GuidelinesAdjuvant Systemic Chemotherapy for Stage II and III Colon Cancer after Complete Resection: An Updated 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 involves metastases to regional lymph nodes. The overall survival of patients with stage II disease is 70–80% 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 40–50%. 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 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 [8], [9], [10], [11], [12], [13]. 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.
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].
Section snippets
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 evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care.
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
Stage II Colon Cancer
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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.
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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,
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 [4], [5], [6], [7], 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
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 Long-term Care.
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On behalf of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care.