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.