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Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer after Complete Resection: An Updated Practice Guideline
Clinical Oncology 23 (2011) 314e322 Contents lists available at ScienceDirect
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Guidelines
Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer after Complete Resection: An Updated Practice Guideline D.J. Jonker *1, K. Spithoff y1, J. Maroun *1 * Ottawa y
Hospital Regional Cancer Centre, Ottawa, Ontario, Canada Cancer Care Ontario Program in Evidence-based Care, McMaster University, Hamilton, Ontario, Canada
Received 27 February 2010; received in revised form 21 December 2010; accepted 10 February 2011
Abstract Aims: The standard adjuvant therapy for resected stage III colon cancer has been intravenous 5-fluorouracil. However, newer chemotherapy agents, such as capecitabine, oxaliplatin and irinotecan, have been investigated in clinical trials since the publication of the original guidelines. The Gastrointestinal Cancer Disease Site Group (DSG) conducted a systematic review of the evidence for the use of adjuvant systemic chemotherapy for patients with resected stage II and III colon cancer and developed an updated practice guideline based on that evidence and expert consensus. The following research questions were addressed: 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, overall survival, adverse effects and quality of life. Materials and methods: A systematic search of published studies was conducted for the time period following the publication of the original guidelines to identify relevant randomised trials and syntheses of evidence in the form of meta-analyses. Recommendations were based on that evidence, evidence contained in the original guidelines and consensus of the Gastrointestinal Cancer DSG. The systematic review and practice guideline were externally reviewed through a mailed survey of practitioners in Ontario, Canada. Results: Recommendations were drafted based on the available evidence and expert consensus. Conclusions: The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, a subset of patients with highrisk stage II disease should be considered for adjuvant therapy. Patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy. 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. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Adjuvant therapy; chemotherapy; colonic neoplasms; colorectal neoplasms; practice guideline
Introduction In Canada, colorectal cancer is the fourth most common cancer site when both genders are combined, representing 13% of all new cancer cases [1]. Prognosis is determined by the clinicopathological stage of the disease at diagnosis. 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
Author for correspondence: D.J. Jonker, The Ottawa Hospital Regional Cancer Centre, Ottawa, Ontario, Canada. Tel.: þ1-613-737-7700x70170; Fax: þ1-613-247-3511. E-mail address: [email protected] (D.J. Jonker). 1 On behalf of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care.
involves metastases to regional lymph nodes. The overall survival of patients with stage II disease is 70e80% 5 years after surgery [2]. More than one-third of patients with colon carcinoma present with lymph node metastases (stage III), and more than half of those patients relapse after initial curative treatment 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 5 year overall survival of 40e50%. The definition of ‘high risk’ is a subject of considerable debate and research, and remains inadequately described in current TNM staging. 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. However, these risk factors have not been confirmed in prospective
0936-6555/$36.00 Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.02.010
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studies where treatment was assigned based on these prognostic factors. Several guidelines regarding adjuvant therapy in stage II or III colon cancer have been previously published. In 1990, a National Institutes of Health Consensus Conference reviewed the available evidence and recommended adjuvant treatment with 5-fluorouracil (5-FU) and levamisole for patients with curatively resected stage III colon cancer [3]. In 1997, the Gastrointestinal Cancer Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-based Care (PEBC) published two separate practice guidelines on the topic of adjuvant therapy for completely resected stage II and III colon cancer [4,5]. On the basis of the evidence reviewed, the Gastrointestinal Cancer DSG recommended 5-FU/leucovorin (LV) as an alternative to 5-FU and levamisole for patients with stage III disease [5], but did not recommend the routine use of adjuvant chemotherapy for resected stage II colon carcinoma [4]. The originally published guidelines were updated with new evidence and posted on the Cancer Care Ontario website (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]. This formed the basis for a mutually endorsed American Society of Clinical Oncology and PEBC clinical guideline, which did not recommend routine adjuvant therapy for patients with resected stage II colon cancer, but recommended that patients with inadequately sampled lymph nodes, T4 lesions, perforation or poorly differentiated histology be considered for adjuvant therapy [7]. 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, as 5-FU plus levamisole has not shown superior efficacy over 5-FU/LV and is associated with significant toxicity [8e13]. 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 two-fold. Trials comparing oral fluoropyrimidines such as capecitabine or tegafur-uracil with intravenous 5-FU have generally been non-inferiority trials, with the goal of using oral therapy being 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 disease-free survival (DFS) and overall survival. A review of 18 randomised trials of adjuvant chemotherapy in colon cancer showed strong concordance between 2 and 3 year DFS and 5 year overall survival [14,15]. The correlation between 3 year DFS and the 5 year overall survival rate was 0.86 and the correlation between 3 year DFS and the overall survival hazard ratio was 0.91 [15]. Subsequent therapy for metastatic recurrence may delay the effect of the improvements in DFS on overall survival. DFS represents a relevant clinical end point, as the avoidance of years of costly and toxic therapy for metastatic disease is of value to patients and those who fund health care alike; therefore, DFS is the primary outcome for this practice guideline.
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As 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 original PEBC guidelines were combined and rewritten to address the questions that clinicians currently face in practice. This publication provides a summary of the updated guidelines; the full guideline report on which this publication is based can be found at www.cancercare.on.ca [16].
Materials and Methods This practice guideline was developed by the Gastrointestinal Cancer DSG of Cancer Care Ontario’s PEBC using the methods of the Practice Guidelines Development Cycle [17]. The practice guideline is intended to promote evidencebased practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care. 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 DFS, overall survival, adverse effects and quality of life. Comparisons of interest were: 1. Fluoropyrimidine-based systemic chemotherapy versus observation. 2. Intravenous 5-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. Intended Users This guideline is intended for use by clinicians and health care providers who are involved in the management or referral of adults with stage II or III colon cancer. Systematic Review The core methodology used to develop the evidentiary base was a systematic review. The MEDLINE (to September 2007), EMBASE (to week 38, 2007) and Cochrane Library (Issue 2, 2007) databases were searched to update the evidence contained in the original PEBC guidelines on adjuvant chemotherapy for stage II and III colon cancer. In
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addition, proceedings from the annual meetings of the American Society of Clinical Oncology (to 2007) were searched for abstract reports of randomised controlled trials (RCTs). Personal reprint files and reference lists of relevant studies were searched, as were references contained in the original PEBC stage II and III colon cancer guidelines. Data were extracted by one reviewer and verified through a dataauditing procedure. The full systematic review on which the recommendations are based is available at www.cancercare. on.ca [16]. Before publication of the guideline, the searches of the MEDLINE and EMBASE databases were updated to November week 3, 2010. Development of Recommendations The Gastrointestinal Cancer DSG reviewed the evidence contained in the original systematic reviews and the evidence identified in the literature search to September 2007. Draft recommendations were developed based on that evidence and the expert opinion of the Gastrointestinal Cancer DSG using informal consensus methods. Internal Review Before submission of the draft report for external review, the report was reviewed by the PEBC Report Approval Panel, which consists of two members, including an oncologist with expertise in clinical and methodology issues. External Review After approval of the draft systematic review and practice guideline by the Gastrointestinal Cancer DSG and the Report Approval Panel in December 2007, the document was distributed through a mailed survey to a sample of 78 health care providers (medical oncologists and surgeons) in Ontario, Canada for review and feedback. These external reviewers were selected by querying the PEBC practitioner database for health care providers of interest who treat gastrointestinal cancer. The questionnaire consisted of items evaluating the methods, results and interpretation of the evidence used to inform the draft recommendations, and of questions about whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed and follow-up reminders were sent to non-responders at 2 and 4 weeks. The Gastrointestinal Cancer DSG reviewed the results of the survey.
Results Literature Search Results Reports on 31 RCTs and 13 meta-analyses of RCTs were identified in 2007 and included in the systematic review on which the recommendations are based. Full details regarding the methodological characteristics and clinical outcomes of these trials can be found in the full guideline
report on the Cancer Care Ontario website (www. cancercare.on.ca) [16]. Information on trials comparing intravenous 5-FU versus oral fluoropyrimidines, fluoropyrimidines versus fluoropyrimidines plus oxaliplatin, and fluoropyrimidines versus fluoropyrimidines plus irinotecan is provided in Tables 1e3. The updated search of the published literature in November 2010 identified updated data for eight of the 31 trials [18e25], and a Cochrane review of fluoropyrimidinebased adjuvant therapy for completely resected stage II colon cancer [26]. The updated data provided added support for the recommendations developed in 2007.
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 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. 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 DSG recommends that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within 8 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 LV and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5-FU/LV/oxaliplatin regimens have shown 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, which 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 neurological conditions or at increased risk of neuropathy, patients at increased risk for infections,
Table 1 Randomised controlled trials of oral fluoropyrimidines versus intravenous 5-fluorouracil (5-FU) Trial, year
Treatment allocation
Months on therapy
Capecitabine Intravenous 5-FU/LV (Mayo regimen)
5.5
Lembersky, 2006 NSABP C-06 [30]
Oral UFT þ LV Intravenous 5-FU/LV
5.8 5.5
Stage II
Stage III
e e
1004 983
365 357
416 413
Median follow-up (years)
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4.25
e e
e e
e e
e e
3 year 64.6% 61.0%
3 year 81.7% 78.3%
HR 0.87 (95% CI 0.75e1.00) * P ¼ 0.053
HR 0.89 (95% CI 0.74e1.07) * P ¼ 0.208
NR
5 year 69.6% 71.5%
5.2
5 year 67.0% 68.2%
5 year 78.5% 78.7%
HR 1.004 (95% CI 0.85e1.19) P ¼ 0.96
HR 1.014 (95% CI 0.83e1.25) P ¼ 0.90
5 year 88.4% 87.0%
NR
P ¼ NR
P ¼ NR
CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; LV, leucovorin; NR, not reported; OS, overall survival; UFT, tegafur-uracil. *P values are for superiority tests. Values for non-inferiority tests are P < 0.0001 for DFS and P < 0.001 for OS. Table 2 Randomised controlled trials of fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone Trial, year
Treatment allocation
Months on therapy
Number of patients evaluated Stage II
Kuebler, 2007 NSABP C-07 [34]
5-FU/LV FLOX
Andre, 2009 MOSAIC [25,32]
LV5FU2 FOLFOX4
6
Stage III
1207 total 1200 total
Median follow-up (years) 3.54
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4 year 67.0% 73.2%
NR
4 year 81.0% 84.2%*
NR
4 year 61.1% 68.9%*
NR
P ¼ NR
HR 0.80 (95% CI 0.69e0.93) P ¼ 0.0034 5.5
448 451
675 672
6.8
P ¼ NR
5 year 67.4% 73.3%
6 year 76.0% 78.5%
5 year 79.9% 83.7%
6 year 86.8% 86.9%
5 year 58.9% 66.4%
6 year 68.7% 72.9%
HR 0.80 (95% CI 0.68e0.93) P ¼ 0.003
HR 0.84 (95% CI 0.71e1.00) P ¼ 0.046
HR 0.84 (95% CI 0.62e1.14) P ¼ 0.258
HR 1.00 (95% CI 0.70e1.41) P ¼ 0.986
HR 0.78 (95% CI 0.65e0.93) P ¼ 0.005
HR 0.80 (95% CI 0.65e0.97) P ¼ 0.023 317
5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; LV, leucovorin; NR, not reported; OS, overall survival. * Data available from appendix published online only.
D.J. Jonker et al. / Clinical Oncology 23 (2011) 314e322
Twelves, 2005 X-ACT [27,28]
Number of patients evaluated
318
Table 3 Randomised controlled trials of fluoropyrimidines plus irinotecan versus fluoropyrimidines alone Trial, year
Bolus 5-FU/LV þ irinotecan
Months on therapy
6.9 7.4
Number of patients evaluated Stage II
Stage III
e e
635 629
Median follow-up (years)
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4.8*
e
e
e
e
3 year 66% 69%
3 year 80% 81% P ¼ 0.74
P ¼ 0.85
Bolus 5-FU/LV
e
39
Sasaki, 2005 (abstract) [37]
Oral 5-FU þ irinotecan Oral 5-FU
6
NR
12
e
47
Van Cutsem, 2009 PETACC3 [22]
LV5FU2 þ irinotecan
6
894 total
2094 total
5.5
Ychou, 2009 ACCORD 2 [24] y
5-FU/LV þ irinotecan
e
199 198
5.25
e
e
e
NR
4 year 86% 75% P ¼ NS
LV5FU2
5-FU/LV
e
5 year 63.8% 61.0% HR 0.89 (95% CI 0.79e1.00) P ¼ 0.045
NR
5 year 80.9% 76.9% HR 0.81 (95% CI 0.61e1.08) P ¼ 0.158
5 year 90.0% 88.8% P ¼ 0.344
e
e
e
e
5 year 56.7% 54.3% HR 0.90 (95% CI 0.79e1.02) P ¼ 0.106
5 year 73.6% 71.3% P ¼ 0.094
3 year 51% 60% HR 1.12 (95% CI 0.85e1.47)z P ¼ 0.42
5 year 61% 67% HR 1.20 (95% CI 0.87e1.67)z P ¼ 0.26
5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; LV, leucovorin; NR, not reported; NS, not significant; OS, overall survival. * Median DFS and OS not reached at time of analysis, but futility boundaries crossed. y Study included only high-risk stage III patients with N2 or N1/N2 detected by occlusion/perforation. z Favours 5-FU/LV.
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Saltz, 2004 CALGB 89803 [36]
Treatment allocation
D.J. Jonker et al. / Clinical Oncology 23 (2011) 314e322
and patients likely to poorly tolerate infections as a result of chemotherapy. For these patients, the treatment options are: - Oral capecitabine administered for 6 months, which has equivalent efficacy to intravenous 5-FU/LV. Capecitabine results in significantly less diarrhoea, stomatitis, neutropenia, nausea/vomiting and alopecia, but significantly more handefoot syndrome when compared with 5-FU/LV. - 5-FU in combination with LV given for 6 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 RCTs comparing adjuvant chemotherapy with observation alone generally showed superior DFS and overall survival, particularly for stage III patients. Although hazard ratios also favoured chemotherapy for stage II patients, these were not statistically significant [16,26]. Oral fluoropyrimidines Two RCTs reported at least equivalent DFS and overall survival results for oral fluoropyrimidines (capecitabine and oral tegafur-uracil) compared with intravenous 5-FU/LV [27e31] (Table 1). In the X-ACT trial, patients in the capecitabine arm experienced significantly less grade 3/4 stomatitis, grade 3/4 neutropenia requiring intervention, febrile neutropenia/sepsis, diarrhoea, nausea and vomiting, and alopecia than patients in the 5-FU/LV arm, but more handefoot syndrome [29]. Quality of life did not differ significantly between treatment arms in either RCT. Fluoropyrimidines plus oxaliplatin Two RCTs compared 5-FU/LV plus oxaliplatin with 5-FU/ LV alone in patients with resected stage II and III colon cancer [25,32e35]: the MOSAIC trial [25,32,33] and the NSABP C-07 trial [34,35] (Table 2). The MOSAIC trial reported a significant benefit in DFS after 5 years of follow-up for stage II and III patients who received FOLFOX4 compared with patients who received 5-FU/LV (hazard ratio 0.80; P ¼ 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 showed a significant benefit in DFS for FOLFOX4 compared with 5-FU/LV in stage III patients (hazard ratio 0.78; P ¼ 0.005; 5 year DFS, 66.4% versus 58.9%), but not in stage II patients (hazard ratio 0.84; P ¼ 0.258; 5 year DFS, 83.7% versus 79.9%). In an exploratory analysis, hazard ratios suggested a possible benefit in DFS for oxaliplatin in patients with high-risk stage II disease (hazard ratio 0.72; P > 0.05) [25]. Exploratory data for lowrisk stage II patients are available only in abstract and online presentation form [33] and suggest no DFS benefit for oxaliplatin in this subgroup (hazard ratio 1.22; P > 0.05). After 6 years of follow-up, overall survival in the MOSAIC trial was significantly improved with the addition of
319
oxaliplatin in the overall analysis of stage II and III patients (hazard ratio 0.84; P ¼ 0.046). Analysis of stage III patients showed a significant benefit for the addition of oxaliplatin (hazard ratio 0.80; P ¼ 0.023; 6 year overall survival 72.9% versus 68.7%), but no difference between treatment arms in the subgroup analysis of stage II patients (hazard ratio 1.00; P ¼ 0.986; 6 year overall survival 86.9% versus 86.8%) [25]. The NSABP C-07 trial showed a significant benefit in DFS for the overall analysis of stage II and III patients (hazard ratio 0.80; P ¼ 0.0034; 4 year DFS 73.2% versus 67.0%) [34]. Fluoropyrimidines plus irinotecan One of the four RCTs [22,24,36,37] comparing fluoropyrimidines plus irinotecan with fluoropyrimidines alone showed a marginal benefit in DFS for the addition of irinotecan in a combined analysis of stage II and III patients [22], whereas two trials reported no significant difference between groups [24,36]. Three trials reported no significant difference in overall survival between treatment groups [24,36,37], although one was small and underpowered [37] (Table 3). Internal and External Review of the Practice Guideline The PEBC Report Approval Panel reviewed the draft systematic review and practice guideline and provided feedback. The draft systematic review and practice guideline were distributed to health care providers in the province of Ontario. Thirty of 78 health care providers (38%) returned the survey and 23 reviewers provided feedback. The results of these two sources of feedback and how they influenced the final recommendations can be found in the full guideline report on the Cancer Care Ontario website (www.cancercare.on.ca) [16].
Discussion and Gastrointestinal Cancer Disease Site Group Consensus Since the publication of the Cancer Care Ontario PEBC guidelines for stage III and II colon cancer in 1997 and 2004, respectively [4e7], there have been several important studies published that necessitate modifications to the original recommendations. Whereas the previous guidelines recommended the use of adjuvant intravenous 5-FU/ 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 5-FU/LV/oxaliplatin and the use of oral fluoropyrimidines as an alternative to intravenous 5-FU/LV. Two studies have been reported that compared 5-FU/LV with and without oxaliplatin in populations that included both stage II and III colon cancer [25,32e35]. The primary end point of these studies was DFS in the entire population and both trials showed a significant DFS benefit for the addition of oxaliplatin to 5-FU/LV. Additional follow-up of the MOSAIC trial published in 2009 also showed a 6 year survival benefit for oxaliplatin [25]. Although the MOSAIC trial reported outcomes separately for stage II and III patients, these are subset analyses
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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 showing the superiority of 5-FU/LV/oxaliplatin over 5-FU/LV alone for patients with stage II and stage III colon cancer. Although these key 5-FU/oxaliplatin adjuvant studies had a primary end point 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 overall survival benefit at all [25,33]. Subset analysis must be interpreted with caution, and additional subset data or a pooled analysis with NSABP CO7 [34] would be helpful. Despite this, the benefit in this population is in question, and treatment of all stage II patients is probably not warranted, particularly in light of the 12e14% 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 seems 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 (nondiploid) DNA, 18q allelic loss, microsatellite stability or low frequency microsatellite instability MSI-L, and maintenance of MMR proteins (hMLH1, hMSH2) by immunohistochemistry. 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 5-FU/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 are required. In addition to factors such as underlying neurological conditions, there may be other factors that lead a physician or patient to avoid 5-FU/LV/oxaliplatin. For patients who are not considered candidates for this combination, the alternatives include 5-FU/LV or capecitabine. Data from the X-ACT trial show that oral capecitabine given for 6 months has equivalent efficacy to intravenous 5-FU/LV [27,28]. However, capecitabine results in significantly less diarrhoea, stomatitis, neutropenia, nausea/vomiting and alopecia, but significantly more handefoot syndrome when compared with 5-FU/LV [29]. For those able to take oral therapy, capecitabine is therefore generally preferred over 5-FU/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 show clear advantages in the regimens studied so far, although trends in improvement 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. The Gastrointestinal Cancer DSG agreed that the new evidence continues to support the use of adjuvant chemotherapy for patients with resected stage III disease but does not support the routine use of adjuvant chemotherapy for all patients with resected stage II disease. Although there was limited evidence to determine which subsets of patients with stage II disease should be offered adjuvant chemotherapy, the DSG agreed that patients with high-risk prognostic features should be considered for adjuvant therapy after a discussion of potential adverse effects and patient preferences. Although not all DSG members were in agreement regarding which adjuvant chemotherapy regimen should be recommended, consensus was reached that the evidence supported intravenous 5-FU plus LV and oxaliplatin as the recommended regimen for suitable patients, and capecitabine or 5-FU/LV alone as alternative options for patients for whom oxaliplatin regimens are not considered appropriate. Review and Update Practice guidelines developed by the PEBC are reviewed and updated regularly. Please visit the Cancer Care Ontario website (www.cancercare.on.ca) for the full evidence-based series report and subsequent updates.
Conflict of Interest Authors disclosed potential conflicts of interest information. One author (JM) reported receiving more than $5000 in a single year as a guest speaker sponsored by Roche. One author (DJ) was a co-investigator on the AVANT, NSABP C-07 and X-ACT trials.
Acknowledgements The authors would like to thank the members of the Gastrointestinal Cancer DSG for their contributions to the development of this practice guideline. The Cancer Care Ontario Program in Evidence-based Care is sponsored by Cancer Care Ontario and the Ministry of Health and Longterm Care.
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D.J. Jonker et al. / Clinical Oncology 23 (2011) 314e322 [4] Figueredo A, Germond C, Maroun J, et al. Adjuvant therapy for stage II colon cancer after complete resection. Cancer Prev Control 1997;1(5):379e392. [5] Figueredo A, Fine S, Maroun J, Walker-Dilks C, Wong S, the Provincial Gastrointestinal Disease Site Group. Adjuvant therapy for stage III colon cancer after complete resection. Cancer Prev Control 1997;1:304e319. [6] 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):3395e3407. [7] Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16):3408e3419. [8] Haller DG, Catalano PJ, MacDonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of intergroup 0089. J Clin Oncol 2005;23:8671e8678. [9] Scheithauer W, Kornek GV, Marczell A, et al. Combined intravenous and intraperitoneal chemotherapy with fluorouracil þ leucovorin vs fluorouracil þ levamisole for adjuvant therapy of resected colon carcinoma. Br J Cancer 1998;77: 1349e1354. [10] Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from the National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17:3553e3559. [11] QUASAR Collaborative Group. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet 2000;355:1588e1596. [12] Porschen R, Bermann A, Loffler T, et al. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 2001;19:1787e1794. [13] Peretz TH, Nissan A, Shani A, et al. Final results of a prospective randomized trial comparing 5-fluorouracil with levamisole to 5-fluorouracil with leucovorin as adjuvant therapy of colorectal e the Israel Cooperative Oncology Group (ICOG) study. Proc Am Soc Clin Oncol 2002;21: abstract 2261. [14] Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005;23: 8664e8670. [15] Sargent DJ, Adjuvant Colon Cancer Endpoints (ACCENT) Group. Endpoints for colon adjuvant clinical trials (CACT): recommendations based on individual patient data (IPD) from 20898 patients (pts) and 18 randomized trials. J Clin Oncol 2005;23(16S):3512. [16] Jonker D, Spithoff K, Maroun J, and the Gastrointestinal Cancer Disease Site Group. Adjuvant systemic chemotherapy for stage II and III colon cancer following complete resection. Available at: http://www.cancercare.on.ca/common/pages/ userfile.aspx?fileid¼14002 [cited 24 02 2011]. [17] Browman GP, Levine MN, Mohide EA, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502e512. [18] Schippinger W, Samonigg H, Schaberl-Moser R, et al. A prospective randomised phase III trial of adjuvant
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chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br J Cancer 2007;97:1021e1027. QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370:2020e2029. Kuebler JP, Colangelo L, O’Connell MJ, et al. Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin. Cancer 2007;110:1945e1950. Laffer U, Metzger U, Aeberhard P, et al. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis 2008;23: 1233e1241. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009;27:3117e3125. Dahl O, Fluge O, Carlsen E, et al. Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group. Acta Oncologica 2009;48:368e376. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 þ irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol 2009;20:674e680. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109e3116. Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database of Systematic Reviews; 2008. Issue 3: doi: 10.1002/14651858. CD005390.pub2. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696e2704. Twelves C, Wong A, Nowacki M, 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. J Clin Oncol 2005;23(16S):3521. Scheithauer W, McKendrick J, Begbie S, 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;14:1735e1743. Lembersky BC, Wieand HS, Petrelli NJ, 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;24:2059e2064. Kopec JA, Yothers G, Ganz PA, 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: 424e430. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343e2351. de Gramont A, Boni C, Navarro M, 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. J Clin Oncol 2007;25(18S):4007. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as
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[36] Saltz LB, Niedzwiecki D, Hollis D, 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;25:3456e3461. [37] Sasaki K, Takasaka H, Kiriyama K, 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. J Clin Oncol 2004;22(14S):3735.
Clinical Oncology journal homepage: www.elsevier.com/locate/clon
Guidelines
Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer after Complete Resection: An Updated Practice Guideline D.J. Jonker *1, K. Spithoff y1, J. Maroun *1 * Ottawa y
Hospital Regional Cancer Centre, Ottawa, Ontario, Canada Cancer Care Ontario Program in Evidence-based Care, McMaster University, Hamilton, Ontario, Canada
Received 27 February 2010; received in revised form 21 December 2010; accepted 10 February 2011
Abstract Aims: The standard adjuvant therapy for resected stage III colon cancer has been intravenous 5-fluorouracil. However, newer chemotherapy agents, such as capecitabine, oxaliplatin and irinotecan, have been investigated in clinical trials since the publication of the original guidelines. The Gastrointestinal Cancer Disease Site Group (DSG) conducted a systematic review of the evidence for the use of adjuvant systemic chemotherapy for patients with resected stage II and III colon cancer and developed an updated practice guideline based on that evidence and expert consensus. The following research questions were addressed: 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, overall survival, adverse effects and quality of life. Materials and methods: A systematic search of published studies was conducted for the time period following the publication of the original guidelines to identify relevant randomised trials and syntheses of evidence in the form of meta-analyses. Recommendations were based on that evidence, evidence contained in the original guidelines and consensus of the Gastrointestinal Cancer DSG. The systematic review and practice guideline were externally reviewed through a mailed survey of practitioners in Ontario, Canada. Results: Recommendations were drafted based on the available evidence and expert consensus. Conclusions: The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, a subset of patients with highrisk stage II disease should be considered for adjuvant therapy. Patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy. 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. Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Adjuvant therapy; chemotherapy; colonic neoplasms; colorectal neoplasms; practice guideline
Introduction In Canada, colorectal cancer is the fourth most common cancer site when both genders are combined, representing 13% of all new cancer cases [1]. Prognosis is determined by the clinicopathological stage of the disease at diagnosis. 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
Author for correspondence: D.J. Jonker, The Ottawa Hospital Regional Cancer Centre, Ottawa, Ontario, Canada. Tel.: þ1-613-737-7700x70170; Fax: þ1-613-247-3511. E-mail address: [email protected] (D.J. Jonker). 1 On behalf of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care.
involves metastases to regional lymph nodes. The overall survival of patients with stage II disease is 70e80% 5 years after surgery [2]. More than one-third of patients with colon carcinoma present with lymph node metastases (stage III), and more than half of those patients relapse after initial curative treatment 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 5 year overall survival of 40e50%. The definition of ‘high risk’ is a subject of considerable debate and research, and remains inadequately described in current TNM staging. 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. However, these risk factors have not been confirmed in prospective
0936-6555/$36.00 Ó 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2011.02.010
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studies where treatment was assigned based on these prognostic factors. Several guidelines regarding adjuvant therapy in stage II or III colon cancer have been previously published. In 1990, a National Institutes of Health Consensus Conference reviewed the available evidence and recommended adjuvant treatment with 5-fluorouracil (5-FU) and levamisole for patients with curatively resected stage III colon cancer [3]. In 1997, the Gastrointestinal Cancer Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-based Care (PEBC) published two separate practice guidelines on the topic of adjuvant therapy for completely resected stage II and III colon cancer [4,5]. On the basis of the evidence reviewed, the Gastrointestinal Cancer DSG recommended 5-FU/leucovorin (LV) as an alternative to 5-FU and levamisole for patients with stage III disease [5], but did not recommend the routine use of adjuvant chemotherapy for resected stage II colon carcinoma [4]. The originally published guidelines were updated with new evidence and posted on the Cancer Care Ontario website (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]. This formed the basis for a mutually endorsed American Society of Clinical Oncology and PEBC clinical guideline, which did not recommend routine adjuvant therapy for patients with resected stage II colon cancer, but recommended that patients with inadequately sampled lymph nodes, T4 lesions, perforation or poorly differentiated histology be considered for adjuvant therapy [7]. 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, as 5-FU plus levamisole has not shown superior efficacy over 5-FU/LV and is associated with significant toxicity [8e13]. 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 two-fold. Trials comparing oral fluoropyrimidines such as capecitabine or tegafur-uracil with intravenous 5-FU have generally been non-inferiority trials, with the goal of using oral therapy being 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 disease-free survival (DFS) and overall survival. A review of 18 randomised trials of adjuvant chemotherapy in colon cancer showed strong concordance between 2 and 3 year DFS and 5 year overall survival [14,15]. The correlation between 3 year DFS and the 5 year overall survival rate was 0.86 and the correlation between 3 year DFS and the overall survival hazard ratio was 0.91 [15]. Subsequent therapy for metastatic recurrence may delay the effect of the improvements in DFS on overall survival. DFS represents a relevant clinical end point, as the avoidance of years of costly and toxic therapy for metastatic disease is of value to patients and those who fund health care alike; therefore, DFS is the primary outcome for this practice guideline.
315
As 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 original PEBC guidelines were combined and rewritten to address the questions that clinicians currently face in practice. This publication provides a summary of the updated guidelines; the full guideline report on which this publication is based can be found at www.cancercare.on.ca [16].
Materials and Methods This practice guideline was developed by the Gastrointestinal Cancer DSG of Cancer Care Ontario’s PEBC using the methods of the Practice Guidelines Development Cycle [17]. The practice guideline is intended to promote evidencebased practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care. 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 DFS, overall survival, adverse effects and quality of life. Comparisons of interest were: 1. Fluoropyrimidine-based systemic chemotherapy versus observation. 2. Intravenous 5-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. Intended Users This guideline is intended for use by clinicians and health care providers who are involved in the management or referral of adults with stage II or III colon cancer. Systematic Review The core methodology used to develop the evidentiary base was a systematic review. The MEDLINE (to September 2007), EMBASE (to week 38, 2007) and Cochrane Library (Issue 2, 2007) databases were searched to update the evidence contained in the original PEBC guidelines on adjuvant chemotherapy for stage II and III colon cancer. In
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addition, proceedings from the annual meetings of the American Society of Clinical Oncology (to 2007) were searched for abstract reports of randomised controlled trials (RCTs). Personal reprint files and reference lists of relevant studies were searched, as were references contained in the original PEBC stage II and III colon cancer guidelines. Data were extracted by one reviewer and verified through a dataauditing procedure. The full systematic review on which the recommendations are based is available at www.cancercare. on.ca [16]. Before publication of the guideline, the searches of the MEDLINE and EMBASE databases were updated to November week 3, 2010. Development of Recommendations The Gastrointestinal Cancer DSG reviewed the evidence contained in the original systematic reviews and the evidence identified in the literature search to September 2007. Draft recommendations were developed based on that evidence and the expert opinion of the Gastrointestinal Cancer DSG using informal consensus methods. Internal Review Before submission of the draft report for external review, the report was reviewed by the PEBC Report Approval Panel, which consists of two members, including an oncologist with expertise in clinical and methodology issues. External Review After approval of the draft systematic review and practice guideline by the Gastrointestinal Cancer DSG and the Report Approval Panel in December 2007, the document was distributed through a mailed survey to a sample of 78 health care providers (medical oncologists and surgeons) in Ontario, Canada for review and feedback. These external reviewers were selected by querying the PEBC practitioner database for health care providers of interest who treat gastrointestinal cancer. The questionnaire consisted of items evaluating the methods, results and interpretation of the evidence used to inform the draft recommendations, and of questions about whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed and follow-up reminders were sent to non-responders at 2 and 4 weeks. The Gastrointestinal Cancer DSG reviewed the results of the survey.
Results Literature Search Results Reports on 31 RCTs and 13 meta-analyses of RCTs were identified in 2007 and included in the systematic review on which the recommendations are based. Full details regarding the methodological characteristics and clinical outcomes of these trials can be found in the full guideline
report on the Cancer Care Ontario website (www. cancercare.on.ca) [16]. Information on trials comparing intravenous 5-FU versus oral fluoropyrimidines, fluoropyrimidines versus fluoropyrimidines plus oxaliplatin, and fluoropyrimidines versus fluoropyrimidines plus irinotecan is provided in Tables 1e3. The updated search of the published literature in November 2010 identified updated data for eight of the 31 trials [18e25], and a Cochrane review of fluoropyrimidinebased adjuvant therapy for completely resected stage II colon cancer [26]. The updated data provided added support for the recommendations developed in 2007.
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 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. 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 DSG recommends that patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy and that this treatment should start within 8 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 LV and oxaliplatin in the regimens known as FOLFOX or FLOX. These 5-FU/LV/oxaliplatin regimens have shown 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, which 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 neurological conditions or at increased risk of neuropathy, patients at increased risk for infections,
Table 1 Randomised controlled trials of oral fluoropyrimidines versus intravenous 5-fluorouracil (5-FU) Trial, year
Treatment allocation
Months on therapy
Capecitabine Intravenous 5-FU/LV (Mayo regimen)
5.5
Lembersky, 2006 NSABP C-06 [30]
Oral UFT þ LV Intravenous 5-FU/LV
5.8 5.5
Stage II
Stage III
e e
1004 983
365 357
416 413
Median follow-up (years)
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4.25
e e
e e
e e
e e
3 year 64.6% 61.0%
3 year 81.7% 78.3%
HR 0.87 (95% CI 0.75e1.00) * P ¼ 0.053
HR 0.89 (95% CI 0.74e1.07) * P ¼ 0.208
NR
5 year 69.6% 71.5%
5.2
5 year 67.0% 68.2%
5 year 78.5% 78.7%
HR 1.004 (95% CI 0.85e1.19) P ¼ 0.96
HR 1.014 (95% CI 0.83e1.25) P ¼ 0.90
5 year 88.4% 87.0%
NR
P ¼ NR
P ¼ NR
CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; LV, leucovorin; NR, not reported; OS, overall survival; UFT, tegafur-uracil. *P values are for superiority tests. Values for non-inferiority tests are P < 0.0001 for DFS and P < 0.001 for OS. Table 2 Randomised controlled trials of fluoropyrimidines plus oxaliplatin versus fluoropyrimidines alone Trial, year
Treatment allocation
Months on therapy
Number of patients evaluated Stage II
Kuebler, 2007 NSABP C-07 [34]
5-FU/LV FLOX
Andre, 2009 MOSAIC [25,32]
LV5FU2 FOLFOX4
6
Stage III
1207 total 1200 total
Median follow-up (years) 3.54
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4 year 67.0% 73.2%
NR
4 year 81.0% 84.2%*
NR
4 year 61.1% 68.9%*
NR
P ¼ NR
HR 0.80 (95% CI 0.69e0.93) P ¼ 0.0034 5.5
448 451
675 672
6.8
P ¼ NR
5 year 67.4% 73.3%
6 year 76.0% 78.5%
5 year 79.9% 83.7%
6 year 86.8% 86.9%
5 year 58.9% 66.4%
6 year 68.7% 72.9%
HR 0.80 (95% CI 0.68e0.93) P ¼ 0.003
HR 0.84 (95% CI 0.71e1.00) P ¼ 0.046
HR 0.84 (95% CI 0.62e1.14) P ¼ 0.258
HR 1.00 (95% CI 0.70e1.41) P ¼ 0.986
HR 0.78 (95% CI 0.65e0.93) P ¼ 0.005
HR 0.80 (95% CI 0.65e0.97) P ¼ 0.023 317
5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; LV, leucovorin; NR, not reported; OS, overall survival. * Data available from appendix published online only.
D.J. Jonker et al. / Clinical Oncology 23 (2011) 314e322
Twelves, 2005 X-ACT [27,28]
Number of patients evaluated
318
Table 3 Randomised controlled trials of fluoropyrimidines plus irinotecan versus fluoropyrimidines alone Trial, year
Bolus 5-FU/LV þ irinotecan
Months on therapy
6.9 7.4
Number of patients evaluated Stage II
Stage III
e e
635 629
Median follow-up (years)
All trial patients
Stage II patients
Stage III patients
DFS
OS
DFS
OS
DFS
OS
4.8*
e
e
e
e
3 year 66% 69%
3 year 80% 81% P ¼ 0.74
P ¼ 0.85
Bolus 5-FU/LV
e
39
Sasaki, 2005 (abstract) [37]
Oral 5-FU þ irinotecan Oral 5-FU
6
NR
12
e
47
Van Cutsem, 2009 PETACC3 [22]
LV5FU2 þ irinotecan
6
894 total
2094 total
5.5
Ychou, 2009 ACCORD 2 [24] y
5-FU/LV þ irinotecan
e
199 198
5.25
e
e
e
NR
4 year 86% 75% P ¼ NS
LV5FU2
5-FU/LV
e
5 year 63.8% 61.0% HR 0.89 (95% CI 0.79e1.00) P ¼ 0.045
NR
5 year 80.9% 76.9% HR 0.81 (95% CI 0.61e1.08) P ¼ 0.158
5 year 90.0% 88.8% P ¼ 0.344
e
e
e
e
5 year 56.7% 54.3% HR 0.90 (95% CI 0.79e1.02) P ¼ 0.106
5 year 73.6% 71.3% P ¼ 0.094
3 year 51% 60% HR 1.12 (95% CI 0.85e1.47)z P ¼ 0.42
5 year 61% 67% HR 1.20 (95% CI 0.87e1.67)z P ¼ 0.26
5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; LV, leucovorin; NR, not reported; NS, not significant; OS, overall survival. * Median DFS and OS not reached at time of analysis, but futility boundaries crossed. y Study included only high-risk stage III patients with N2 or N1/N2 detected by occlusion/perforation. z Favours 5-FU/LV.
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Saltz, 2004 CALGB 89803 [36]
Treatment allocation
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and patients likely to poorly tolerate infections as a result of chemotherapy. For these patients, the treatment options are: - Oral capecitabine administered for 6 months, which has equivalent efficacy to intravenous 5-FU/LV. Capecitabine results in significantly less diarrhoea, stomatitis, neutropenia, nausea/vomiting and alopecia, but significantly more handefoot syndrome when compared with 5-FU/LV. - 5-FU in combination with LV given for 6 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 RCTs comparing adjuvant chemotherapy with observation alone generally showed superior DFS and overall survival, particularly for stage III patients. Although hazard ratios also favoured chemotherapy for stage II patients, these were not statistically significant [16,26]. Oral fluoropyrimidines Two RCTs reported at least equivalent DFS and overall survival results for oral fluoropyrimidines (capecitabine and oral tegafur-uracil) compared with intravenous 5-FU/LV [27e31] (Table 1). In the X-ACT trial, patients in the capecitabine arm experienced significantly less grade 3/4 stomatitis, grade 3/4 neutropenia requiring intervention, febrile neutropenia/sepsis, diarrhoea, nausea and vomiting, and alopecia than patients in the 5-FU/LV arm, but more handefoot syndrome [29]. Quality of life did not differ significantly between treatment arms in either RCT. Fluoropyrimidines plus oxaliplatin Two RCTs compared 5-FU/LV plus oxaliplatin with 5-FU/ LV alone in patients with resected stage II and III colon cancer [25,32e35]: the MOSAIC trial [25,32,33] and the NSABP C-07 trial [34,35] (Table 2). The MOSAIC trial reported a significant benefit in DFS after 5 years of follow-up for stage II and III patients who received FOLFOX4 compared with patients who received 5-FU/LV (hazard ratio 0.80; P ¼ 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 showed a significant benefit in DFS for FOLFOX4 compared with 5-FU/LV in stage III patients (hazard ratio 0.78; P ¼ 0.005; 5 year DFS, 66.4% versus 58.9%), but not in stage II patients (hazard ratio 0.84; P ¼ 0.258; 5 year DFS, 83.7% versus 79.9%). In an exploratory analysis, hazard ratios suggested a possible benefit in DFS for oxaliplatin in patients with high-risk stage II disease (hazard ratio 0.72; P > 0.05) [25]. Exploratory data for lowrisk stage II patients are available only in abstract and online presentation form [33] and suggest no DFS benefit for oxaliplatin in this subgroup (hazard ratio 1.22; P > 0.05). After 6 years of follow-up, overall survival in the MOSAIC trial was significantly improved with the addition of
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oxaliplatin in the overall analysis of stage II and III patients (hazard ratio 0.84; P ¼ 0.046). Analysis of stage III patients showed a significant benefit for the addition of oxaliplatin (hazard ratio 0.80; P ¼ 0.023; 6 year overall survival 72.9% versus 68.7%), but no difference between treatment arms in the subgroup analysis of stage II patients (hazard ratio 1.00; P ¼ 0.986; 6 year overall survival 86.9% versus 86.8%) [25]. The NSABP C-07 trial showed a significant benefit in DFS for the overall analysis of stage II and III patients (hazard ratio 0.80; P ¼ 0.0034; 4 year DFS 73.2% versus 67.0%) [34]. Fluoropyrimidines plus irinotecan One of the four RCTs [22,24,36,37] comparing fluoropyrimidines plus irinotecan with fluoropyrimidines alone showed a marginal benefit in DFS for the addition of irinotecan in a combined analysis of stage II and III patients [22], whereas two trials reported no significant difference between groups [24,36]. Three trials reported no significant difference in overall survival between treatment groups [24,36,37], although one was small and underpowered [37] (Table 3). Internal and External Review of the Practice Guideline The PEBC Report Approval Panel reviewed the draft systematic review and practice guideline and provided feedback. The draft systematic review and practice guideline were distributed to health care providers in the province of Ontario. Thirty of 78 health care providers (38%) returned the survey and 23 reviewers provided feedback. The results of these two sources of feedback and how they influenced the final recommendations can be found in the full guideline report on the Cancer Care Ontario website (www.cancercare.on.ca) [16].
Discussion and Gastrointestinal Cancer Disease Site Group Consensus Since the publication of the Cancer Care Ontario PEBC guidelines for stage III and II colon cancer in 1997 and 2004, respectively [4e7], there have been several important studies published that necessitate modifications to the original recommendations. Whereas the previous guidelines recommended the use of adjuvant intravenous 5-FU/ 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 5-FU/LV/oxaliplatin and the use of oral fluoropyrimidines as an alternative to intravenous 5-FU/LV. Two studies have been reported that compared 5-FU/LV with and without oxaliplatin in populations that included both stage II and III colon cancer [25,32e35]. The primary end point of these studies was DFS in the entire population and both trials showed a significant DFS benefit for the addition of oxaliplatin to 5-FU/LV. Additional follow-up of the MOSAIC trial published in 2009 also showed a 6 year survival benefit for oxaliplatin [25]. Although the MOSAIC trial reported outcomes separately for stage II and III patients, these are subset analyses
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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 showing the superiority of 5-FU/LV/oxaliplatin over 5-FU/LV alone for patients with stage II and stage III colon cancer. Although these key 5-FU/oxaliplatin adjuvant studies had a primary end point 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 overall survival benefit at all [25,33]. Subset analysis must be interpreted with caution, and additional subset data or a pooled analysis with NSABP CO7 [34] would be helpful. Despite this, the benefit in this population is in question, and treatment of all stage II patients is probably not warranted, particularly in light of the 12e14% 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 seems 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 (nondiploid) DNA, 18q allelic loss, microsatellite stability or low frequency microsatellite instability MSI-L, and maintenance of MMR proteins (hMLH1, hMSH2) by immunohistochemistry. 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 5-FU/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 are required. In addition to factors such as underlying neurological conditions, there may be other factors that lead a physician or patient to avoid 5-FU/LV/oxaliplatin. For patients who are not considered candidates for this combination, the alternatives include 5-FU/LV or capecitabine. Data from the X-ACT trial show that oral capecitabine given for 6 months has equivalent efficacy to intravenous 5-FU/LV [27,28]. However, capecitabine results in significantly less diarrhoea, stomatitis, neutropenia, nausea/vomiting and alopecia, but significantly more handefoot syndrome when compared with 5-FU/LV [29]. For those able to take oral therapy, capecitabine is therefore generally preferred over 5-FU/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 show clear advantages in the regimens studied so far, although trends in improvement 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. The Gastrointestinal Cancer DSG agreed that the new evidence continues to support the use of adjuvant chemotherapy for patients with resected stage III disease but does not support the routine use of adjuvant chemotherapy for all patients with resected stage II disease. Although there was limited evidence to determine which subsets of patients with stage II disease should be offered adjuvant chemotherapy, the DSG agreed that patients with high-risk prognostic features should be considered for adjuvant therapy after a discussion of potential adverse effects and patient preferences. Although not all DSG members were in agreement regarding which adjuvant chemotherapy regimen should be recommended, consensus was reached that the evidence supported intravenous 5-FU plus LV and oxaliplatin as the recommended regimen for suitable patients, and capecitabine or 5-FU/LV alone as alternative options for patients for whom oxaliplatin regimens are not considered appropriate. Review and Update Practice guidelines developed by the PEBC are reviewed and updated regularly. Please visit the Cancer Care Ontario website (www.cancercare.on.ca) for the full evidence-based series report and subsequent updates.
Conflict of Interest Authors disclosed potential conflicts of interest information. One author (JM) reported receiving more than $5000 in a single year as a guest speaker sponsored by Roche. One author (DJ) was a co-investigator on the AVANT, NSABP C-07 and X-ACT trials.
Acknowledgements The authors would like to thank the members of the Gastrointestinal Cancer DSG for their contributions to the development of this practice guideline. The Cancer Care Ontario Program in Evidence-based Care is sponsored by Cancer Care Ontario and the Ministry of Health and Longterm Care.
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