Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial

Abstract

Context: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer.

Objective: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer.

Design, setting, and participants: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses.

Main outcome measures: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity.

Results: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.

Conclusion: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival.

Trial registration: clinicaltrials.gov Identifier: NCT00079274.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Alberts reported receiving grants from Pfizer, Bristol-Myers Squibb, and sanofi-aventis by the North Central Cancer Treatment Group (NCCTG) for support of the conduct of this trial. Dr Sargent reported receiving grants from Pfizer, Bristol-Myers Squibb, and sanofi-aventis for support to NCCTG for conduct of this trial. Dr Nair reported receiving support for travel to meetings from National Cancer Institute Cooperative Group. Dr Sinicrope reported receiving consultancy fees from Merck Serono, receiving grants from the National Institutes of Health, payment for lectures including service on service bureaus from the University of Kansas, and travel meeting expenses from the American Society of Clinical Oncology. Dr Chan reported receiving a grant from the Eastern Cooperative Oncology Group; being a board member of Colorectal Cancer Index and Reviews and HCPLive.com Oncology Advisory Board; being a consultant on advisory boards of Amgen, ImClone, Bristol-Myers Squibb, Genentech, Pfizer, and Celgene; receiving grants and travel meeting expenses from National Comprehensive Cancer Network; receiving travel meeting expenses from Chemotherapy Foundation; and being an institutional investigator in numerous clinical trials involving multiple pharmaceutical companies. Dr Gill reported receiving payment for lectures including service on speakers bureaus from Bristol-Myers Squibb. Dr Kahlenberg reported receiving payment for lectures including service on speakers bureaus from Genentech. Dr Shields reported receiving grant and support for travel to meetings for the study from Southwest Oncology Group. Dr Grothey reported receiving grants and consultancy fees from sanofi-aventis. No other authors provided any financial disclosures.

Figures

Figure 1

Flow of Patients Through the Trial mFOLFOX6 indicates the modified sixth version of the leucovorin, fluorouracil, and oxaliplatin regimen. aThese patients were enrolled after the prospective preregistration for KRAS testing and added but did not go on to the subsequent step of registration due to rumor tissue could not be evaluated for KRAS, investigator or participant decision, eligibility criteria were not met, or other unspecified reasons. bEither did not have an end-of-treatment form or did not have an end-of-treatment reason on the form. cIncludes 17 ineligible patients (6 improper histology, 1 pretreatment lab values >14 days from randomization, 2 positive margins, 2 resection not en bloc, and 6 surgery >56 days before randomization). dIncludes 6 ineligible patients (4 improper histology and 2 positive margins). eIncludes 16 ineligible patients (9 improper histology, 1 positive margin, 2 resection not en bloc, and 4 surgery >56 days before randomization). fIncludes 10 ineligible patients (5 improper histology, 2 positive margins, 2 resection not en bloc, and 1 surgery >56 days before randomization).

Figure 2

Disease-Free Survival After Treatment With mFOLFOX6 Alone and mFOLFOX6 With Cetuximab in the Wild-Type KRAS, Mutated KRAS, and Wild-Type KRAS and Mutated KRAS With Age <70 and ≥70 Years Patient Groups mFOLFOX6 indicates the modified sixth version of the leucovorin, fluorouracil, and oxaliplatin regimen; HR, hazard ratio.