Fluorouracil and Leucovorin With or Without Irinotecan in Treating Patients Following Surgery for Stage III Colorectal Cancer

Multicenter Phase III Open Label Randomized Trial Comparing CPT-11 In Combination With A 5-FU/FA Infusional Regimen To The Same 5-FU/FA Infusional Regimen Alone As Adjuvant Treatment Of Stage III Colon Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them after surgery may kill more tumor cells.

PURPOSE: Randomized phase III trial to compare the effectiveness of fluorouracil and leucovorin with or without irinotecan in treating patients who have undergone surgery for stage III colorectal cancer.

OBJECTIVES:

• Compare the disease-free survival at 3 years of patients with resected stage III colorectal cancer treated with adjuvant fluorouracil and leucovorin calcium with or without irinotecan.
• Compare the disease-free and overall survival at 5 years of patients treated with these regimens.
• Compare the safety profiles of these treatment regimens in these patients.
• Compare the quality-adjusted survival of patients treated with these regimens.
• Correlate the expression of putative prognostic markers (thymidylate synthase, telomerase, topoisomerase) with disease-free and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

Arm I

• Patients receive irinotecan IV over 30-90 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV over 24 hours weekly for 6 weeks. Courses repeat every 7 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
• As an alternative schedule, patients may receive irinotecan IV over 30-90 minutes and day 1 and leucovorin calcium IV over 2 hours and fluorouracil IV over 22 hours on days 1 and 2 every 2 weeks for 6 weeks. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Arm II

• Patients receive leucovorin calcium and fluorouracil as in arm I. Quality of life may be assessed at baseline; prior to courses 2, 3, and 4; and at 1, 3, and 6 months.

Patients are followed every 3 months for 3 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 1800 patients (900 per arm) will be accrued for this study within 24 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or intraperitoneal rectum

  • Stage III

  • Completely resected within the past 3-8 weeks

    • No gross or microscopic evidence of residual disease after surgery

• No rectal cancer requiring total meso-rectal resection or pre- or postoperative radiotherapy

• No prior curatively resected synchronous metastasis of colorectal cancer

PATIENT CHARACTERISTICS:

Age:

• 18 to 75

Performance status:

• WHO 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 2,000/mm^3
• Platelet count at least 150,000/mm^3
• Hemoglobin at least 10 g/dL

Hepatic:

• Bilirubin no greater than upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN
• Alkaline phosphatase no greater than 2.5 times ULN

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No myocardial infarction with the past year
• No uncontrolled hypertension
• No high-risk uncontrolled arrhythmia
• No unstable angina pectoris

Other:

• HIV negative
• No chronic diarrhea
• No current chronic inflammation or subobstruction of bowel after surgery
• No active uncontrolled infection
• No other prior or concurrent malignancy except curatively treated nonmelanoma skin cancer or carcinoma in situ of the cervix
• No psychological, social, familial, or geographical condition that would preclude follow-up
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior antineoplastic chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• See Disease Characteristics

Surgery:

• See Disease Characteristics
• No prior celioscopic resection of primary tumor

Other:

• At least 30 days since prior participation in another clinical trial with any investigational drug
• No other concurrent experimental drugs
• No other concurrent anticancer therapy