Disease-Free Survival in Colon Cancer: Still Relevant After All These Years!

Abstract

TO THE EDITOR: We read R.J. Mayer’s commentary on the recently published long-term outcomes data from the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial with great interest. 1,2 He provided a detailed analysis of the clinical trials leading to the current acceptance as standard of care of oxaliplatin-based adjuvant therapy in stage III and select high-risk patients with stage II colon cancer. The editorial highlights the relatively modest benefit of adding oxaliplatin to fluoropyrimidines in this setting with regard to benefit in overall survival (OS), particularly in elderly or stage II patients, despite the previously observed initial significant improvement in disease-free survival (DFS) that was noted in both stage II and stage III cancers. Given that 3-year DFS improvements in stage II colon cancer did not translate into any long-term OS, he suggests that 3-year DFS, which was found to be a surrogate for 5-year OS in a meta-analysis of fluoropyrimidine-alone adjuvant trials, 3 should not remain the primary end point when conducting future adjuvant trials in colon cancer. In agreement with Mayer’s assessment, a 2007 analysis of 18 randomized adjuvant trials in colon cancer in the Adjuvant Colon Cancer Endpoints (ACCENT) database demonstrated that the correlation between DFS and OS in trials of stage II patients is weak at best. 4 The lack of an additional oxaliplatin benefit observed in MOSAIC stage II patients reintroduces the question of whether there is any OS benefit of adjuvant chemotherapy in stage II colon cancer. The only prospective data demonstrating OS improvement after fluoropyrimidine-based adjuvant therapy is derived from the Quick and Simple and Reliable (QUASAR) trial in which the median number of resected lymph nodes was six, and thus was likely contaminated by stage III patients. 5 The cross-trial analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials 6 and the previous International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) pooled analysis 7 suffered the same limitation of the likely presence of a substantial number of undetected stage III patients incorrectly classified as stage II patients. However, if we require an OS benefit as the primary end point for