Evidence-based Series 2-29 IN REVIEW
A Quality Initiative of the
Program in Evidence-based 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 2-29 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 2015.
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 Evidence-based Series 2-29 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 http://www.cancercare.on.ca/ or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: ccopgi@mcmaster.ca
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 Evidence-based Care Evidence-based Series No.: 2-29 IN REVIEW.
EBS 2-29 IN REVIEW
Evidence-based Series #2-29: 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 Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Report Date: April 17, 2008
Evidence-based Series (EBS) #2-29 replaces Practice Guidelines #2-1 and #2-2
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 disease-free survival (DFS), overall survival (OS), adverse effects, and quality of life. Comparisons of interest were:
1. Fluoropyrimidine-based systemic chemotherapy versus observation. 2. Intravenous (IV) 5-fluorouracil (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 high-risk 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 high-risk prognostic features on individual prognosis, and patient preferences.
EBS 2-29 IN REVIEW
When treated with adjuvant therapy, high-risk stage II patients should receive similar regimens to those recommended for stage III patients.
The enrolment of resected high-risk 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:
5-FU given intravenously in combination with leucovorin (LV) and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5-FU/LV/oxaliplatin regimens have demonstrated superior DFS when compared with 5-FU 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 5-FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more hand-foot syndrome when compared with 5-FU/LV.
5-FU 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 meta-analyses 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 5-FU/LV (1-5). In the X-ACT 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 5-FU/LV arm, but more hand-foot syndrome. Quality of life did not differ significantly between treatment arms in either RCT.
Two RCTs compared 5-FU/LV plus oxaliplatin with 5-FU/LV alone in patients with resected stage II and III colon cancer (6-9) 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 follow-up for stage II and III patients who received FOLFOX4 compared with patients who received 5-FU/LV (HR, 0.80; p=0.003). Five-year DFS was 73.3% in the FOLFOX4 group and 67.4% in the 5-FU/LV group. A subgroup analysis by disease stage
EBS 2-29 IN REVIEW
demonstrated a significant benefit in DFS for FOLFOX4 compared with 5-FU/LV in stage III patients (HR, 0.78; p=0.005; 5-year DFS, 66.4% versus [vs] 58.9%) but not in stage II patients (HR, 0.84; p=0.258; 5-year DFS, 83.7% vs 79.9%). In an exploratory analysis, HRs suggested a possible benefit in DFS for oxaliplatin in patients with high-risk stage II disease (HR, 0.74; p>0.05) but not for low-risk 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 follow-up, 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; 6-year 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; 6-year OS, 73.0% vs 68.6%) (7).
NSABP C-07:
o The NSABP C-07 RCT demonstrated a significant benefit in DFS for the overall analysis of stage II and III patients (HR, 0.80; p=0.0034; 4-year DFS, 73.2% vs 67.0%) (8).
None of the four RCTs comparing fluoropyrimidines with irinotecan to fluoropyrimidines alone (10-13) 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 (11-13).
Funding
The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent
from its funding source.
Copyright
This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario
reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
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, Co-Chair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W, Kingston, ON, K7L 5P9
TEL 613-544-2630 ext. 4502; FAX 613-546-8209.
For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/
or contact the PEBC office at:
EBS 2-29 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;352:2696-704.
2. Twelves C, Wong A, Nowacki M, McKendrick J, van Hazel G, Douillard J, et al. Updated efficacy findings from the X-ACT phase III trial of capecitabine (X) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with Dukes’ C colon cancer. Proc Annu Meet Soc Clin Oncol. 2005;23(16S):A3521.
3. Scheithauer W, McKendrick J, Begbie S, Borner M, Burns WI, Burris HA, et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol. 2003;14:1735-43.
4. 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 C-06. J Clin Oncol. 2006;24:2059-64.
5. 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 C-06. J Clin Oncol. 2007;25:424-30.
6. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.
7. 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 follow-up of six years. Proc Annu Meet Soc Clin Oncol. 2007;25(18S):A4007.
8. 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 C-07. J Clin Oncol. 2007;25:2198-204. 9. 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 C-07. J Clin Oncol. 2007;25:2205-11. 10. 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 89803. J Clin Oncol. 2007;25:3456-61.
11. Ychou M, Raoul J, Douillard J, Bugat R, Mineur L, Viret F, et al. A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). Proc Annu Meet Soc Clin Oncol. 2005;23(16S)A3502.
12. Van Cutsem E, Labianca R, Hossfeld D, Bodoky G, Roth A, Aranda E, et al. Randomized phase III trial comparing infused irinotecan / fluorouracil (FU)/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):A8.
13. Sasaki K, Takasaka H, Kiriyama K, Inafuku Y, Yabana T, Furuhata T, et al. Adjuvant postoperative chemotherapy for Dukes C colorectal cancer; weekly low-dose Irinotecan (CPT-11) plus oral 5-FU versus oral 5-FU only. Proc Annu Meet Soc Clin Oncol. 2004;22(14S):A3735.
Evidence-based Series #2-29: 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 Evidence-based Care (PEBC), Cancer Care Ontario (CCO) Report Date: April 17, 2008
Evidence-based Series (EBS) #2-29 replaces Practice Guidelines #2-1 and #2-2
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 disease-free survival (DFS), overall survival (OS), adverse effects, and quality of life. Comparisons of interest were:
1. Fluoropyrimidine-based systemic chemotherapy versus observation. 2. Intravenous (IV) 5-fluorouracil (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 clinico-pathologic 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. High-risk stage II disease is associated with an outcome similar to that of patients with stage III disease, with a five-year 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
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 5-FU 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 5-FU 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 Evidence-based Care (PEBC) section of the Cancer Care Ontario (CCO) Web site (http://www.cancercare.on.ca) in 2000. 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 5-FU with LV, also known as folinic acid (FA), since 5-FU plus levamisole has not demonstrated superior efficacy over 5-FU/LV and is associated with significant toxicity. Studies have indicated that treatment durations of six months with 5-FU/LV are as effective as 12 months of 5-FU with levamisole (8-13). 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 tegafur-uracil (UFT) with intravenous 5-FU have generally been non-inferiority 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 (4-6).
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 three-year DFS and five-year OS once complete five-year survival was available for all patients, the primary
outcome for this review was DFS. In this analysis, the correlation between three-year DFS (minimum follow-up, three years), the five-year OS rate was 0.86, and the correlation between three-year 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 evidence-based 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 up-to-date 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 evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source.
Literature Search Strategy
The MEDLINE (1987 through September 2007), EMBASE (1987 through week 38 2007), 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, meta-analyses, 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 meta-analyses 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 fluoropyrimidine-based chemotherapy versus observation alone, oral fluoropyrimidines versus intravenous 5-FU, fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone, or fluoropyrimidines plus irinotecan versus fluoropyrimidines alone.
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 English-language publications.
4. The clinical trials were published after 1987. Buyse et al (17) summarized the results of randomized trials of adjuvant therapy for colorectal cancer up to 1987. The results of this meta-analysis 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 meta-analyses 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 5-FU, fluoropyrimidines plus irinotecan versus fluoropyrimidines alone, or fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone.
RESULTS
Meta-analysis of Adjuvant Therapy (RCTs to 1987)
In 1988, Buyse et al conducted a meta-analysis 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 5-FU 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 (18-55), representing 31 RCTs and 13 meta-analyses of RCTs (56-68) 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
Fluoropyrimidine-based Systemic CT vs Observation
21 (18-40) Appendix 4
Oral fluoropyrimidines vs IV 5-FU 2 (41-45) Table 2
Fluoropyrimidines + oxaliplatin vs fluoropyrimidines 3 (46-50) Table 3 Fluoropyrimidines + irinotecan vs fluoropyrimidines 5 (51-55) Table 4
Meta-analyses of Randomized Controlled Trials
Fluoropyrimidine-based CT vs Observation 13 (56-68) Appendix 4
Adjuvant Fluoropyrimidine-based Systemic Chemotherapy versus Observation
Randomized Controlled Trials
The comparison of adjuvant fluoropyrimidine-based 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 (18-40) have compared the use of various intravenous and oral fluoropyrimidine-based 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 high-risk 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 high-risk and low-risk stage II patients, making this assessment difficult.
Meta-analyses of Randomized Controlled Trials
Meta-analyses 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 (56-68) (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 high-risk versus low-risk patients; therefore, these studies alone are insufficient to base recommendations for the high-risk stage II population.
Oral Fluoropyrimidines versus Intravenous 5-FU
Two RCTS have sought to demonstrate non-inferiority of oral over IV fluoropyrimidines, with the goal of having a less toxic or more convenient mode of delivery. The X-ACT trial compared oral capecitabine with intravenous bolus 5-FU/LV (Mayo Clinic regimen) (41) and the NSABP C-06 trial compared oral UFT plus LV with intravenous 5-FU/LV in patients with resected colon carcinoma (44) (Table 2). The X-ACT trial included only patients with resected stage III tumours while the NSABP C-06 included patients with either stage II or III tumours. Both studies have been fully published, and updated efficacy data for the X-ACT trial are available in abstract form (42). Both RCTs reported pharmaceutical sponsorship, and neither study was blinded or placebo-controlled. The method of patient randomization was adequately described for the X-ACT study but was not reported in the NSABP C-06 study. The NSABP C-06 study stratified patients by the number of involved lymph nodes, and the X-ACT study stratified patients by treatment centre. Both studies reported the statistical calculations used to determine trial power and target sample sizes.
Disease-free Survival
Both the X-ACT study (41,42) and the NSABP C-06 study (44) demonstrated equivalent efficacy with respect to DFS for oral fluoropyrimidines compared with intravenous 5-FU/LV. Using predetermined non-inferiority margins of 1.25 and 1.20 for the HR to demonstrate at least equivalence for the two treatment regimens, the X-ACT study showed capecitabine to be at least as effective as 5-FU/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 non-significant (p=0.053). Similarly, the NSABP C-06 study concluded that the UFT/LV and 5-FU/LV were equivalent for DFS (HR, 1.004, favouring 5-FU/LV). Results for the DFS outcome were not reported separately for stage II and III patients in this study.
Overall Survival
Both studies comparing oral regimens with intravenous 5-FU/LV demonstrated no significant difference in OS between treatment groups (41,42,44). In the X-ACT study of stage III patients, the mortality HR was 0.89 favouring capecitabine (non-inferiority p<0.001); however, this difference was not significant in the superiority analysis (p=0.208). The NSABP C-06 study reported a mortality HR of 1.014 favouring 5-FU/LV for the overall analysis of stage II and III patients, but this difference was also not significant (p=0.90). Although five-year OS data were reported separately for stage II and III patients, no statistical comparisons were performed.
Adverse Effects
A safety analysis of the X-ACT 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 5-FU/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 treatment-related toxicity that occurred more frequently in patients who received capecitabine compared with those who received 5-FU/LV was hand-foot 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 5-FU/LV) but median time to first dose reduction was longer in the capecitabine group (78 vs 41 days).
In the NSABP C-06 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 X-ACT 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 5-FU/LV group, but both increased slightly at week 25 of treatment. In the NSABP C-06 study, quality of life results were reported in a separate publication (45). Health-related quality of life (HRQL) was measured at baseline, at week 15-16, 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 5-FU/LV scored marginally higher on the SF-36 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 5-FU plus oxaliplatin with 5-FU alone for the adjuvant treatment of colon carcinoma: the MOSAIC (46), NSABP C-07 (48), and XELOXA studies (50) (Table 3). The MOSAIC and the NSABP C-07 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 follow-up is continuing for the NSABP C-07 and XELOXA RCTs. Two of the RCTs administered oxaliplatin with intravenous 5-FU/LV, one using the FOLFOX4 regimen (46) and one using the FLOX regimen (48), while one of the RCTs compared capecitabine plus oxaliplatin (XELOX)
with bolus 5-FU/LV (50) (see Appendix 3 for regimen details). The MOSAIC (46) and the NSABP C-07 (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.
Disease-Free Survival
In overall analyses of patients with resected stage II and III colon cancer, both the MOSAIC study (46,47) and the NSABP C-07 study (48) demonstrated a significant benefit in DFS for 5-FU/LV plus oxaliplatin compared with 5-5-FU/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 high-risk and low-risk stage II patients was also reported. In this analysis, patients were considered high-risk 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, five-year DFS was 82.1% versus 74.9%, favouring FOLFOX4 (HR, 0.74; 95% CI, 0.52-1.06; p>0.05). In low-risk stage II patients, five-year DFS was 86.3% versus 89.1%, favouring LV5FU2 (HR, 1.22; 95%, CI 0.66-2.26; p>0.05). These data are available only in a public online presentation (47). The NSABP C-07 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 5-FU/LV alone. After six years of follow-up, the MOSAIC trial reported a trend towards improved survival in the oxaliplatin group (HR, 0.85); however, the difference between groups was marginally non-significant (p=0.057). Separate analyses by disease stage indicated a significant survival benefit for oxaliplatin compared with 5-FU/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 5-FU/LV plus oxaliplatin compared with patients who received 5-FU/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 C-07 study reported neurosensory toxicity in 8.4% of patients who received oxaliplatin in the FLOX regimen, compared to 0.7% of patients who received 5-FU/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 5-FU/LV group. Patients in the XELOX group experienced less neutropenia, febrile neutropenia, and stomatitis but more thrombocytopenia, neurosensory toxicity, and hand-foot syndrome than did patients in the bolus 5-FU/LV group. Sixty-day all-cause mortality (1% in each group) and treatment-related death within 28 days from last dose (0.6% in each group) were similar between treatment groups (50).
Quality of Life
None of the three RCTs comparing 5-FU plus oxaliplatin with 5-FU 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 5-FU plus irinotecan with 5-FU 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 (52-55). One study has only reported safety data to date (55). Four of the RCTs administered irinotecan with intravenous 5-FU/LV (51,53-55), and one RCT administered irinotecan with oral 5-FU (52). Two RCTs included patients with both stage II and III disease (54,55), and three RCTs included only patients with stage III disease (51-53), one of which was limited to only patients with high-risk 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 placebo-controlled. 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).
Disease-Free survival
Three studies reported DFS data for patients with stage III disease (51,53,54) and none demonstrated a significant difference between 5-FU plus irinotecan and 5-FU alone for these patients. Of the two studies that reported hazard ratios, one favoured 5-FU/LV plus irinotecan (HR, 0.89; p=0.091) (54) and one favoured 5-FU/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 5-FU plus irinotecan versus 5-FU alone (51,52), and both included only patients with stage III disease. The CALGB study reported no benefit for 5-FU/LV plus irinotecan over 5-FU/LV alone in OS (p=0.74) after a median follow-up of 4.8 years (51). The Japanese study reported no benefit for oral 5-FU plus irinotecan over oral 5-FU alone in one-year survival (100% vs 100%), two-year survival (91% vs 89%), or four-year survival (86% vs 75%) (52).
Adverse Effects
The Japanese study of oral 5-FU plus irinotecan versus oral 5-FU 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 5-FU/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 5-FU/LV alone (54). The Papakostas study has reported only safety data to date as patient follow-up is ongoing (55). Safety data from 826 of 910 enrolled patients indicate comparable and manageable toxicity in both groups, although
significantly higher grade 3/4 neutropenia was reported in patients who received 5-FU/LV with irinotecan compared with 5-FU/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 5-FU regimen plus irinotecan with a 5-FU regimen alone reported data for quality of life (51-55).
Table 2. Randomized controlled trials of oral fluoropyrimidines versus intravenous 5-FU. Trial, year (reference) Treatment allocation Months on therapy Number of patients evaluated Median follow-up (years)
All trial patients Stage II patients Stage III patients
DFS OS DFS OS DFS OS
Stage II Stage III
Twelves, 2005 X-ACT (41,42) Capecitabine IV 5-FU/LV (Mayo regimen) 5.5 - - 1004 983 4.25 - - - - - - - - 3-year 64.6% 61.0% HR 0.87 (95% CI 0.75-1.00) p=0.053* 3-year 81.3% 77.6% HR 0.89 (95% CI 0.74-1.07) p=0.208* Lembersky, 2006 NSABP C-06 (44) Oral UFT + LV IV 5-FU/LV 5.8 5.5 365 357 416 413 5.2 5-year 67.0% 68.2% HR 1.004 (95% CI 0.85-1.19) p=0.96 5-year 78.5% 78.7% HR 1.014 (95% CI 0.83-1.25) p=0.90 NR 5-year 88.4% 87.0% p=NR NR 5-year 69.6% 71.5% p=NR
Notes: 5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; LV, leucovorin; NR, not reported; OS, overall survival; UFT, tegafur-uracil.
Table 3. Randomized controlled trials of fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone. Trial, year (reference) Treatment allocation Months on therapy Number of patients evaluated Median follow-up (years)
All trial patients Stage II patients Stage III patients
DFS OS DFS OS DFS OS
Stage II Stage III Andre, 2004 MOSAIC (46,47)‡ LV5FU2 FOLFOX4 5.5 898 total 1348 total 6 5-year 67.4% 73.3% HR 0.80 (95% CI 0.68-0.93) p=0.003 6-year 76.0% 78.6% HR 0.85 (95% CI 0.72-1.01) p=0.057 5-year 79.9% 83.7% HR 0.84 (95% CI 0.62-1.14) p=0.258† 6-year 86.8% 86.9% HR 1.00 (95% CI 0.71-1.42) p=0.996 5-year 58.9% 66.4% HR 0.78 (95% CI 0.65-0.93) p=0.005 6-year 68.6% 73.0% HR 0.80 (95% CI 0.66-0.98) p=0.029 Kuebler, 2007 NSABP C-07
(48) 5-FU/LV FLOX 6 1207 total 1200 total 3.54
4-year 67.0% 73.2% HR 0.80 (95% CI 0.69-0.93) p=0.0034 NR 4-year 81.0% 84.2%* p=NR NR 4-year 61.1% 68.9%* p=NR NR Schmoll, 2007 XELOXA (50) Bolus 5-FU/LV XELOX 5.5 or 7.4 5.5 942 944 1.96 NR NR NR NR NR NR
Notes: 5-FU, 5-fluorouracil; DFS, disease-free survival; LV, leucovorin; NR, not reported; OS, overall survival; vs, versus; XELOX, capecitabine plus oxaliplatin. * Data available from Appendix published online only.
† Exploratory analysis of high-risk stage II patients: 5-year DFS 82.1% vs 74.9% favouring FOLFOX4, HR 0.74 (95% CI 0.52-1.06; p=NS). Low-risk stage II patients: 5-year DFS 86.3% vs 89.1% favouring LV5FU2, HR 1.22 (95% CI 0.66-2.26; p=NS)
Table 4. Randomized controlled trials of fluoropyrimidines plus irinotecan versus fluoropyrimidines alone. Trial, year (reference) Treatment allocation Months on therapy Number of patients evaluated Median follow-up (years)
All trial patients Stage II patients Stage III patients
DFS OS DFS OS DFS OS Stage II Stage III Saltz, 2004 CALGB (51) Bolus 5-FU/LV + irinotecan Bolus 5-FU/LV 6.9 7.4 - - 635 629 4.8‡ - - - - 3-year 66% 69% p=0.85 3-year 80% 81% p=0.74 Ychou, 2005 ACCORD 2 (abstract) (53)§ 5-FU/LV + irinotecan 5-FU/LV - 200 200 3 - - - - 3-year 51%* 60%* HR 1.19 (95% CI 0.90-1.59)¶ p=0.22 NR Van Cutsem, 2005 PETACC3 (abstract) (54) LV5FU2 + irinotecan LV5FU2 6 894 total 2094 total 3.2 3-year 69.6% 66.8% HR 0.88 (95% CI 0.77-1.00) p=0.050 NR 3-year 84.8% 82.0% HR 0.80 (95% CI 0.58-1.11) p=0.184 NR 3-year 63.3% 60.3% HR 0.89 (95% CI 0.77-1.11) p=0.091 NR Sasaki, 2005 (abstract) (52) Oral 5-FU + irinotecan Oral 5-FU 6 12 - - 39 47 NR - - - - NR 4-year 86% 75% p=NS Papakostas, 2007 (abstract) (55) 5-FU/LV + irinotecan 5-FU/LV 3 5.5 415 411 NR NR NR NR NR NR NR
Notes: 5-FU, 5-fluorouracil; DFS, disease-free survival; LV, leucovorin; NR, 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 high-risk stage III patients with N2 or N1/N2 detected by occlusion/perforation ¶ Favours 5-FU/LV
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 high-risk 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 5-FU/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 12-14% chronic (i.e. permanent) sensory neuropathy. The subset analysis of the high-risk 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 high-risk molecular markers include aneuploid/tetraploid (non-diploid) DNA, 18q allelic loss, MSS or low frequency microsatellite instability MSI-L, and maintenance of MMR proteins (hMLH1, hMSH2) by immunohistochemistry (69-84). 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 X-ACT trial demonstrate that oral capecitabine administered for six months has equivalent efficacy to IV 5-FU/LV. However, capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more hand-foot syndrome when compared with 5-FU/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
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 5-FU 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 5-FU/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
More adverse effects, including neuropathy, compared with 5-FU/LV
Alternatives Oral capecitabine. 6 months
Equivalent efficacy to IV 5-FU/LV Generally fewer adverse events compared with IV 5-FU/LV
More hand-food syndrome compared with 5-FU/LV
IV 5-FU/LV Less hand-foot syndrome
compared with oral capecitabine
More adverse effects (diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia) compared with oral
capecitabine.
Not
recommended
5-FU with irinotecan -- No significant benefit in DFS or
OS compared with 5-FU/LV. More adverse effects compared with 5-FU/LV. Notes: 5-FU, 5-fluorouracil; FOLFOX, 5-fluorouracil + leucovorin + oxaliplatin; FLOX, 5-fluorouracil + leucovorin + oxaliplatin; IV, intravenous; LV, leucovorin; FOLFIRI, 5-fluorouracil + 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 co-investigator on the AVANT, NSABP C-07 and X-ACT trials.
JOURNAL REFERENCES
The following updated guideline for EBS #2-29 has been published in Clinical Oncology (© 2011 The Royal College of Radiologists. Published by Elsevier Ltd. Available from: http://www.elsevier.com/locate/clon):
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). 2011 Mar 10. doi:10.1016/j.clon.2011.02.010. Epub 2011 Mar.
Practice Guidelines #2-1 and #2-2 were published as:
Figueredo A, Germond C, Maroun J, Browman G, Walker-Dilks C, Wong S, et al. Adjuvant therapy for Stage II colon cancer following complete resection. Cancer Prev Control. 1997;1(5):379-92.
Figueredo A, Fine S, Maroun J, Walker-Dilks C, Wong S, and the Provincial Gastrointestinal Disease Site Group. Adjuvant therapy for stage III colon cancer after complete resection. Cancer Prev Control. 1997;1:304-19.
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 Evidence-based Care’s Gastrointestinal Cancer Disease Site Group. J Clin Oncol. 2004;22(16);3395-407.
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. Walker-Dilks 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 http://www.cancercare.on.ca/
Funding
The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent
from its funding source.
Copyright
This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario
reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
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, Co-Chair, Gastrointestinal Cancer Disease Site Group, Cancer Centre of Southeastern Ontario, Kingston General Hospital, 25 King St W,
Kingston, ON, K7L 5P9.
TEL 613-544-2630 ext. 4502; FAX 613-546-8209.
For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/
or contact the PEBC office at:
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