High-Dose Fluorouracil With or Without Leucovorin Compared With Standard Fluorouracil Plus Leucovorin Following Surgery in Treating Patients With Stage III Colon Cancer

Pan-European Trials in Adjuvant Colon Cancer (PETACC-2): Randomized Phase III Intergroup Trial of High-Dose Infusional 5-FU (+ or - Folinic Acid) Versus Standard Bolus 5-FU/Folinic Acid

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective for colon cancer.

PURPOSE: This randomized phase III trial is studying high-dose fluorouracil with or without leucovorin to see how well it works compared to standard-dose fluorouracil and leucovorin in treating patients who have undergone surgery for stage III colon cancer.

OBJECTIVES:

• Compare recurrence-free survival and duration of survival in patients with stage III adenocarcinoma of the colon treated with adjuvant high-dose fluorouracil with or without leucovorin calcium versus standard fluorouracil with leucovorin calcium following curative radical resection.
• Compare the safety of these regimens in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to regional lymph node involvement (N1 (1-3 pericolic lymph nodes) vs N2 (more than 3 pericolic lymph nodes) and participating center.

Patients are randomized to one of two treatment arms.

• Arm I: Patients receive leucovorin calcium IV followed by fluorouracil IV on days 1-5. Treatment repeats every 4 weeks for 6 courses.
• Arm II: Patients receive high-dose fluorouracil IV continuously over 48 hours weekly for 8 weeks. Treatment repeats every 8 weeks for 3 courses.

OR

• Patients receive leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 24 hours weekly for 6 weeks. Treatment repeats every 7 weeks for 3 courses.

OR

• Patients receive leucovorin calcium IV over 2 hours followed by fluorouracil IV bolus and then fluorouracil IV continuously over 22 hours on days 1 and 2. Treatment repeats every 2 weeks for 12 courses.

Patients are followed at 1 month, every 6 months for 4.5 years, and then annually thereafter until death.

PROJECTED ACCRUAL: Approximately 1,600 patients (800 per treatment arm) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed stage III adenocarcinoma or mucinous adenocarcinoma of the colon

• Must have had curative radical resection within 56 days prior to study

  • No local tumor therapy (i.e., polypectomy, local excision or limited intestinal resection)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• WHO 0-1

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin greater than 10.0 g/dL

Hepatic:

• Bilirubin no greater than 2.0 mg/dL

Renal:

• Creatinine no greater than 1.5 mg/dL

Cardiovascular:

• No severe coronary heart disease
• No New York Heart Association class III or IV heart failure

Other:

• No other malignancy within the past 10 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix
• No uncontrolled infection
• No other severe disease
• No known allergy to leucovorin calcium
• No known familial adenomatous polyposis, Crohn's disease, or ulcerative colitis
• No hereditary syndrome (e.g., Gardner's syndrome, Turcot's syndrome, hereditary nonpolyposis colon cancer)
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy for colon cancer

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy for colon cancer

Surgery:

• See Disease Characteristics

Other:

• No other concurrent systemic anticancer therapy