Combination Chemotherapy in Treating Patients With Unresectable Metastatic Colorectal Cancer

OBJECTIVES: * Compare the efficacy of combination chemotherapy comprising fluorouracil (5-FU) with leucovorin calcium (CF) and either irinotecan (CPT-11) or oxaliplatin vs standard sequential single-agent therapy comprising 5-FU with CF followed by CPT-11 in patients with unresectable metastatic colorectal cancer. * Determine whether combination chemotherapy is best used as first-line therapy or reserved for second-line therapy after progression on first-line single-agent therapy in these patients. * Compare the efficacy and toxicity of an irinotecan-containing regimen vs an oxaliplatin-containing regimen in these patients. * Compare the overall survival, progression-free survival, and quality of life of patients treated with these regimens. * Compare the safety and toxicity of these regimens in these patients. OUTLINE: This is a randomized, open-label, multicenter study. Patients are randomized to one of five treatment arms. * Arm I (standard therapy): Patients receive first-line chemotherapy comprising leucovorin calcium IV over 2 hours on day 1 followed by fluorouracil IV continuously over 46 hours on days 1-2 every 14 days. Patients with progressive disease then receive second-line therapy comprising irinotecan IV over 90 minutes on day 1 every 21 days. * Arm II: Patients receive first-line chemotherapy as in arm I. Patients with progressive disease then receive second-line therapy comprising irinotecan IV over 30 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1-2 every 14 days. * Arm III: Patients receive first-line chemotherapy comprising irinotecan, leucovorin calcium, and fluorouracil as in second-line therapy of arm II. * Arm IV: Patients receive first-line chemotherapy as in arm I. Patients with progressive disease then receive second-line therapy comprising leucovorin calcium IV and oxaliplatin IV over 2 hours on day 1 followed by fluorouracil IV continuously over 46 hours on days 1-2 every 14 days. * Arm V: Patients receive first-line chemotherapy comprising leucovorin calcium, oxaliplatin, and fluorouracil as in second-line therapy of arm IV. Treatment continues in all arms in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, at weeks 6 and 12, and then every 12 weeks thereafter. PROJECTED ACCRUAL: A total of 2,100 patients (700 in arm I and 350 each in arms II-V) will be accrued for this study.