This randomized phase III trial was originally designed to compare three different combination chemotherapy regimens to see how well they work. As of September 1, 2004, the study was expanded to a total of 6 arms (the original 3 arms (A, B, C) and 3 additional arms which were the same as the first 3 but with cetuximab) in treating patients who have undergone surgery for stage III colon cancer. Drugs used in chemotherapy, such as irinotecan hydrochloride, fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining more than one chemotherapy drug with monoclonal antibody therapy and giving them after surgery may kill any remaining tumor cells. It was not known at the time this study was developed which combination chemotherapy regimen is more effective after surgery in treating colon cancer. This study had several key changes, based on the results of other phase III trials. As of 6/1/2005, patients no longer received irinotecan on this study and treatment arms B, C, E, and F were discontinued. Patients on arms B and C crossed to arm A. Patients on arms E and F crossed to arm D. Patients on arms C and F who had not gotten to irinotecan continued on arms A and D, respectively. As of 8/18/2008, pre-screening for Kirsten rat sarcoma (KRAS) status was added with mutant KRAS (or KRAS not evaluable) patients put on arm G and wild-type KRAS patients randomized between arm A and arm D. Patients on arm G were treated per physician discretion and followed for disease and survival status. KRAS was determined in a central laboratory and was process for all patients on this study. The primary endpoint of this study was modified on 8/18/2008 to focus on patients having wild-type KRAS tumors. All modifications were approved by the Central Institution Review Board, local Institutional Review Boards, NCI, and the NCCTG Data Safety Monitoring Board.

PRIMARY OBJECTIVES:

I. Disease-free Survival (Arms A and D: Wild-type KRAS Patients)

SECONDARY OBJECTIVES:

I. Disease-free Survival (Arms A and D: Mutant KRAS Patients) II. Disease-free Survival III. Overall Survival IV. Toxicity

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to positive lymph node involvement (1-3 vs 4 or more), histology (high [poorly differentiated or undifferentiated] vs low [well to moderately differentiated]), and clinical T stage (T1 or T2 vs T3 vs T4). Patients are randomized to 1 of 6 treatment arms (as of 6/1/2005, patients are randomized to treatment arms I and IV only; arms II, III, V, and VI are closed to accrual). As of 8/18/2008, pre-screening for KRAS status was added with mutant KRAS (or KRAS not evaluable) patients put on arm G and wild-type KRAS patients randomized between arm A and arm D.

ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours on days 1. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

ARM B (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm I for remainder of therapy): Patients receive irinotecan hydrochloride IV over 2 hours on day 1 and leucovorin calcium and fluorouracil as in arm A. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

ARM C (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm I for remainder of therapy): Patients receive the same treatment as in arm A for 6 courses followed by the same treatment as in arm B for 6 courses (total of 12 courses). Treatment continues in the absence of unacceptable toxicity or recurrent disease.

ARM D: Patients receive cetuximab* IV over 1 hour on days 1 and 8 and oxaliplatin, leucovorin calcium, and fluorouracil as in arm A. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

ARM E (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm D for remainder of therapy): Patients receive cetuximab* as in arm D and irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in arm B. Treatment repeats every 14 days for up to 12 courses in the absence of unacceptable toxicity or recurrent disease.

ARM F (closed to accrual as of 6/1/2005--currently enrolled patients may cross over to arm D for remainder of therapy): Patients receive cetuximab* as in arm D and chemotherapy as in arm C.

ARM G (added as of 8/18/2008, mutant KRAS (or KRAS not evaluable) patients): Locally directed therapy.

NOTE: *Cetuximab is administered over 2 hours at a higher dose on day 1 of course 1 only.

Quality of life (QOL) is assessed at baseline, 3 months, and at the end of therapy. As of 8/18/2008, QOL was discontinued.

Patients are followed for a maximum of 8 years from randomization.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the colon

  • Stage III disease
  • No resected stage IV disease

• No rectal cancer

  • Gross inferior (caudad) margin of the primary tumor must be ≥ 12 cm from the anal verge by rigid proctoscopy

• Stage III tumor must have been completely resected within the past 56 days

  • Must have documented en bloc resection in patients with tumor adherence to adjacent structures
  • Tumor-related obstructions and colonic perforation are allowed
  • Tumor samples must be available

• At least 1 pathologically confirmed positive lymph node

  • No evidence of residual involved lymph node disease

• Synchronous primary colon cancer allowed

• No distant metastatic disease

• Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9 g/dL

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Creatinine ≤ 1.5 times ULN

• No uncontrolled high blood pressure

• No unstable angina

• No symptomatic congestive heart failure

• No myocardial infarction with the past 6 months

• No New York Heart Association class III or IV heart disease

• No symptomatic pulmonary fibrosis

• No symptomatic interstitial pneumonitis

• No prior allergic reaction (known sensitivity) to chimerized or murine monoclonal antibody therapy

• No known allergy to platinum compounds

• No documented presence of human anti-mouse antibodies (HAMA)

• No active uncontrolled bacterial, viral, or systemic fungal infection

• HIV negative

• No clinically defined AIDS

• Not pregnant or nursing

• Negative pregnancy test

• No men or women of childbearing potential who are unwilling to employ adequate contraception

• No inadequately treated gastrointestinal bleeding

• No ≥ grade 2 pre-existing peripheral sensory or motor neuropathy

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or lobular carcinoma in situ in 1 breast

• No other concurrent medical condition that would preclude study participation

• No concurrent biologic therapy

• No prior chemotherapy for colon cancer

• No other concurrent chemotherapy

• No prior radiotherapy for colon cancer

• No concurrent targeted agents

• No prior agents directed against epidermal growth factor-receptor

• No other concurrent anticancer therapy