title: Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00079274.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. alberts.steven@mayo.edu
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Suresh
authors.initials: S
authors.lastname: Nair
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Margaret
authors.initials: M
authors.lastname: Mooney
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Sharlene
authors.initials: S
authors.lastname: Gill
authors.forename: Morton S
authors.initials: MS
authors.lastname: Kahlenberg
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.forename: James T
authors.initials: JT
authors.lastname: Quesenberry
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Webb
authors.forename: Gist H
authors.initials: GH
authors.lastname: Farr
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Pockaj
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil