Combination Chemotherapy as First-Line Therapy in Treating Older Patients With Metastatic Colorectal Cancer That Cannot Be Removed By Surgery

Randomized Study of Classic vs Simplified Leucovorin Calcium and Fluorouracil With or Without Irinotecan in Patients Aged At Least 75 Years With Advanced Colorectal Cancer

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) in different doses or combinations may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating colorectal cancer.

PURPOSE: This randomized clinical trial is studying how well fluorouracil works together with leucovorin with or without irinotecan in treating older patients with metastatic colorectal cancer .

OBJECTIVES:

Primary

• Compare the progression-free survival of elderly patients with unresectable metastatic colorectal cancer treated with 1 of 2 different chemotherapy regimens comprising fluorouracil and leucovorin calcium with vs without irinotecan hydrochloride.

Secondary

• Compare the tumor response rate and overall survival of patients treated with these regimens.
• Compare the tolerability of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter, prospective study. Patients are stratified according to participating center, gender, Karnofsky score (60-70% vs 80-90% vs 100%), associated comorbidities (Charlson Index 0 vs 1-2 vs 3+), age (75 to 79 years vs ≥ 80 years), alkaline phosphatase level (≤ 2 times normal vs > 2 times normal), and prior adjuvant chemotherapy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 22 hours on days 1 and 2.
• Arm II: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 2.
• Arm III: Patients receive leucovorin calcium and fluorouracil as in arm I and irinotecan hydrochloride IV over 90 minutes on day 1.
• Arm IV: Patients receive leucovorin calcium and fluorouracil as in arm II and irinotecan hydrochloride as in arm III.

In all arms, treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery within 3-10 weeks after completing chemotherapy.

Quality of life is assessed at baseline and then every 2 months thereafter.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 282 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum

  • Metastatic disease
  • Unresectable disease

• Measurable disease that is outside the field of prior irradiation

• No brain metastases

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Transaminases ≤ 5 times normal
• Bilirubin ≤ 1.5 times normal
• Alkaline phosphatase < 3 times normal (5 times normal if due to hepatic involvement)
• Creatinine clearance > 45 mL/min
• Life expectancy > 3 months
• No psychological, social, or geographical situation that would preclude study treatment
• No chronic diarrhea or enteropathy
• No coronary insufficiency or symptomatic cardiac disease
• No other malignancy unless curatively treated
• No contraindication to chemotherapy

PRIOR CONCURRENT THERAPY:

• At least 6 months since prior adjuvant chemotherapy for the primary tumor
• No prior extensive resection
• No other concurrent anticancer therapy