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.

• Authors: Steven R Alberts, Daniel J Sargent, Suresh Nair, Michelle R Mahoney, Margaret Mooney, Stephen N Thibodeau, Thomas C Smyrk, Frank A Sinicrope, Emily Chan, Sharlene Gill, Morton S Kahlenberg, Anthony F Shields, James T Quesenberry, Thomas A Webb, Gist H Farr Jr, Barbara A Pockaj, Axel Grothey, Richard M Goldberg
• Journal: JAMA (JAMA) Vol. 307 Issue 13 Pg. 1383-93 (Apr 04 2012) ISSN: 1538-3598 [Electronic] United States
• PMID: 22474202 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• KRAS protein, human
• Organoplatinum Compounds
• Proto-Oncogene Proteins
• Oxaliplatin
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Cetuximab
• Leucovorin
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Cetuximab
• Chemotherapy, Adjuvant
• Colonic Neoplasms (drug therapy, genetics, surgery)
• Disease-Free Survival
• Female
• Fluorouracil (administration & dosage)
• Humans
• Leucovorin (administration & dosage)
• Male
• Middle Aged
• Mutation
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Treatment Outcome
• Young Adult
• ras Proteins (genetics)