Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer after Complete Resection: An Updated Practice Guideline

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 high-risk 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.

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].