Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer

• Locally Advanced or Metastatic Colorectal Cancer
• Eligible patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have either locally advanced (unresectable) or metastatic disease. Patients with resected primary tumors who have documented metastases are eligible. Documentation of residual disease by CT scan or surgeon's notes is required for all patients, and histologic confirmation of metastases is strongly encouraged.
• Patients with a history of colorectal cancer treatment by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless:
• Either an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease or
• The primary cancer was stage I. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.
• At the time of randomization, the intent of this treatment must be indicated palliative or neoadjuvant chemotherapy with the potential for resection of all sites of metastatic disease.
• Only patients with a wildtype K-ras gene as determined by the laboratory at the SWOG Solid Tumor Repository or by a local CLIA-certified laboratory are eligible. Patients with a mutation in the K-ras gene are ineligible. All patients must have available for analysis of K-ras status at least one H and E slide and one paraffin block of the previously resected primary colorectal tumor and/or a tumor deposit. For patients registered and randomized based on local CLIA-certified laboratory results, SWOG analysis will be confirmatory only.
• Prior Treatment
• No prior systemic treatment for advanced or metastatic colorectal cancer is allowed. Prior regional chemotherapy (eg, hepatic arterial infusion) is also not allowed.
• Patients may have received prior adjuvant chemotherapy that included fluorouracil alone or in combination with fluorouracil and oxaliplatin or irinotecan (no more than 6 months); or radiation with radiosensitizing chemotherapy.
• The last course of adjuvant chemotherapy must have concluded > 12 months prior to colorectal cancer recurrence.
• Patients may have received neoadjuvant chemo-radiation with capecitabine or 5-fluorouracil.
• Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to randomization.
• No prior exposure to any tyrosine kinase inhibitors or other agents (including protein products, monoclonal antibodies, antisense, etc.) that target VEGF or EGF receptors is allowed.
• No prior treatment with bevacizumab or cetuximab.
• Patients may not have had prior radiotherapy to greater than 25% of bone marrow.

(Standard adjuvant rectal cancer chemoradiation will not exclude patient from protocol entry.) Radiation must have concluded ≥ 4 weeks prior to randomization.

• Patients should have completed any major surgery ≥ 4 weeks from randomization. Patients must have completed any minor surgery ≥ 2 weeks prior to randomization. Patients must have fully recovered from the procedure. (Insertion of a vascular access device is not considered major or minor surgery.)
• No previous or concurrent malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years.
• For patients who are to receive FOLFIRI: No evidence of Gilbert's Syndrome or of homozygosity for the UGT1A1*28 allele.
• Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome would include a prior finding of an isolated elevation of indirect bilirubin.
• UGT1A1 genotyping is not required on this study. Howev