studies. Several guidelines on the use of adjuvant therapy for patients with stage II or III colon cancer have been published in the past. In 1990, a National Institute of Health (NIH) Consensus Conference reviewed the available evidence and recommended adjuvant treatment with 5FU and levamisole for patients with curatively resected stage III colon cancer (3). Many questions remained about other therapies. In 1997, the Gastrointestinal Cancer Disease Site Group (DSG) completed and published two separate practice guidelines on the topic of adjuvant therapy in stage II and stage III colon cancer following complete resection (4,5). Based on the evidence reviewed, the Gastrointestinal Cancer DSG recommended adjuvant treatment with 5 FU/leucovorin (LV) as a treatment option, in addition to the standard treatment of 5FU and levamisole, for patients with stage III disease (5) but did not recommend the routine use of adjuvant chemotherapy for the management of patients with resected stage II colon carcinoma (4). After approval and subsequent publication, the original guidelines were reviewed and updated versions with new evidence incorporated were posted on the Program of Evidencebased Care (PEBC) section of the Cancer Care Ontario (CCO) Web site ( in In addition, an updated systematic review of adjuvant therapy for stage II colon cancer was published in 2004 (6) that formed the basis for a collaborative project between the American Society of Clinical Oncology (ASCO) and the PEBC to formulate mutually endorsed clinical recommendations (7). The joint guideline did not recommend routine adjuvant therapy for patients with resected stage II colon cancer but did recommend that patients with inadequately sampled lymph nodes, T4 lesions, perforation, or poorly differentiated histology be considered for adjuvant therapy. Since the publication of the original guidelines, the standard of care for patients with stage III resected colon cancer has been 5FU with LV, also known as folinic acid (FA), since 5FU plus levamisole has not demonstrated superior efficacy over 5FU/LV and is associated with significant toxicity. Studies have indicated that treatment durations of six months with 5FU/LV are as effective as 12 months of 5FU with levamisole (813). Intraperitoneal administration and portal venous infusion of chemotherapy for these patients are no longer routinely used. In addition, treatment regimens containing immunotherapy agents and semustine are also not commonly used for patients with resected colon cancer in Ontario and are considered historical regimens. New Agents A number of trials investigating newer agents, including oxaliplatin, irinotecan, and oral fluoropyrimidines, have become available since the approval of the original guidelines. The goals of newer agents are twofold. Trials comparing oral fluoropyrimidines such as capecitabine or tegafururacil (UFT) with intravenous 5FU have generally been noninferiority trials, as the goal of using oral therapy is primarily to reduce toxicity and improve the ease of administration compared with intravenous therapy. The goal of adding other agents, such as oxaliplatin or irinotecan, to fluoropyrimidines is to seek improvements in DFS and OS. Data for regimens and comparisons that are no longer considered relevant (e.g., intraperitoneal chemotherapy, immunotherapy, semustine) can be found in the publications of previous versions of the guidelines (46). New Endpoints Since a recent retrospective study (14,15) of 18 randomized trials of adjuvant chemotherapy in colon cancer has demonstrated a high concordance between two and threeyear DFS and fiveyear OS once complete fiveyear survival was available for all patients, the primary EVIDENTIARY BASE page 2

8 outcome for this review was DFS. In this analysis, the correlation between threeyear DFS (minimum followup, three years), the fiveyear OS rate was 0.86, and the correlation between threeyear DFS and the OS hazard ratio was 0.91 (15). Subsequent therapy for metastatic recurrence may delay the impact of improvements in DFS on OS. DFS represents a relevant clinical endpoint, since the avoidance of years of costly and toxic therapy for metastatic disease is of value to both patients and those who fund health care. Stage II and III Disease Since it remains unclear whether patients with stage II disease should receive adjuvant therapy, and several recent and ongoing trials include patients with both stage II and III disease, the guidelines were combined and rewritten in 2007 to address the questions that clinicians currently face in practice. Higher risk stage II patients have a risk of recurrence similar to stage III patients, and benefits of adjuvant therapy appear to be seen in stage II patients as well. METHODS The evidencebased series (EBS) guidelines developed by the CCO PEBC use the methods of the Practice Guidelines Development Cycle (16). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by one member of the PEBC Gastrointestinal Cancer DSG and methodologists. This systematic review is a convenient and uptodate source of the best available evidence on adjuvant chemotherapy for stage II and III colon cancer following complete resection. The body of evidence in this review is primarily comprised of mature randomized controlled trial data, and that evidence forms the basis of a clinical practice guideline developed by the Gastrointestinal Cancer DSG. The systematic review and companion recommendations are intended to promote evidencebased practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and LongTerm Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Literature Search Strategy The MEDLINE (1987 through September 2007), EMBASE (1987 through week ), CANCERLIT (1987 through October 2002), and Cochrane Library (through Issue 2, 2007) databases were searched using the medical subject heading (MeSH) colonic neoplasms, colorectal neoplasms, adjuvant chemotherapy, and the text words colon cancer, colorectal cancer, and colonic neoplasms. These terms were then combined with the search terms for the following study designs: practice guidelines, metaanalyses, and randomized controlled trials. In addition, proceedings from the annual meetings of the American Society of Clinical Oncology (ASCO) (1998 to 2007) were searched for reports of newly completed trials. Personal reprint files and reference lists of relevant studies were also searched. Study Selection Criteria Articles were selected for inclusion in this systematic review of the evidence if they met the following criteria: 1. They were fully published reports or published abstracts of randomized controlled trials (RCTs) or metaanalyses of RCTs involving patients with stage II or III colon cancer who had undergone surgery with curative intent. The studies had to include at least one of the following comparisons: adjuvant systemic fluoropyrimidinebased chemotherapy versus observation alone, oral fluoropyrimidines versus intravenous 5FU, fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone, or fluoropyrimidines plus irinotecan versus fluoropyrimidines alone. EVIDENTIARY BASE page 3

9 2. The primary outcome of interest was DFS. Secondary outcomes of interest were OS, treatment toxicity, and quality of life. Articles had to report data for one of these outcomes. 3. They were Englishlanguage publications. 4. The clinical trials were published after Buyse et al (17) summarized the results of randomized trials of adjuvant therapy for colorectal cancer up to The results of this metaanalysis are reviewed at the beginning of the Results section. Synthesizing the Evidence Individual patient data were not available for review. No data pooling was conducted in this review due to the availability of published metaanalyses comparing adjuvant chemotherapy with observation alone in both stage II and stage III colon cancer and the limited trial data available for the comparisons of oral fluoropyrimidines versus intravenous 5FU, fluoropyrimidines plus irinotecan versus fluoropyrimidines alone, or fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone. RESULTS Metaanalysis of Adjuvant Therapy (RCTs to 1987) In 1988, Buyse et al conducted a metaanalysis of all English trials of adjuvant therapy for colorectal cancer (all stages included) (17). Seventeen trials compared adjuvant chemotherapy with surgery alone in patients with colorectal cancer (6,791 patients). The pooled results detected no significant difference in the odds of death (mortality odds ratio = OR) between treatment and control (OR, 0.96; 95% confidence interval [CI], 0.87 to 1.06). Stage could not be examined due to the lack of standardization of staging methods. For the subgroup of patients treated with 5FU for at least one year, a significant decrease in the odds of death was detected (OR, 0.83; 95% CI, 0.70 to 0.98; p=0.03) when compared with untreated controls. Literature Search Results (Post 1987) The literature search identified 38 relevant reports (1855), representing 31 RCTs and 13 metaanalyses of RCTs (5668) published after 1987 (Table 1). Where multiple reports were published for a single RCT, only the most recent report was included in this review, unless older reports contained data that were not available in the most recent publication. For the abbreviations of clinical trial group names, please see Appendix 2, and for details regarding chemotherapy regimens, see Appendix 3. Table 1. Summary of Included Studies. Study Type Number of Studies in Category References Summary of Results Randomized Controlled Trials Fluoropyrimidinebased Systemic CT vs 21 (1840) Appendix 4 Observation Oral fluoropyrimidines vs IV 5FU 2 (4145) Table 2 Fluoropyrimidines + oxaliplatin vs 3 (4650) Table 3 fluoropyrimidines Fluoropyrimidines + irinotecan vs fluoropyrimidines 5 (5155) Table 4 Metaanalyses of Randomized Controlled Trials Fluoropyrimidinebased CT vs Observation 13 (5668) Appendix 4 Notes: 5FU, 5fluorouracil; CT, chemotherapy; vs, versus. EVIDENTIARY BASE page 4

10 Adjuvant Fluoropyrimidinebased Systemic Chemotherapy versus Observation Randomized Controlled Trials The comparison of adjuvant fluoropyrimidinebased systemic chemotherapy versus observation has been addressed in previously published systematic reviews for both stage II and stage III colon cancer. The literature search for this comparison was updated, and new trials were identified. These results are consistent with prior recommendations and are described in more detail in Appendix 4. In total, 21 trials (1840) have compared the use of various intravenous and oral fluoropyrimidinebased chemotherapy regimens with observation alone in patients with colon or colorectal cancer. Many trials included patients with both stage II and III colon cancer, and several also included patients with rectal cancer. The convention has been that highrisk stage II patients with a risk of recurrence approximating that of stage III patients are also likely to obtain similar benefit from chemotherapy. These trials, however, have not generally reported outcomes separately for highrisk and lowrisk stage II patients, making this assessment difficult. Metaanalyses of Randomized Controlled Trials Metaanalyses of trials comparing adjuvant chemotherapy with observation for colorectal cancer have been previously reviewed by the Gastrointestinal Cancer DSG. New studies identified in the updated literature search demonstrated pooled results that were consistent with the prior recommendations (5668) (Appendix 4). These reviews generally demonstrate superior DFS and OS, particularly for stage III patients. Although HRs also favoured chemotherapy for stage II patients, these were not statistically significant. These pooled analyses did not separate highrisk versus lowrisk patients; therefore, these studies alone are insufficient to base recommendations for the highrisk stage II population. Oral Fluoropyrimidines versus Intravenous 5FU Two RCTS have sought to demonstrate noninferiority of oral over IV fluoropyrimidines, with the goal of having a less toxic or more convenient mode of delivery. The XACT trial compared oral capecitabine with intravenous bolus 5FU/LV (Mayo Clinic regimen) (41) and the NSABP C 06 trial compared oral UFT plus LV with intravenous 5FU/LV in patients with resected colon carcinoma (44) (Table 2). The XACT trial included only patients with resected stage III tumours while the NSABP C06 included patients with either stage II or III tumours. Both studies have been fully published, and updated efficacy data for the XACT trial are available in abstract form (42). Both RCTs reported pharmaceutical sponsorship, and neither study was blinded or placebocontrolled. The method of patient randomization was adequately described for the X ACT study but was not reported in the NSABP C06 study. The NSABP C06 study stratified patients by the number of involved lymph nodes, and the XACT study stratified patients by treatment centre. Both studies reported the statistical calculations used to determine trial power and target sample sizes. Diseasefree Survival Both the XACT study (41,42) and the NSABP C06 study (44) demonstrated equivalent efficacy with respect to DFS for oral fluoropyrimidines compared with intravenous 5FU/LV. Using predetermined noninferiority margins of 1.25 and 1.20 for the HR to demonstrate at least equivalence for the two treatment regimens, the XACT study showed capecitabine to be at least as effective as 5FU/LV for stage III patients (p<0.0001). These results demonstrated a trend towards superiority in DFS for capecitabine; however, the observed difference between groups was marginally nonsignificant (p=0.053). Similarly, the NSABP C06 study concluded that the UFT/LV and 5FU/LV were equivalent for DFS (HR, 1.004, favouring 5FU/LV). Results for the DFS outcome were not reported separately for stage II and III patients in this study. EVIDENTIARY BASE page 5

11 Overall Survival Both studies comparing oral regimens with intravenous 5FU/LV demonstrated no significant difference in OS between treatment groups (41,42,44). In the XACT study of stage III patients, the mortality HR was 0.89 favouring capecitabine (noninferiority p<0.001); however, this difference was not significant in the superiority analysis (p=0.208). The NSABP C06 study reported a mortality HR of favouring 5FU/LV for the overall analysis of stage II and III patients, but this difference was also not significant (p=0.90). Although fiveyear OS data were reported separately for stage II and III patients, no statistical comparisons were performed. Adverse Effects A safety analysis of the XACT study was performed 19 months after the enrolment of the last patient, and the results were published separately from the efficacy results (43). Patients in the capecitabine group experienced significantly less grade 3/4 stomatitis (2% vs 14%), grade 3/4 neutropenia requiring intervention (0.6% vs 5%), and febrile neutropenia/sepsis (0.3% vs 3%) than did those in the 5FU/LV group. In addition, patients who received capecitabine experienced significantly less diarrhea (46% vs 64%), nausea/vomiting (36% vs 51%), and alopecia (6% vs 22%) of all grades. The only treatmentrelated toxicity that occurred more frequently in patients who received capecitabine compared with those who received 5FU/LV was handfoot syndrome (62% vs 10% all grades, 18% vs 0.6% grade 3, p<0.001). Dose reduction was similar in both treatment groups (42% in patients who received capecitabine and 44% in patients who received 5FU/LV) but median time to first dose reduction was longer in the capecitabine group (78 vs 41 days). In the NSABP C06 study, toxicities were similar for patients who received UFT/LV and 5 FU/LV (44). In both treatment arms, 38% of patients experienced a grade 3 or higher nonhematologic toxicity as their worst toxicity, and 20% experienced a grade 4 or higher nonhematologic toxicity as their worst toxicity. Diarrhea was the most frequent severe toxicity in both groups (29%). Quality of Life In the XACT study, quality of life was measured by the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC) at baseline and at the beginning of every treatment cycle (41). The scores remained relatively constant over time in both the capecitabine group and the 5FU/LV group, but both increased slightly at week 25 of treatment. In the NSABP C06 study, quality of life results were reported in a separate publication (45). Healthrelated quality of life (HRQL) was measured at baseline, at week 1516, and at one year. No difference in HRQL was reported between the UFT/LV group and the 5 FU/LV group. A convenience of care scale and symptoms scales were administered at baseline, at the beginning of each treatment cycle, and at one year. Patients who received UFT/LV scored significantly higher on the convenience of care scale and on two symptoms scales. Patients who received 5FU/LV scored marginally higher on the SF36 Vitality Scale. Overall HRQL scores improved slightly over time in both treatment arms. Fluoropyrimidines plus Oxaliplatin versus Fluoropyrimidines Alone Three RCTs were obtained that compared 5FU plus oxaliplatin with 5FU alone for the adjuvant treatment of colon carcinoma: the MOSAIC (46), NSABP C07 (48), and XELOXA studies (50) (Table 3). The MOSAIC and the NSABP C07 studies have been fully published, with additional updated efficacy data for the MOSAIC trial available in abstract form and publicly as an online presentation (47). Only safety data are available for the XELOXA RCT (50), and followup is continuing for the NSABP C07 and XELOXA RCTs. Two of the RCTs administered oxaliplatin with intravenous 5FU/LV, one using the FOLFOX4 regimen (46) and one using the FLOX regimen (48), while one of the RCTs compared capecitabine plus oxaliplatin (XELOX) EVIDENTIARY BASE page 6

12 with bolus 5FU/LV (50) (see Appendix 3 for regimen details). The MOSAIC (46) and the NSABP C07 (48) trials included patients with stage II and III disease, while the XELOXA study (50) included only patients with stage III disease. One of the RCTs reported pharmaceutical sponsorship (46), and none of the studies were blinded or placebo controlled. The method of patient randomization was not reported in any of the reports. DiseaseFree Survival In overall analyses of patients with resected stage II and III colon cancer, both the MOSAIC study (46,47) and the NSABP C07 study (48) demonstrated a significant benefit in DFS for 5 FU/LV plus oxaliplatin compared with 5FU/LV regimens alone. The MOSAIC study performed separate analyses of stage II and III patients and demonstrated a significant benefit for the addition of oxaliplatin in stage III patients (HR, 0.78; p=0.005) but not for stage II patients (HR 0.84; p=0.258). An exploratory analysis of highrisk and lowrisk stage II patients was also reported. In this analysis, patients were considered highrisk stage II if they had at least one of the following characteristics: T4, tumour perforation, bowel obstruction, poorly differentiated tumour, venous invasion, or less than 10 lymph nodes examined. In these patients, fiveyear DFS was 82.1% versus 74.9%, favouring FOLFOX4 (HR, 0.74; 95% CI, ; p>0.05). In lowrisk stage II patients, fiveyear DFS was 86.3% versus 89.1%, favouring LV5FU2 (HR, 1.22; 95%, CI ; p>0.05). These data are available only in a public online presentation (47). The NSABP C07 study reported an absolute benefit of 7.8% for patients with stage III disease and 3.2% for patients with stage II disease; however, no statistical comparisons between treatment groups were reported for these subgroup analyses. Overall Survival To date, only the MOSAIC trial (47) has reported overall survival data for fluoropyrimidines plus oxaliplatin compared with 5FU/LV alone. After six years of followup, the MOSAIC trial reported a trend towards improved survival in the oxaliplatin group (HR, 0.85); however, the difference between groups was marginally nonsignificant (p=0.057). Separate analyses by disease stage indicated a significant survival benefit for oxaliplatin compared with 5FU/LV alone in stage III patients (HR, 0.80; p=0.029) but no difference between groups in stage II patients (HR, 1.00; p=0.996). Adverse Effects The MOSAIC study reported significantly higher grade 3 or 4 paresthesia, neutropenia, thrombocytopenia, nausea, diarrhea, vomiting, allergic reaction, and neutropenia with fever or infection in patients who received 5FU/LV plus oxaliplatin compared with patients who received 5FU/LV alone. During treatment, 92.1% of patients who received oxaliplatin had peripheral neuropathy but only 12.4% experienced grade 3 neuropathy (46). After three years, 15.5% of evaluable patients continued to experience peripheral sensory neuropathy of any grade: 12% grade 1, 2.8% grade 2, and 0.7% grade 3 (47). The NSABP C07 study reported neurosensory toxicity in 8.4% of patients who received oxaliplatin in the FLOX regimen, compared to 0.7% of patients who received 5FU/LV alone (48). A subset of patients from this study (395 patients) completed a validated neurotoxicity scale, and higher mean neurotoxicity was reported for patients in the oxaliplatin arm throughout the period of study (p<0.0001), remaining higher at 18 months (p=0.009) (49). A final safety analysis of the XELOXA study reported 55% grade 3 or 4 adverse events in the XELOX group compared to 47% in the bolus 5FU/LV group. Patients in the XELOX group experienced less neutropenia, febrile neutropenia, and stomatitis but more thrombocytopenia, neurosensory toxicity, and handfoot syndrome than did patients in the bolus 5FU/LV group. Sixtyday allcause mortality (1% in each group) and treatmentrelated death within 28 days from last dose (0.6% in each group) were similar between treatment groups (50). EVIDENTIARY BASE page 7

13 Quality of Life None of the three RCTs comparing 5FU plus oxaliplatin with 5FU alone have reported data for quality of life outcomes (46,48,50). Fluoropyrimidines plus Irinotecan versus Fluoropyrimidines Alone The following five RCTs were obtained that compared 5FU plus irinotecan with 5FU alone for the adjuvant treatment of colon carcinoma: INT CALGB C89803 (51), Japanese (52), Accord 2 (53), PETACC 3 (54), and Papakostas (55) (Table 4). Four of the five RCTs have only been published in abstract form and provide limited details regarding study methodology (5255). One study has only reported safety data to date (55). Four of the RCTs administered irinotecan with intravenous 5FU/LV (51,5355), and one RCT administered irinotecan with oral 5FU (52). Two RCTs included patients with both stage II and III disease (54,55), and three RCTs included only patients with stage III disease (5153), one of which was limited to only patients with highrisk stage III disease (53). The Accord 2 RCT reported that the two treatment arms were unbalanced for important prognostic factors (53). One trial abstract reported pharmaceutical sponsorship (54), while the other four trials did not report funding, and none of the trials were blinded or placebocontrolled. Only three of the studies reported statistical calculations to determine trial power and target sample sizes (51,53,54). The Japanese trial was small and evaluated only 86 patients (52). DiseaseFree survival Three studies reported DFS data for patients with stage III disease (51,53,54) and none demonstrated a significant difference between 5FU plus irinotecan and 5FU alone for these patients. Of the two studies that reported hazard ratios, one favoured 5FU/LV plus irinotecan (HR, 0.89; p=0.091) (54) and one favoured 5FU/LV alone (HR, 1.19; p=0.22) (53) Only the PETACC3 study (54) has reported DFS results for patients with stage II disease and no significant difference was detected, although the hazard ratio favoured LV5FU2 plus irinotecan (HR, 0.80; p=0.184). In this study, overall analysis of stage II and III patients demonstrated a marginal benefit for LV5FU2 plus irinotecan over LV5FU2 alone (HR, 0.88; p=0.050). Overall Survival Only two studies have reported OS results for the comparison of 5FU plus irinotecan versus 5FU alone (51,52), and both included only patients with stage III disease. The CALGB study reported no benefit for 5FU/LV plus irinotecan over 5FU/LV alone in OS (p=0.74) after a median followup of 4.8 years (51). The Japanese study reported no benefit for oral 5FU plus irinotecan over oral 5FU alone in oneyear survival (100% vs 100%), twoyear survival (91% vs 89%), or fouryear survival (86% vs 75%) (52). Adverse Effects The Japanese study of oral 5FU plus irinotecan versus oral 5FU alone reported no grade 3 or 4 toxicities in either study group (52). The CALGB study reported greater grade 3/4 neutropenia in patients who received irinotecan compared with those who received bolus 5 FU/LV alone (43% vs 5%, p<0.0001), febrile neutropenia (4% vs 1%, p=0.0005), and deaths during treatment (2.8% vs 1.0 %, p=0.008) (51). Grade 3/4 diarrhea (31% vs 35%) and nausea (13% vs 11%) were not significantly different between groups. The Accord 2 study reported more grade 3/4 neutropenia in patients who received irinotecan compared with those who received 5FU/LV alone (28% vs 4%, p<0.001) (53). The PETACC 3 study reported an acceptable safety profile for patients who received irinotecan, although they experienced slightly more toxicity than in patients who received 5FU/LV alone (54). The Papakostas study has reported only safety data to date as patient followup is ongoing (55). Safety data from 826 of 910 enrolled patients indicate comparable and manageable toxicity in both groups, although EVIDENTIARY BASE page 8

14 significantly higher grade 3/4 neutropenia was reported in patients who received 5FU/LV with irinotecan compared with 5FU/LV alone (11% vs 3%; p<0.001). Grade 3/4 diarrhea was common in both treatment groups. Quality of Life None of the five RCTs that compared a 5FU regimen plus irinotecan with a 5FU regimen alone reported data for quality of life (5155). EVIDENTIARY BASE page 9

15 Table 2. Randomized controlled trials of oral fluoropyrimidines versus intravenous 5FU. Trial, year (reference) Twelves, 2005 XACT (41,42) Lembersky, 2006 NSABP C06 (44) Treatment allocation Capecitabine IV 5FU/LV (Mayo regimen) Oral UFT + LV IV 5FU/LV Months on therapy Number of patients evaluated Stage II Stage III Median followup (years) All trial patients Stage II patients Stage III patients DFS OS DFS OS DFS OS 5year 67.0% 68.2% HR (95% CI ) p=0.96 5year 78.5% 78.7% HR (95% CI ) p=0.90 3year 64.6% 61.0% HR 0.87 (95% CI ) p=0.053* Notes: 5FU, 5fluorouracil; CI, confidence interval; DFS, diseasefree survival; HR, hazard ratio; LV, leucovorin;, not reported; OS, overall survival; UFT, tegafururacil. * p values are for superiority tests. Values for noninferiority tests are p< for DFS and p<0.001 for OS. 5year 88.4% 87.0% p= 3year 81.3% 77.6% HR 0.89 (95% CI ) p=0.208* 5year 69.6% 71.5% p= EVIDENTIARY BASE page 10

16 Table 3. Randomized controlled trials of fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone. Trial, year (reference) Andre, 2004 MOSAIC (46,47) Treatment allocation Months on therapy LV5FU2 FOLFOX total Number of patients evaluated Stage II Stage III 1348 total Median followup (years) 6 All trial patients Stage II patients Stage III patients DFS OS DFS OS DFS OS 5year 67.4% 73.3% HR 0.80 (95% CI ) p= year 76.0% 78.6% HR 0.85 (95% CI ) p= year 79.9% 83.7% HR 0.84 (95% CI ) p= year 86.8% 86.9% HR 1.00 (95% CI ) p= year 58.9% 66.4% HR 0.78 (95% CI ) p= year 68.6% 73.0% HR 0.80 (95% CI ) p=0.029 Kuebler, 2007 NSABP C07 (48) 5FU/LV FLOX total 1200 total year 67.0% 73.2% 4year 81.0% 84.2%* 4year 61.1% 68.9%* Schmoll, 2007 XELOXA (50) Bolus 5 FU/LV XELOX 5.5 or HR 0.80 (95% CI ) p= p= p= 1.96 Notes: 5FU, 5fluorouracil; DFS, diseasefree survival; LV, leucovorin;, not reported; OS, overall survival; vs, versus; XELOX, capecitabine plus oxaliplatin. * Data available from Appendix published online only. Exploratory analysis of highrisk stage II patients: 5year DFS 82.1% vs 74.9% favouring FOLFOX4, HR 0.74 (95% CI ; p=ns). Lowrisk stage II patients: 5year DFS 86.3% vs 89.1% favouring LV5FU2, HR 1.22 (95% CI ; p=ns) Additional data available from a presentation at the ASCO Annual Meeting 2007 EVIDENTIARY BASE page 11

17 Table 4. Randomized controlled trials of fluoropyrimidines plus irinotecan versus fluoropyrimidines alone. Trial, year (reference) Saltz, 2004 CALGB (51) Ychou, 2005 ACCORD 2 (abstract) (53) Van Cutsem, 2005 PETACC3 (abstract) (54) Sasaki, 2005 (abstract) (52) Papakostas, 2007 (abstract) (55) Treatment allocation Bolus 5FU/LV + irinotecan Bolus 5FU/LV 5FU/LV + irinotecan 5FU/LV LV5FU2 + irinotecan LV5FU2 Oral 5FU + irinotecan Oral 5FU 5FU/LV + irinotecan 5FU/LV Months on therapy Number of patients evaluated Stage II Stage III total total Median followup (years) All trial patients Stage II patients Stage III patients DFS OS DFS OS DFS OS year 69.6% 66.8% HR 0.88 (95% CI ) p=0.050 Notes: 5FU, 5fluorouracil; DFS, diseasefree survival; LV, leucovorin;, not reported; OS, overall survival. *DFS data from publicly available online ASCO presentation Median DFS and OS not reached at time of analysis but futility boundaries crossed Study included only highrisk stage III patients with N2 or N1/N2 detected by occlusion/perforation Favours 5FU/LV year 84.8% 82.0% HR 0.80 (95% CI ) p= year 66% 69% p=0.85 3year 51%* 60%* HR 1.19 (95% CI ) p=0.22 3year 63.3% 60.3% HR 0.89 (95% CI ) p= year 80% 81% p=0.74 4year 86% 75% p=ns EVIDENTIARY BASE page 12

18 DISCUSSION Since the publication of the CCO PEBC guidelines for stage III and II colon cancer in 1997 and 2004, there have been several important studies published that necessitate modifications to the original recommendations. Whereas the previous guidelines recommended the use of adjuvant IV 5FU/LV for stage III colon cancer and consideration of the same for selected highrisk stage II colon cancer patients, there are now new data for the combination of 5FU/LV/oxaliplatin and the use of oral fluoropyrimidines as an alternative to IV 5FU/LV. Two studies have been reported that have compared 5FU/LV with and without oxaliplatin in populations that included both stage II and III colon cancer. The primary endpoint of these studies was DFS in the entire population. Although one of these studies reported outcomes separately for stage II and III patients, these are subset analyses and not necessarily powered to analyse the effect of the addition of oxaliplatin in a specific stage. Therefore, these two trials must be judged as demonstrating the superiority of 5FU/LV/oxaliplatin over 5FU/LV alone for patients with stage II and stage III colon cancer. Although these key 5FU/oxaliplatin adjuvant studies had a primary endpoint involving both stage II and III patients together, it is clear from a review of the absolute differences in DFS for the stage II subset that a benefit for those patients is smaller and that in the MOSAIC study there may be no OS benefit at all. Subset analysis must be interpreted with caution, and additional subset data or a pooled analysis with NSABP CO7 would be helpful. Despite this, the benefit in this population is in question, and treatment of all stage II patients is likely not warranted, particularly in light of the 1214% chronic (i.e. permanent) sensory neuropathy. The subset analysis of the highrisk stage II patients from the MOSAIC study provides reassurance that this group appears to benefit to a greater extent, similar to stage III patients. The definition of high risk is not clearly defined in the current TNM staging system nor is there clear consensus in the medical literature. Factors variably reported as independently predictive for high risk of tumour recurrence in patients with resected stage II colon cancer include T4 stage, presence of vascular invasion, and less than 12 nodes sampled. Less consistent factors include male gender, poor differentiation, and bowel obstruction. Putative highrisk molecular markers include aneuploid/tetraploid (nondiploid) DNA, 18q allelic loss, MSS or low frequency microsatellite instability MSIL, and maintenance of MMR proteins (hmlh1, hmsh2) by immunohistochemistry (6984). Of these many factors, there is current consensus that inadequately sampled nodes (<12), T4 lesions (that includes tumour perforation), and poorly differentiated histology warrant additional consideration for patients with stage II colon cancer. Neurotoxicity with 5FU/LV/oxaliplatin may be severe, and, although it has a significant reversible component, may leave patients with prolonged, and rarely, severe numbness and paresthesias. In the adjuvant setting this risk of permanent deficit is of greater importance. Careful patient selection, informed consent, patient monitoring, and dose modification is required. In addition to factors such as underlying neurologic conditions, there may be other factors that lead a physician or patient to avoid 5FU/LV/oxaliplatin. For patients who are not considered candidates for this combination, the alternatives include 5FU/LV or capecitabine. Data from the XACT trial demonstrate that oral capecitabine administered for six months has equivalent efficacy to IV 5FU/LV. However, capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more handfoot syndrome when compared with 5FU/LV. For those able to take oral therapy, capecitabine is therefore generally preferred over 5FU/LV due to its toxicity profile and ease of administration. In addition to the advances seen with capecitabine and oxaliplatin, there have been disappointments. Irinotecan, although important in the advanced setting, has failed to demonstrate clear advantages in the regimens studied so far, although trends in improvement in the PETACC3 study suggest that there may be a role for further study in alternative regimens or EVIDENTIARY BASE page 13

19 combinations. In the meantime, irinotecan cannot be recommended as an adjuvant therapy outside of a clinical trial. ONGOING TRIALS The National Cancer Institute (U.S.) database of ongoing clinical trials was checked on April 10, 2007 for new trial reports. A list of relevant ongoing trials appears in Appendix 5. CONCLUSIONS Patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy. The recommended treatment option is intravenous 5FU given with LV and oxaliplatin in the regimens known as FOLFOX or FLOX. This recommendation is based on evidence for improved DFS at four years with oxaliplatin regimens compared with 5FU/LV alone. For patients with a contraindication to oxaliplatin or for whom the adverse effects of oxaliplatin are unacceptable, the treatment options are oral capecitabine or intravenous 5 FU/LV. Patients with resected stage II colon cancer should not routinely receive adjuvant chemotherapy; however, patients considered to be at high risk for systemic recurrence, including those with inadequately sampled lymph nodes, T4 lesions, perforation, or poorly differentiated histology, should be considered for similar adjuvant therapy to that recommended for patients with resected stage III colon cancer. Treatment decisions should be based on the anticipated morbidity of treatment, and patient suitability and preference. Table 5. Summary of adjuvant therapy options for patients with resected colon cancer. Regimen Pros Cons Recommended FOLFOX or FLOX Superior DFS compared with 5 FU/LV Alternatives Oral capecitabine. 6 months IV 5FU/LV Equivalent efficacy to IV 5FU/LV Generally fewer adverse events compared with IV 5FU/LV Less handfoot syndrome compared with oral capecitabine More adverse effects, including neuropathy, compared with 5 FU/LV More handfood syndrome compared with 5FU/LV More adverse effects (diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia) compared with oral capecitabine. Not recommended 5FU with irinotecan No significant benefit in DFS or OS compared with 5FU/LV. More adverse effects compared with 5FU/LV. Notes: 5FU, 5fluorouracil; FOLFOX, 5fluorouracil + leucovorin + oxaliplatin; FLOX, 5fluorouracil + leucovorin + oxaliplatin; IV, intravenous; LV, leucovorin; FOLFIRI, 5fluorouracil + leucovorin + irinotecan; OS, overall survival. CONFLICT OF INTEREST Members of the Gastrointestinal Cancer DSG who were involved in the development of this systematic review were polled for potential conflicts of interest. One author (JM) reported receiving more than $5,000 in a single year as a guest speaker sponsored by Roche during the past two years. One author (DJ) was a coinvestigator on the AVANT, NSABP C07 and XACT trials. JOURNAL REFERENCES The following updated guideline for EBS #229 has been published in Clinical Oncology ( 2011 The Royal College of Radiologists. Published by Elsevier Ltd. Available from: EVIDENTIARY BASE page 14

20 Jonker DJ, Spithoff K, Maroun J. Adjuvant Systemic Chemotherapy for Stage II and III colon cancer after complete resection: an updated practice guideline. Clin Oncol (R Coll Radiol) Mar 10. doi: /j.clon Epub 2011 Mar. Practice Guidelines #21 and #22 were published as: Figueredo A, Germond C, Maroun J, Browman G, WalkerDilks C, Wong S, et al. Adjuvant therapy for Stage II colon cancer following complete resection. Cancer Prev Control. 1997;1(5): Figueredo A, Fine S, Maroun J, WalkerDilks C, Wong S, and the Provincial Gastrointestinal Disease Site Group. Adjuvant therapy for stage III colon cancer after complete resection. Cancer Prev Control. 1997;1: Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. Adjuvant therapy for Stage II colon cancer: a systematic review from the Cancer Care Ontario Program in Evidencebased Care s Gastrointestinal Cancer Disease Site Group. J Clin Oncol. 2004;22(16); ACKNOWLEDGEMENTS The Gastrointestinal Cancer DSG would like to thank Dr. D. Jonker, Dr. J. Maroun, and Ms. K. Spithoff for taking the lead in drafting and revising this systematic review. The DSG would also like to thank Dr. A. Figueredo, Dr. C. Germond, Dr. S. Fine, Dr. J. Maroun, Dr. G. Browman, and Ms. WalkerDilks C, Ms. Wong, and Mr. R.B. Rumble for drafting the original guidelines on stage II and III colon cancer on which the current guideline is based. For a complete list of the Gastrointestinal Cancer members, please visit the CCO website at Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and LongTerm Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. Contact Information For further information about this series, please contact: Dr. Jim Biagi, CoChair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W, Kingston, ON, K7L 5P9. TEL ext. 4502; FAX 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: ext Fax: [email protected] EVIDENTIARY BASE page 15

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26 stage II colon cancer. Eur J Surg Oncol. 2003;29: Berger AC, Sigurdson ER, LeVoyer T, Hanlon A, Mayer RJ, Macdonald JS, et al. Colon cancer survival is associated with decreasing ratio of metastatic to examined lymph nodes. J Clin Oncol. 2005;23: Galandiuk S, Wieand HS, Moertel CG, Cha SS, Fitzgibbons RJ Jr, Pemberton JH, et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet. 1992;174: Cohen AM, Minsky BD, Schilsky RL. Colon cancer. In: DeVita V Jr, Hellman S, Rosenberg SA, editors. Cancer: principles & practice of oncology. 5th ed. Philadelphia (PA): JB Lippincott; p EVIDENTIARY BASE page 21

27 Appendix 1. Comparison of staging systems for colorectal cancer*. AJCC UICC Astler Coller Dukes Stage I Tumour invades submucosa T1, N0, M0 Tumour invades muscularis propria T2, N0, M0 Stage I 1A T1,N0, M0 1B T2,N0,M0 A B1 A Stage II Tumour invades through muscularis propria into the subserosa, or into nonperitonealized pericolic or perirectal tissues T3,N0,M0 Stage II T3,T4,N0,MO (T3a with fistula) (T3b without fistula) B2 B Tumour perforates the visceral peritoneum, or directly invades other organs or structures T4,N0,M0 Stage III Any degree of bowel wall with regional node metastasis Stage III Any T,N1,M0 C1 C2 C1/C2 Any T,N13, M0 Stage IV Any invasion of bowel wall, with or without regional lymph node metastasis, but with evidence of distant metastasis Any T, and N,M1 Stage IV Any T, any N, M1 Note: AJCC, American Joint Commission on Cancer; UICC, International Union Against Cancer. *Further details about these staging systems are in Cohen (85). D Type 4 (socalled D) EVIDENTIARY BASE page 22

28 Appendix 2. Abbreviations of names of clinical trials groups. Abbreviation ANZBCTG CCCSG (Japan) ECOG EORTC GIVIOSITAC IMPACT INT INT CALGB MOSAIC NCCTG NGTATG NSABP (US) PETACC 3 QUASAR (UK) SAKK SWOG (US) XACT XELOXA Clinical Trial Group Australia and New Zealand Breast Cancer Trials Group Colorectal Cancer Chemotherapy Study Group Eastern Cooperative Oncology Group European Organization for Research and Treatment of Cancer Gruppo Italiano Valutazione Interventi in Oncologia Studio Italiano Terapia Adiuvante Colon International Multicentre Pooled Analysis of Colon Cancer Trials Intergroup of US Clinical Trial Groups Intergroup Cancer and Leukemia Group B Multicentre International Study of Oxaliplatin/5Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer North Central Cancer Therapy Group Nordic Gastrointestinal Tumour Adjuvant Therapy Group National Surgical Adjuvant Breast and Bowel Project PanEuropean Trials in Adjuvant Colon Cancer Quick and Simple and Reliable Swiss Group for Clinical Cancer Research Southwest Oncology Group Xeloda for the Adjuvant therapy for colon cancer Xeloda plus Oxaliplatin EVIDENTIARY BASE page 23

29 Appendix 3. Chemotherapy regimens. Adjuvant Chemotherapy versus Observation Trial (reference) Regimen 5FU IV, 1g following surgery and on first 2 postoperative days, 1 g orally, weekly Windle (18) for 6 months. Levamisole, oral, 150mg on first 3 postoperative days. Gray (19) 5FU, IV, 600mg/m 2 per day for 7 days immediately following surgery. Methyl CCNU, oral, 175mg/m 2 day 1, 5FU IV bolus, 400mg/m2 days 1,8, and 15. Panetierre (20) Repeat cycle every 8 weeks for one year. Connaught strain BCG, 1 vial (600,000,000 viable organisms), orally, every 2 weeks for one year. FUra IV bolus, 325mg/m 2 days 15, 375mg/m 2 days 3640 of every cycle. Wolmark (21) Semustine oral, 130mg/m 2 day 1 of every cycle. Vincristine IV, 1mg/m 2 days 1 and 36 prior to other chemotherapeutic agents. Repeat cycle every 10 weeks up to 8 cycles or treatment failure. Levamisole, 50mg every 8 hours over 3 days. Cycle repeated every 2 weeks for Laurie (23) 1 year. 5FU, IV bolus, 450mg/m 2 per day for 5 consecutive days. 5FU, IV, 450mg/m 2 weekly beginning on day 28. 5FU therapy continued for 1 year. Marangolo (24) 5FU, 400mg/m 2, IV bolus, days 15, and CCNU, 100mg/m 2, day 5, cycle repeated every 6 weeks, 9 cycles. Hafstrom (25) 5FU, 500mg/m 2, IV, day 1, and 5FU, 500mg/m 2 oral, days 25, and CCNU, 80mg/m 2, oral, day 1 and vincristine, 1.0mg/m 2, IV, day 1, cycle repeated every 6 weeks, 8 cycles. Treatment initiated within 3 weeks of surgery. Francini (26) 5FU, IV, 400mg/m 2 days 15. Folinic acid 200mg/m 2 days 15. Cycle repeated every 4 weeks, for 12 cycles Levamisole, oral, 50mg every 8 hours for 3 days, cycle repeated every 2 weeks Moertel (27,28) for 1 year. 5FU, no earlier than 21 days after surgery, bolus, 450mg/m2 per day for 5 consecutive days. 5FU, IV, 450mg/m 2 weekly beginning on day 28. Weekly dose CCCSG of Japan (29) Ito (30) O Connell (31) Zaniboni (32) Laffer (33) Taal (34) Kato (35) continued for 48 weeks. MMC, IV bolus, 6mg/m 2 days 7 and 14 after surgery, then bimonthly for 6 months. 5FU, oral, daily at 200mg/day, initiated 2 weeks after surgery, for 6 months. Treatment initiated within 4 weeks of surgery. Carmofur (HCFU), oral, 8mg/kg of body weight per day, divided 2 or 3 times per day, for 12 months. 5FU, bolus, 425mg/m 2 per day for 5 consecutive days. Leucovorin, bolus, 20mg/m 2 immediately preceding each dose of 5 FU. Courses repeated at 4 weeks, 8 weeks, then every 5 weeks for a total of 6 cycles. Chemotherapy initiated within 5 weeks of surgery. 5FU, 370 mg/m 2 daily for 5 days every 4 weeks for 6 cycles. Folinic acid, 200 mg/m 2 daily for 5 days every 4 weeks for 6 cycles. 5FU, IV, 500mg/m 2 per day for 7 days immediately following surgery. MMC 10mg/m 2 on day 1. Treatment initiated within 8 weeks of surgery. 5FU, bolus, 450mg/m2 per day for 5 consecutive days. 5FU, IV, 450mg/m2 weekly beginning on day 28. Weekly dose continued for 48 weeks. Levamisole, oral, 50mg in 3 daily doses for 3 days, cycle repeated every 2 weeks for 1 year. Postoperative radiotherapy varied by centre. UFT, oral, 400mg/day, 2 caps twice daily, 2 years. EVIDENTIARY BASE page 24

30 Folinic acid, 2hr infusion, 200mg/m 2, followed by 5FU, IV bolus, 400 mg/m 2 and McDermott (36) 5FU, 22hr infusion, 400mg/m 2 for 2 consecutive days, cycle repeated every 2 weeks for 8 cycles. 5FU, IV, 370mg/m 2, either six 5day, 4weekly, or 30 onceweekly courses. Gray (37) Lfolinic acid, either high dose (175mg) or low dose (25mg) Levamisole or placebo. Watanabe (38) Mitomycin C (MMC) IV, 5FU IV, and oral HCFU. Hamaguchi (40) UFT 400mg/m 2 /day, 5 consecutive days per week for 1 year. Schippinger (39) 5FU 450mg/m 2 plus LV 100mg/m 2 weekly, weeks 16, in 8week cycles for 7 cycles. Trial (reference) Twelves (41) Lembersky (44) Trial (reference) Ychou (53) Van Cutsem (54) Saltz (51) Adjuvant Oral fluoropyrimidines versus Intravenous 5FU Regimen 5FU/LV arm: Leucovorin, IV bolus, 20mg/m 2, followed immediately by 5FU, IV bolus, 425mg/m2 days 15, cycle repeated every 28 days, 6 cycles. Capecitabine arm: Capecitabine, oral, 1250mg/m 2, twice daily, days 114, cycle repeated every 21 days, 8 cycles. 5FU/ LV arm: Leucovorin, 2hr infusion, 500mg/m 2 and 5FU, IV bolus, 1 hr after leucovorin infusion, weekly for six weeks, cycle repeated after 2 weeks rest, 3 cycles. UFT + LV arm: UFT, oral, 300mg/m 2 per day and LV, oral, 90mg per day, daily doses divided in 3 and taken every 8 hrs, for 4 weeks, cycle repeated after 1 week rest, 5 cycles. Adjuvant 5FU plus irinotecan versus 5FU Regimen LV5FU2 arm: Leucovorin, 2hr infusion, 200mg/m 2 and 5FU 400mg/m 2, bolus, 400mg/m 2 and 5FU, 22hr continuous infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. LV5FU2 + irinotecan arm: Irinotecan, 90min infusion, 180mg/m 2 day 1, plus leucovorin, 2hr infusion, 200mg/m 2 and 5FU 400mg/m 2, bolus, 400mg/m 2 and 5FU, 22hr continuous infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. 5FU/LV arm: Leucovorin, 2hr infusion, 200mg/m 2 and 5FU 400mg/m 2, bolus, 400mg/m 2 and 5FU, 22hr continuous infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. or AIO regimen, weekly 5FU/LV + irinotecan arm: Irinotecan, IV, 180mg/m 2 day 1, plus leucovorin, 2hr infusion, 200mg/m 2 and 5 FU 400mg/m 2, bolus, 400mg/m 2 and 5FU, 22hr continuous infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. or AIO regimen plus irinotecan, 80mg/m 2, weekly. 5FU/LV arm: Roswell park regimen Leucovorin, 2hr infusion, 500mg/m 2, then 5FU, 500mg/m 2, 1 hr after start of leucovorin, for 6 weeks, cycle repeated every 8 weeks, 4 cycles. IFL arm: Irinotecan, 90min infusion, 125mg/m 2, followed by leucovorin, IV bolus, 20mg/m 2, then 5FU, IV bolus, 500mg/m 2, for 4 weeks, cycle repeated every 6 weeks, 5 cycles. EVIDENTIARY BASE page 25

31 5FU arm: Sasaki (52) 5FU, oral, daily for 12 months. 5FU + irinotecan arm: Irinotecan, 1hr infusion, 30mg/m 2, weekly for 6 months. 5FU, oral, daily for 12 months. Papakostas (55) 5FU 450mg/m2 bolus, FA 200 mg/m2 120 min infusion, CPT11 80mg/m 2 90 min infusion, 4 weeks on, 2 weeks off, for 6 cycles. 5FU 500mg/m 2 bolus, FA 200mg/m min infusion, 6 weeks on, 2 weeks off, for 4 cycles. Trial (reference) Andre (46) Wolmark (48) Adjuvant 5FU plus oxaliplatin versus 5FU Regimen 5FU/LV arm: Leucovorin, 2hr infusion, 200mg/m 2, then 5FU, IV bolus, 400mg/m 2 and 5FU, 22hr infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. 5FU/LV + oxaliplatin arm: Leucovorin, 2hr infusion, 200mg/m 2, then 5FU, IV bolus, 400mg/m 2 and 5FU, 22hr infusion, 600mg/m 2, days 12, cycle repeated every 2 weeks, 12 cycles. Oxaliplatin, 2hr infusion, 85mg/m 2 day 1, given simultaneously with leucovorin. 5FU/LV arm: 5FU, IV bolus, 500mg/m 2, and leucovorin, IV, 500mg/m 2, weekly for 6 weeks, cycle repeated every 8 weeks, 3 cycles. 5FU/LV + oxaliplatin (FLOX) arm: 5FU, IV bolus, 500mg/m 2, and leucovorin, IV, 500mg/m 2, weekly for 6 weeks, cycle repeated every 8 weeks, 3 cycles. Oxaliplatin, IV, 85mg/m 2, weeks 1, 3, and 5 of each 8week cycle, 3 cycles. EVIDENTIARY BASE page 26

32 Appendix 4. Fluoropyrimidinebased systemic chemotherapy versus observation. Randomized Controlled Trials Twentyone RCTs were obtained that compared a fluoropyrimidinebased systemic chemotherapy regimen with observation alone in patients with resected stage II or III colon cancer (Table 6) (1840). Only ten (19,2529,32,3740) of the 21 RCTs reported results for patients with stage II and III colon cancer separately in subgroup analyses, and twelve of the RCTs (18,20,23,25,29,30,3337,40) included patients with rectal cancer. Four of the 21 RCTs have only been published in abstract form (33,36,39,40). None of the 21 RCTs were blinded or placebocontrolled, and the randomization method was adequately described in only nine studies (26,27,29,30,32,34,35,37,38). Statistical calculations to determine study power and target sample size were reported in nine RCTs (23,26,27,29,32,34,35,37,38), and one study reported that it was statistically underpowered (36). Three studies were terminated early (26,34,39). DiseaseFree Survival Of the 13 RCTs that reported statistical comparisons for DFS data of all study patients (19 24,26,3035,38), three out of four reported a significant benefit for 5FU (with or without LV) (26,31,32), two out of two reported a benefit for 5FU plus levamisole (23,34), one out of three reported a benefit for 5FU plus semustine or lomustine (21,22), and two out of three reported a benefit for oral fluoropyrimidines compared with observation alone (30,38). Of the six trials that reported comparative DFS data for patients with stage II colon cancer receiving various chemotherapy regimens (19,2729,32,38,39,), only one reported a significant benefit for chemotherapy over observation with a regimen of 5FU plus mitomycin C (MIFU) and carmofur (HCFU) (38). Of the eight trials that reported comparative DFS data for patients with stage III colon cancer (19,2529,32,38,40), two out of three reported a significant benefit for 5FU (with or without LV) (26,32), one reported a benefit for 5FU plus levamisole (27,28), and one out of three reported a significant benefit for oral fluoropyrimidines compared with observation alone. In general, the evidence suggests a benefit in DFS for adjuvant chemotherapy compared with observation alone in patients with stage III disease but not in patients with stage II disease. No separate DFS data for highrisk and lower risk stage II patients are available. Overall Survival Of the 17 RCTs that reported statistical comparisons for OS data of all study patients (18 24,26, 3038), four out of seven reported a significant benefit for 5FU (with or without LV) (26,31,32,37), two out of three reported a benefit for 5FU plus levamisole (18,34), and one out of three reported a benefit for 5FU plus lomustine (21,22). None of the six trials that reported comparative OS data for patients with stage II colon cancer demonstrated a benefit for adjuvant chemotherapy over observation alone (19,2729,32,37,39). Of the seven trials that reported comparative OS data for patients with stage III colon cancer (19,2529,32,40), two out of three reported a benefit for 5FU (with or without LV) (26,32), one reported a benefit for 5FU plus levamisole (27,28), and one out of two reported a benefit for oral fluoropyrimidines over observation (29). No separate OS data for highrisk and lower risk stage II patients were reported. Adverse Effects Of the 21 RCTs that compared fluoropyrimidinebased adjuvant chemotherapy with observation alone, 16 reported adverse effects data (18,20,21,23,24,2632,3538,40). The adverse effects reported in the trials varied by treatment regimen. Six RCTs comparing 5FU, with or without LV, with surgery alone reported data for adverse effects (18,26,31,32,36). Toxicity was mainly gastrointestinal, including stomatitis and diarrhea. EVIDENTIARY BASE page 27

33 Grade 3/4 toxicities included mucositis in 5.3% of patients (32), diarrhea in 2.4% to 24% (31,32,36), nausea and vomiting in 0.8% to 7% (31,32,36), stomatitis in 36% (31), and leukopenia in 14% (31). The addition of levamisole to 5FU did not result in an increase in toxicity over that expected with 5FU alone in three trials (18,23,27,28). One death possibly related to chemotherapy was reported in the QUASAR trial (37). Three RCTs reported adverse effects data for the addition of nitrosoureas to 5FU (20 22,24). One trial comparing 5FU plus semustine, with or without the immunotherapy agent BCG, with observation alone reported moderate or worse toxicity in 75% of patients who received chemotherapy or chemoimmunotherapy; however, no fatal acute toxicities were reported (20). One study of 5FU plus CCNU (24) reported nausea and vomiting in 70% of treated patients, diarrhea in 17.5%, asthenia in 22.5%, mucositis in 12.5%, liver toxicity in 10%, leukopenia in 50% (mostly grade 1), and thrombocytopenia in 28.7%. Chemotherapy was stopped due to toxicity in 16 out of 92 patients. Five percent of patients receiving MOF chemotherapy in the NSABP C01 trial experienced platelet counts below 25x10 9 /L, while 2% experienced white blood cell (WBC) counts below 1x10 9 /L (21). Severe nausea and vomiting was reported in 6% of patients receiving chemotherapy. Three patients in this group were diagnosed with acute myelocytic leukemia. Five RCTs reported adverse effects data for oral fluoropyrimidines compared with surgery alone (29,30,35,38,40). One RCT of 1hexylcarbamoyl5fluorouracil (carmofur); LEV, levamisole; LV, leucovorin calcium HCFU compared with observation reported no severe side effects (30). Toxicity was limited to increased urinary frequency in eight patients, a hot sensation and dizziness in three patients each, and numbness and diarrhea in two patients each. The CCCSG trial of Japan (29) comparing 5fluorouracil + mitomycin C (MIFU) with observation reported mild but significant decreases in the WBC and platelet counts in the treatment arm. Mild anorexia and diarrhea were also observed more frequently in patients who received MIFU. The trial by Watanabe et al comparing MIFU plus HCFU with observation reported a high incidence of adverse reactions in the treatment arm compared with the control arm; however, incidence of severe side effects (grade 3 or greater) was low and no deaths due to treatment were reported (38). One RCT comparing oral uracil and tegafur (UFT) with observation reported no toxicity of grade 3 or more and no significant difference in incidence of adverse events between treatment groups (35). Quality of Life Only two of the 21 RCTs that compared fluoropyrimidinebased adjuvant chemotherapy with observation reported data for quality of life outcomes (32,37). In one trial (32), patients completed selfadministered questionnaires at the time of discharge from the treatment centre and at six and 12 months after randomization. Thirtyseven percent of patients completed only the first two questionnaires, and 27% had data available for all three time points. Study coordinators developed the validated questionnaires to evaluate global quality of life, emotional wellbeing, satisfaction with care, worry about the future, change in social life, impact of disease, and followup. No statistically significant difference was found between the patients who received highdose 5FU/LV and those who underwent observation alone. In the QUASAR trial (37), quality of life measurements directly related to chemotherapy toxicity (diarrhea, nausea, vomiting, mouth pain, fatigue, appetite loss, and social functioning) were significantly worse during treatment in patients who received chemotherapy compared with patients who underwent observation alone (p<0.001). EVIDENTIARY BASE page 28

34 Table 6. Randomized controlled trials of systemic fluoropyrimidinebased chemotherapy versus observation in patients with stage II and III resected colorectal cancer. Trial, year (reference) 5FU (+ LV) Windle, 1987 (18) Gray, 1987 ANZBCT 8201 (19) Francini, 1994 (26) Treatment allocation Obs 5FU Obs 5FU Obs 5FU/LVld Months on therapy 6 7 days 12 Number of patients evaluated Rectal Colon Stage II Stage III Median followup (years) >5 232 total All trial patients Stage II colon patients Stage III colon patients DFS% OS% DFS% OS% DFS% OS% p>0.05 p=ns p<0.01 p= p<0.01 P=NS p=ns p= p<0.01 p= p<0.01 O Connell, 1997 NCCTG (31) Zaniboni, 1998 GIVIOSITAC 01 (32) McDermott, 2003 (abstract) (36) Gray, 2007 QUASAR (37) Schippinger, 2007 (abstract) (39) 5FU + LEV Windle, 1987 (18) Laurie, 1989 (23) Moertel, 1995 INT 0035 (27,28) Taal, 2001 (34) Obs 5FU/LVld Obs 5FU/LVhd Obs 5FU/LV Obs 5FU/LV (high dose or low dose LV) p< p= p= p=0.155** p= p< p=0.03 p= p=0.008 Obs 5FU/LV p=ns p= Obs 5FU + LEV Obs 5FU + LEV Obs 5FU + LEV Obs 5FU + LEV > p= p= p= (6.5 stage III) p< p= p=ns p= p= p= p= EVIDENTIARY BASE page 29

35 Trial, year (reference) 5FU (IV) + MMC Laffer, 1998 Obs (abstract) MIFU SAKK 40/87 (33) 5FU + nitrosoureas Treatment allocation Months on therapy Number of patients evaluated Rectal Colon Stage II Stage III Median followup (years) 7 days total >5 All trial patients Stage II colon patients Stage III colon patients DFS% OS% DFS% OS% DFS% OS% p=ns p=ns Panettiere, 1988 SWOG 7510 (20) Obs 5FU + mccnu 5FU + mccnu + BCG Marangolo, 1989 (24) Obs 5FU + CCNU Wolmark 1988 NSABP C01 (21,22) Hafstrom, 1990 (25) Obs MOF Oral fluoropyrimidines Obs MIFU CCCSG Japan 1995 (29) Ito, 1996 Tokai (30) Kato, 2002 (35) Obs 5FU + CCNU + vincristine Obs HCFU Obs UFT *** (mean) >5 >7.0 p=ns RFS p= * 56* p=0.03 p=0.69 p= p= * 64* p= p=ns p=ns װװp=0.91 װ 63 װ 77 p= װװ 77 p= P=NS 84 װװ 84 p= p< װװ 48 p= p=0.012 Watanabe, 2006 (38) Obs MIFU + HCFU p= p=0.218 p= p=0.131 Hamaguchi, 2007 (abstract) (40) Obs UFT RFS p=0.559 Notes: 5FU, 5flourouracil; BCG, Bacillus CalmetteGuerin; CCNU, lomustine; DFS, diseasefree survival; HCFU, 1hexylcarbamoyl5fluorouracil (carmofur); LEV, levamisole; LV, leucovorin calcium; mccnu, semustine; MIFU, 5fluorouracil + mitomycin C; MMC, mitomycin C; MOF, 5fluorouracil/leucovorin + lomustine + vincristine; Obs, observation; OS, overall survival; UFT, oral tegafur and uracil. * 10year DFS hazard ratio 1.14 (95% CI, , p=0.17), 10year OS hazard ratio 1.12 (95% CI, , p=0.27) p=0.394 EVIDENTIARY BASE page 30

36 Relapsefree survival. Of 254 total patients, 164 had stage II disease and 90 had stage III disease. For all stage II patients (including rectal), OS was 73% in the Obs group and 76% in the 5FU/LV group. For all stage III patients, OS was 47% in the Obs group and 51% in the 5 FU/LV group. For patients with colon cancer, DFS was 69% in the Obs group and 86% in the HCFU group (logrank p=0.0498). For all patients with lymph node metastases, DFS was 49% in the װ Obs group and 70% in the HCFU group (logrank p=0.0710). Compared with observation. **Reported as in the text of the article. 17.4% of patients in chemotherapy arm also received levamisole. Also included patients with stage I disease. 92% of all patients had stage II disease. Up to 5 years. cancer. Results for all patients with colon װװ *** 23% of patients in the 5FU + CCNU arm did not begin adjuvant therapy and only 38 patients completed the entire treatment protocol. EVIDENTIARY BASE page 31

37 Published Metaanalyses of Randomized Controlled Trials In 1988, Buyse et al conducted a metaanalysis of all English trials of adjuvant therapy for colorectal cancer of all stages (17) (Table 7). Seventeen trials, including a total of 6,791 patients with colorectal cancer, compared adjuvant chemotherapy with surgery alone. The pooled results detected no significant difference in the odds of death between treatment and control (OR, 0.96; 95% CI, 0.87 to 1.06). Outcome by stage could not be examined due to the lack of standardization of staging methods. For the subgroup of patients treated with 5FU for at least one year, a significant decrease in the odds of death was detected (OR, 0.83; 95% CI, 0.70 to 0.98; p=0.03) when compared with untreated controls. Four additional metaanalyses were identified that reported pooled overall survival results of RCTs comparing adjuvant intravenous chemotherapy with observation alone without a separate analysis by disease stage (59,61,62) (See Table 8). Three reports included trials of both colon and rectal cancer patients (59,60,61). and three included only patients with stage II or III disease (59,61,62). One metaanalysis is only available in abstract form (60). All four metaanalyses demonstrated a significant survival benefit for adjuvant chemotherapy over observation. The Zalcberg et al metaanalysis of 17 RCTs comparing 5FUbased chemotherapy with observation further analysed trials by dose and suggested a greater survival benefit with higher doses (p=0.02) (59). Analysis by regimen suggested a greater survival benefit for trials of 5FU plus levamisole compared with no levamisole; however, a multivariate analysis indicated that the effect of levamisole became nonsignificant after adjusting for dose. Grey et al reported in an abstract that pooled analysis demonstrated that the benefits for adjuvant therapy were greater in studies testing 5FU/LV (29% reduction in mortality rate; p=0.0007) than in studies testing unmodulated 5FU (6% reduction in mortality rate; p=0.11). Dube et al (61) conducted a separate analysis for patients with colon cancer in studies with quality scores >50% and demonstrated a mortality OR of 0.80 (95% CI, 0.70 to 0.92; p<0.05), an absolute mortality reduction of 5%. The Sargent et al (62) metaanalysis of individual patient data from seven randomized controlled trials comparing 5FU combined with levamisole or folinic acid with observation reported a significant benefit in recurrencefree survival (HR, 0.68; 95% CI, 0.60 to 0.76; p<0.001) for adjuvant therapy compared with observation. No significant interaction was observed between age and treatment effect for overall or recurrencefree survival. Four metaanalyses were identified that pooled data from RCTs comparing adjuvant intravenous chemotherapy with observation with separate analyses by disease stage (56,60,63,64) (See Table 8). Three of the four metaanalyses included only patients with colon cancer (56,60,63), while one included both colon and rectal cancer (64). The majority of the evidence demonstrated a benefit for adjuvant therapy in stage III colon cancer but not in stage II disease. In 1995, the IMPACT investigators pooled individual patient data from three similar RCTs of 5FU/LV versus observation alone in stage II or III colon cancer (IMPACT 1) (56). In stage II patients, neither the OS rate nor the DFS rate was significantly different between groups after three years of followup. In both the analysis of stage III patients alone and the combined analysis of stage II and III patients, a significant benefit for adjuvant therapy with 5FU plus LV was reported for OS and for DFS. After up to 10 years of followup (57), mortality was not significantly reduced in stage II patients with adjuvant chemotherapy compared with surgery alone, despite a 21% decrease in mortality for adjuvant chemotherapy in the entire study population. In stage III patients, mortality was significantly reduced with adjuvant chemotherapy compared with surgery alone at 10 years of followup. In 1999, the IMPACT investigators conducted another metaanalysis using individual patient data from stage II patients from five RCTs of 5FU plus LV compared with observation (IMPACT 2) (60). Median followup of these patients was 5.75 years. There was no significant difference in fiveyear eventfree survival or OS for 5FU plus LV compared with observation. EVIDENTIARY BASE page 32

38 Using the database developed by Sargent et al (62), Gill et al performed an analysis based on a Cox proportional hazards model (63). Prognostic factors considered were adjuvant treatment, age, gender, tumour location, T stage, nodal status, and tumour grade. Only nodal status, T stage, and tumour grade were identified as independently significant prognostic factors for both DFS and OS. Age greater than or less than 60 was a significant prognostic factor only for OS. A 30% proportional reduction in risk of recurrence (HR, 0.70; 95% CI, 0.63 to 0.78) and a 26% proportional reduction in risk of death (HR, 0.74; 95% CI, 0.66 to 0.83) were reported for patients who received adjuvant treatment compared with those who were randomized to surgery alone. Glimelius et al (64) reported a pooled analysis of RCTs run in parallel by the NGTATG of adjuvant chemotherapy versus observation in patients with stage II or III colon cancer. Patients in the adjuvant therapy group received 5FU plus levamisole, 5FU/LV, or 5FU/LV plus levamisole. Patients were analyzed after a minimum followup of five years. No significant difference in fiveyear OS was detected between treatment groups for stage II patients or stage III patients. Oral Chemotherapy Versus Observation Four metaanalyses by Sakamoto et al using individual patient data to compare oral adjuvant chemotherapy to observation in patients with resected stage I to stage III colorectal cancer were obtained (6568) (See Table 8). Three metaanalyses included RCTs comparing adjuvant oral fluoropyrimidines in general with observation (6567), while one specifically compared oral carmofur with observation (68). In 1999, a metaanalysis of three RCTs performed in the 1980s comparing adjuvant oral fluoropyrimidines with observation that randomized patients by sealed envelopes reported no significant benefit for oral fluoropyrimidines over observation alone on DFS or OS in the overall analysis of colon cancer patients or the subgroup analyses by disease stage (65). In 2004, a metaanalysis of three RCTs performed in the 1980 s with the same comparison but which randomized patients by centralized randomization was completed (67). At five years, a marginally significant benefit favouring adjuvant oral chemotherapy was detected in both and for patients with colon cancer. Results for colon cancer patients by disease stage were not reported separately. Another metaanalysis, available only in abstract form (66), pooled six RCTs examining regimens with oral fluoropyrimidines. It is unclear whether this metaanalysis included the trials pooled in the 1999 and 2004 metaanalyses described above. Benefits in both OS and DFS favouring adjuvant treatment were detected, although results for patients with colon cancer were not reported separately. The metaanalyses that compared oral carmofur with observation alone in patients with stage I to III colorectal cancer pooled individual patient data of all eligible RCTs, including 2,152 patients with colon cancer (68). A benefit favouring carmofur was detected for both OS and DFS. Analysis stratified by disease stage indicated no significant benefit for carmofur in OS in either stage II or III disease but a significant benefit in DFS for both stage II and III disease. EVIDENTIARY BASE page 33

39 Table 7. Published metaanalyses of randomized controlled trials comparing adjuvant chemotherapy with observation. Author, year (reference) Patient Population # of RCTs (# of Patients) References of included studies Treatment Allocation All Patients Stage II Colon Stage III Colon Patients Patients DFS OS DFS OS DFS OS Buyse 1988 (17) IMPACT (56) 3year followup update 2001 (57) 10year followup IMPACT (58) Zalcberg 1996 (59) Gray 1997 (abstract) (60) Dube 1997 (61) Sargent 2001 (62) Colorectal cancer Stage II and III colon cancer Stage II colon cancer Dukes B and C colorectal cancer Colorectal cancer Dukes C colon and Dukes B or C rectal cancer Stage II or III colon cancer 17 () Adjuvant CT Observation 3 (1493) IPD 5 (1016) IPD 30 Two unpublished: Canadian and French 3032 Two unpublished: Canadian and French 17 () 17,21,22,28/29 Others not included in (18,000) 29 (12,079) 18 (Buyse metaanalysis) Others 19,21,22,24,28/29 Others not included in (3351) 24,27,28/29,54 (3 trials) One not included in 229 High dose 5FU/LV Observation 5FU/LV Observation 5FUbased CT Observation Adjuvant CT Observation Adjuvant CT Observation 5FU (plus LEV or LV) Observation OR, 0.96; 95% CI, 0.87 to 1.06* HR 0.65; 95% CI 0.54 to 0.78; p< HR, 0.78; 95% CI 0.62 to 0.97; p=0.029 HR 0.79; p=0.013 HR 0.84; 95% CI HR, 0.88; 90% CI, 0.72 to 1.07; p=0.137 OR 0.82; 95% CI, ; p<0.001 Annual death rate reduction 11%, p=0.001 OR % CI, ; p<0.05 HR 0.76; 95% CI, ; p<0.001 HR 0.91; 95% CI HR 0.92; p=0.658 HR, 0.86; 90% CI, 0.68 to 1.07; p=0.130 HR 0.55; 95% CI, , p<0.05 HR 0.70; 95% CI , p<0.05 HR 0.70; p=0.003 EVIDENTIARY BASE page 34

40 Author, year (reference) Gill 2004 (63) Patient Population Stage II or III colon cancer # of RCTs (# of Patients) References of included studies 7 (3302) Same as Sargent 2001 Treatment Allocation 5FU (plus LEV or LV) Observation All Patients Stage II Colon Stage III Colon Patients Patients DFS OS DFS OS DFS OS HR 0.70; HR, 0.74; HR 0.831, HR 0.855, p<0.05 p< % CI, 95% CI, p= p= Glimelius 2005 (64) Stage II or III colorectal cancer (2211) 5FU (plus LEV or LV) Observation 5year OS p=0.81 5year OS p=0.15 Oral chemotherapy Sakamoto 1999 (65) Sakamoto 2001 (abstract) (66) Sakamoto 2004 (67) Sakamoto 2005 (68) Stage IIII colorectal cancer Stage IIII colorectal cancer Stage IIII colorectal cancer Stage IIII colon cancer 3 (4960) IPD 6 (9819) IPD 3 (5233) IPD 3 (2152) IPD 30,31, 1 Japanese Oral fluoropyrimidines Observation Oral fluoropyrimidines Observation 1 Japanese 1 unpublished 1 only rectal pts published Oral fluoropyrimidines Observation 30, 2 Japanese Oral carmofur Observation p=0.242 p=ns p=0.296 p=0.721 p= p=0.417 p< p=0.022 HR=0.87; 95% CI, HR 0.77; 95% CI, , p=0.025 HR=0.86; 95% CI, HR 0.82; 95% CI, , p=0.038 p<0.05 p=ns p<0.05 p=ns Notes: RCT, randomized controlled trial; DFS, diseasefree survival; OS, overall survival; OR, odds ratio; HR, hazard ratio; CT, chemotherapy; CI, confidence interval; NS, not significant; IPD, individual patient data;, not reported; 5FU, 5fluorouracil; LV, leucovorin; * For patients who received 5FU for at least 1 year, OR, 0.83; 95% CI, 0.70 to 0.98; p=0.03. Data are for colon patients only Stratified by stage and country Stratified by age and grade 1999 publication pooled 3 RCTs randomized using sealed envelopes and the 2004 publication pooled 3 RCTs that used central randomization. Results by disease stage were reported for colon and rectal cancer combined. A significant benefit in DFS and OS favouring carmofur was detected in stage III but not stage I or II patients. EVIDENTIARY BASE page 35

41 Appendix 5. Ongoing trials. Phase III Randomized Study of Oxaliplatin (OXAL) Plus 5Fluorouracil (5FU)/Leucovorin (CF) With or Without Cetuximab (C225) After Curative Resection for Patients with Stage III Colon Cancer Protocol ID: NCCTGN0147, ECOGN0147, NCT Date last modified: September 11, 2007 Type of trial: Randomized, multicentre study, active control Primary endpoint: Diseasefree survival at 3 years Accrual: A total of 2,300 patients will be accrued for this study within 3 years. Sponsorship: NCCTG, ECOG, NCI, NCIC Status: Open and active (Note: Treatment arms containing irinotecan closed to accrual as of June 1, 2005) Phase III Randomized Study of Adjuvant Chemotherapy Comprising Fluorouracil and Irinotecan With or Without Leucovorin Calcium Versus No Adjuvant Therapy in Patients With Resected Stage II Adenocarcinoma of the Colon Protocol ID: FFCDEORTC40012, PETACC4, NCT Date last modified: December 18, 2006 Type of trial: Randomized, multicentre study, active control Primary endpoint: 5year diseasefree survival Accrual: A total of 1,976 patients (988 per treatment arm) will be accrued for this study within 4.5 years. Sponsorship: Federation Francophone de Cancerologie Digestive Status: Closed to accrual Phase III Randomized Study of Adjuvant Chemotherapy Comprising Fluorouracil, Leucovorin Calcium, and Oxaliplatin With Versus Without Bevacizumab in Patients With Resected Stage II or III Adenocarcinoma of the Colon Protocol ID: NSABPC08, NCT Date last modified: October 11, 2006 Type of trial: Randomized, multicentre study, active control Primary endpoint: Diseasefree survival Accrual: A total of 2,632 patients (1,316 per treatment arm) will be accrued for this study within 2.5 years. Sponsorship: National Surgical Adjuvant Breast and Bowel Project, NCI Status: Closed to accrual Phase III Randomized Study of Oxaliplatin, Leucovorin Calcium, and Fluorouracil With Versus Without Bevacizumab in Patients With Resected Stage II Colon Cancer and at High Risk for Recurrence Based on Molecular Markers Protocol ID: ECOGE5202, NCT Date last modified: September 11, 2007 Type of trial: Randomized study, active control Primary endpoint: 3year diseasefree survival Accrual: A total of 3,610 patients will be accrued for this study within 5.8 years. Sponsorship: ECOG, NCI Status: Open and active Randomized Phase III Trial Comparing Adjuvant Oral UFT/LV to 5FU/lLV in Stage III Colorectal Cancer Protocol ID: JCOG0205MF, NCT , C Date last modified: May 31, 2007 Type of trial: Randomized, multicentre study, open label, active control Primary endpoint: Diseasefree survival Accrual: A total of 1,100 patients were to be accrued for this study. EVIDENTIARY BASE page 36

42 Sponsorship: Status: Japan Clinical Oncology Group at National Cancer Center Japanese Ministry of Health, Labour and Welfare Closed to accrual Phase III Randomized Study of Adjuvant Combination Chemotherapy Comprising Oxaliplatin, Leucovorin Calcium, and Fluorouracil With Versus Without Cetuximab in Patients With Completely Resected Stage III Colon Cancer Protocol ID: FFCDPETACC8, EU20547, EUDRACT , NCT Date last modified: August 23, 2007 Type of trial: Randomized, multicentre study, open label, active control Primary endpoint: Diseasefree survival Accrual: A total of 2,000 patients will be accrued for this study. Sponsorship: Federation Francophone de Cancerologie Digestive Status: Open and active Phase III Randomized Study of Adjuvant Oxaliplatin, Leucovorin Calcium, and Fluorouracil (FOLFOX4) Versus Bevacizumab and FOLFOX4 Versus Bevacizumab, Oxaliplatin, and Capecitabine in Patients With HighRisk Stage II or Stage III Colon Cancer Protocol ID: UCLA , ROCHEB017920A, NCT Date last modified: August 29, 2007 Type of trial: Randomized, multicentre study, open label, active control Primary endpoint: Diseasefree survival Accrual: A total of 3,450 patients (1,150 per treatment arm) were to be accrued for this study within 23 months. Sponsorship: Jonsson Comprehensive Cancer Center at UCLA, NCI Status: Closed Phase III randomized trial (ColonOxalad) of adjuvant therapy of very high risk colon cancer patients with bolus 5fluorouracil and folinic acid +/ oxaliplatin Protocol ID: ColonOxalad Group Argentina Date last modified: No data available Type of trial: Randomized, multicentre study Primary endpoint Unknown Accrual: 104 patients have been randomized into two treatment arms as of 2002 Sponsorship: Pharmacia Argentina, Debiopharm (Buenos Aires) Status: Unknown. Safety data were presented at ASCO 2002 (Abstract 656) Phase III randomized study of adjuvant tegafururacil versus observation only in patients with curatively resected stage II colorectal cancer Protocol ID: TMDUBRICC0501, NCT Date last modified: July 11, 2007 Type of trial: Randomized study, active control Primary endpoint Diseasefree survival Accrual: 2,000 patients will be accrued Sponsorship: Tokyo Medical and Dental University Status: Open and active EVIDENTIARY BASE page 37

43 Evidencebased Series #229: Section 3 Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection: EBS Development Methods and External Review Process D. Jonker, K. Spithoff, J. Maroun, and the Gastrointestinal Cancer Disease Site Group. A Quality Initiative of the Program in Evidencebased Care (PEBC), Cancer Care Ontario (CCO) Report Date: April 17, 2008 Evidencebased Series (EBS) #229 replaces Practice Guidelines #21 and #22 THE PROGRAM IN EVIDENCEBASED CARE The Program in Evidencebased Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO) (1). The PEBC mandate is to improve the lives of Ontarians affected by cancer, through the development, dissemination, implementation, and evaluation of evidencebased products designed to facilitate clinical, planning, and policy decisions about cancer care. The PEBC supports a network of diseasespecific panels, termed Disease Site Groups (DSGs) and Guideline Development Groups (GDGs), as well as other groups or panels called together for a specific topic, all mandated to develop the PEBC products. These panels are comprised of clinicians, other health care providers and decision makers, methodologists, and community representatives from across the province. The PEBC is well known for producing evidencebased guidelines, known as Evidencebased Series (EBS) reports, using the methods of the Practice Guidelines Development Cycle (1,2). The EBS report consists of an evidentiary base (typically a systematic review), an interpretation of and consensus agreement on that evidence by our Groups or Panels, the resulting recommendations, and an external review by Ontario clinicians and other stakeholders in the province for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each document, through the periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original guideline information. DEVELOPMENT & REVIEW page 1

44 The Evidencebased Series: Each Evidencebased Series is comprised of three sections. Section 1: Guideline Recommendations. Contains the clinical recommendations derived from a systematic review of the clinical and scientific literature and its interpretation by the Group or Panel involved and a formalized external review in Ontario by review participants. Section 2: Evidentiary Base. Presents the comprehensive evidentiary/systematic review of the clinical and scientific research on the topic and the conclusions reached by the Group or Panel. Section 3: EBS Development Methods and External Review Process. Summarizes the evidencebased series development process and the results of the formal external review of the draft version of Section 1: Recommendations and Section 2: Evidentiary Base. DEVELOPMENT OF THIS EVIDENCEBASED SERIES Development and Internal Review This evidencebased series was developed by the Gastrointestinal Cancer DSG of CCO's PEBC. The DSG comprises medical oncologists, radiation oncologists, surgeons, a methodologist, and a community representative. The series is a convenient and uptodate source of the best available evidence on adjuvant systemic chemotherapy for the treatment of stage II or III resected colon cancer, developed through systematic review, evidence synthesis, and input from practitioners in Ontario. A complete list of Gastrointestinal Cancer DSG members can be found at Report Approval Panel Prior to the submission of this EBS draft report for external review, the report was reviewed and approved by the PEBC Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. Key issues raised by the Report Approval Panel included: For the comparison of fluoropyrimidines versus surgery alone, the authors should highlight which data are new since the original publications, and indicate how the conclusions have changed. The authors should consider which components can be historical narrative and removed from the Results section. The authors should consider summarizing the published metaanalyses in tabular form. The document would benefit from better framing the hypothesis of oral fluoropyrimidines versus intravenous fluoropyrimidines in terms of efficacy noninferiority, ease of administration, quality of life, and potential cost. A more definitive conclusion about which option, oral or intravenous, is preferred, or what tradeoffs exist, would be helpful. The authors should more specifically indicate what constitutes highrisk and which stage II patients should be treated. Summary statements of conclusions for stage II and III patients should be added to each component of the Results section. The information should be reframed along the lines of disease stage in the Discussion section. Modifications in Response to Report Approval Panel Feedback: The results for the fluoropyrimidinebased chemotherapy versus surgery alone comparison were moved to an appendix so that Section 2 focuses on the important new findings since the original publications. The published metaanalyses for fluoropyrimidinebased chemotherapy versus surgery alone were summarized in a table in Appendix 4. DEVELOPMENT & REVIEW page 2

45 Statements were added to indicate that trials comparing oral and intravenous fluoropyrimidines have generally been noninferiority trials with the goal of reducing toxicity and improving ease of administration. A discussion of toxicity associated with either method was expanded, and a statement that oral fluoropyrimidines are generally preferred was added. The issue of what constitutes highrisk stage II disease was expanded in the Discussion section of Section 2 and was clarified in the recommendations in Section 1. Further details were added to the Results section regarding results by disease stage, where available. The issue of treatment for stage II and III disease was expanded in the Discussion section. External Review by Ontario Clinicians Following the review and discussion of Section 1: Recommendations and Section 2: Evidentiary Base of this EBS and review and approval of the report by the PEBC Report Approval Panel, the Gastrointestinal Cancer DSG circulated Sections 1 and 2 to external review participants in Ontario for review and feedback. Box 1 summarizes the draft recommendations and supporting evidence developed by the Gastrointestinal Cancer DSG. BOX 1: DRAFT RECOMMENDATIONS (approved for external review December 10, 2007) Target Population These recommendations apply to adult patients with stage II or III colon cancer who have undergone resection with curative intent as primary therapy. Recommendations Stage II Colon Cancer The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, the subset of patients with highrisk stage II disease who should be considered for adjuvant therapy includes patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of highrisk prognostic features on individual prognosis, and patient preferences. When treated with adjuvant therapy, highrisk stage II patients should receive similar regimens to those recommended for stage III patients. The enrolment of resected highrisk 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. Stage III Colon Cancer The Gastrointestinal Cancer Disease Site Group (DSG) recommends that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within eight weeks of surgery. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment. The recommended treatment option is: 5FU given intravenously in combination with leucovorin (LV) and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5FU/LV/oxaliplatin DEVELOPMENT & REVIEW page 3

46 regimens have demonstrated superior fouryear diseasefree survival when compared with 5FU plus LV and are the recommended regimens. Oxaliplatin administration is associated with a 1% risk of persistent grade 3 neuropathy that needs to be considered in conjunction with expected benefits of therapy. For patients for whom oxaliplatin is not considered appropriate, the treatment options are: Oral capecitabine administered for six months, which has equivalent efficacy to intravenous 5FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more handfoot syndrome when compared with 5FU/LV. 5FU in combination with LV administered for six months using either the weekly or monthly schedule. Suitable patients should be offered entry into clinical trials testing new adjuvant treatments for resected stage III colon cancer. Methods Feedback was obtained through a mailed survey of 78 external review participants in Ontario (28 medical oncologists and 50 surgeons). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a guideline. Written comments were invited. The survey was mailed out on December 10, Followup 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. Results As of February 27, 2008, 30 responses were received out of the 78 surveys sent (38% response rate). Responses include returned completed surveys as well as phone, fax, and responses. Of the participants who responded, 21 indicated that the report was relevant to their practice or organizational position, and 23 completed the survey (77%). Key results of the feedback survey are summarized in Table 8. Table 8. Responses to eight items on the feedback survey. Number (%) Item Strongly agree or agree Neither agree nor disagree Strongly disagree or disagree The rationale for developing a guideline, as stated in the 21 (91) 2 (9) Introduction section of the report, is clear. There is a need for a guideline on this topic. 23 (100) The literature search is relevant and complete. 20 (87) 3 (13) The results of the trials described in the report are 20 (91) 2 (9) interpreted according to my understanding of the data. The draft recommendations in the report are clear. 20 (87) 3 (13) I agree with the draft recommendations as stated. 20 (87) 1 (4) 2 (9) This report should be approved as a practice guideline. 19 (83) 3 (13) 1 (4) 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 18 (82) 1 (5) 3 (14) Not at all likely or unlikely DEVELOPMENT & REVIEW page 4

47 Summary of Written Comments Five respondents (22%) provided written comments regarding the content of the guideline. The main points contained in the comments were: 1. The statement, Five year DFS was 83.7% in the FOLFOX4 group, should read 73.7%. 2. The QUASAR study previously published in abstract form has now been published. 3. Updated data from the MOSAIC trial presented at ASCO 2007 should be used. 4. I cannot accept the statement that high risk stage II patients should receive similar regimens to those recommended for stage III patients. The MOSAIC study showed a trend for increased DFS in high risk stage II but no overall survival difference in high risk patients. One has to balance the toxicity of FOLFOX versus an increase in DFS but no increase in overall survival. 5. The presented material was not very clear. An appendix recapping stage II and III would be very useful. More attention to clarity regarding absolute benefits of adjuvant therapy with more use of confidence intervals would be very useful. A better analysis of treatmentrelated morbidity (riskbenefit analysis) would be of great value to the average patient and practitioner. A clearer Section 1 could be produced, given the work that went into producing this guideline. A better discussion of the original work of no treatment versus adjuvant treatment would also be very beneficial. 6. Given delays at each level of care after surgery (i.e., delay in getting pathology report, then appointment for cancer clinic), I do not see too many people starting chemotherapy within eight weeks of surgery. Remember, the ideal was six weeks at one time! 7. The guideline is very comprehensive and should be approved. Modifications and Response to Written Comments In response to the written comments received from external review participants, the following modifications were made: 1. In Section 1, Key Evidence, the statement that five year DFS was 83.7% in the FOLFOX4 group of the MOSAIC trial was corrected to read 73.3%. 2. Abstract data for the QUASAR trial were replaced with data from the full report, published in December 2007 (3). 3. Data from the MOSAIC trial presented at ASCO 2007 were already included in the draft guideline. In Section 1, Recommendations for stage III patients, the statement These 5 FU/LV/oxaliplatin regimens have demonstrated superior fouryear diseasefree survival when compared with 5FU plus LV was replaced with These 5FU/LV/oxaliplatin regimens have demonstrated superior diseasefree survival when compared with 5FU plus LV. 4. The statement that high risk stage II patients should receive similar regimens to those recommended for stage III patients was retained, The recommendations emphasize that the decision to use adjuvant chemotherapy in stage II patients should be based on discussions regarding perceived risk of recurrence, anticipated toxicity, and patient preferences. More extensive discussion of the pros and cons of treatment with FOLFOX and alternative regimens are found in both the recommendations for stage III patients and in Section 2. There is flexibility in the recommendations for stage III patients to allow the use of capecitabine or 5FU if a patient is not considered appropriate for oxaliplatin regimens or if the potential toxicities associated with oxaliplatin are unacceptable. 5. In order to clarify the recommendations in Section 1, the following statement was added: Some patients would not be considered appropriate for oxaliplatin regimens. Examples include patients with underlying neurologic conditions or at increased risk of neuropathy DEVELOPMENT & REVIEW page 5

48 and patients at increased risk for or likely to poorly tolerate infections as a result of chemotherapy. Absolute benefits can be derived from DFS and OS percentage data presented for each key trial in the Key Evidence of Section 1. The authors did not feel that the addition of absolute benefit data with confidence intervals for each trial was necessary. Stage II and III data are presented in the Results of Section 2 and are discussed in the Discussion section. The authors did not feel that an additional appendix recapping results and recommendations for stage II and III patients was required. Treatmentrelated morbidity is discussed extensively in Section 2. Trials comparing adjuvant chemotherapy to surgery alone are reported in detail in Appendix 4, and this comparison was not the focus of the current review. Readers are encouraged to see publications of previous CCO guidelines for further discussion of these data (46). 6. The authors recognize that delays occur that may prevent patients from receiving chemotherapy within eight weeks of surgery; however, it was felt that the recommendation should be retained based on the evidence available. Policy Review This document was submitted to the Committee to Evaluate Drugs (CED) in 2006 to inform a decision on the funding of oxaliplatin for the adjuvant treatment of colon cancer. Conclusion This EBS report reflects the integration of feedback obtained through the external review process with final approval given by the Gastrointestinal Cancer DSG and the Report Approval Panel of the PEBC. Updates of the report will be conducted as new evidence informing the question of interest emerges. Funding The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and LongTerm Care. All work produced by the PEBC is editorially independent from its funding agencies. Copyright This evidencebased series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidencebased series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any for their application or use in any way. Contact Information For further information about this report, please contact: Dr. Jim Biagi, CoChair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W, Kingston, ON, K7L 5P9. TEL ext. 4502; FAX 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: ext Fax: [email protected] DEVELOPMENT & REVIEW page 6

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