Combination Chemotherapy in Treating Patients With Colorectal Cancer

OBJECTIVES:

• Determine the role of peak delivery time on the tolerability of irinotecan when administered with chronomodulated fluorouracil, leucovorin calcium, and oxaliplatin as first- or second-line therapy in patients with locoregional or metastatic colorectal cancer.
• Determine the antitumor activity of this regimen.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, WHO performance status (0-1 vs 2), and line of treatment (first vs second). Patients are randomized to receive irinotecan at 1 of 6 different times of the day.

Patients receive irinotecan IV over 6 hours on day 1 and fluorouracil IV and leucovorin calcium IV over 11 hours followed by oxaliplatin IV over 11 hours on days 2-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 4 weeks until disease progression and then every 8 weeks thereafter.

PROJECTED ACCRUAL: A maximum of 186 patients (31 per irinotecan administration time) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer
• Unresectable metastatic or locoregional disease
• At least 1 measurable lesion outside a previously irradiated area or an area treated with physical devices (e.g., cryotherapy, laser, or thermoablation)
• No prior enrollment in EORTC-05963
• No symptomatic brain metastases

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count greater than 2,000/mm^3
• Platelet count at least 90,000/mm^3

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)

Renal:

• Creatinine no greater than 1.5 times ULN
• No uncontrolled hypercalcemia

Cardiovascular:

• No overt cardiac disease

Pulmonary:

• No severe respiratory illness

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Male patients must use effective barrier contraception during and for up to 6 months after study
• No baseline diarrhea greater than grade I (must have less than 4 stools per 24 hours)
• No prior grade III or IV toxicity related to irinotecan
• No sensory or motor neuropathy with functional impairment
• No prior hypersensitivity to any study drug
• No other primary tumor except basal cell skin cancer or carcinoma in situ of the cervix
• No uncontrolled infectious or chronic disease
• No psychological, familial, sociological, or geographical condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent prophylactic growth factor therapy

Chemotherapy:

• At least 1 month since prior chemotherapy
• No prior irinotecan, fluorouracil, leucovorin calcium, and oxaliplatin as combination therapy
• Other prior therapy containing irinotecan and/or oxaliplatin allowed
• No more than 1 prior chemotherapy regimen for metastatic or locoregional disease
• Adjuvant chemotherapy considered first-line therapy if tumor relapsed within 6 months of completion of therapy

Endocrine therapy:

• No concurrent corticosteroids except for emergencies

Radiotherapy:

• See Disease Characteristics
• Palliative radiotherapy for bone lesion allowed except for disease progression

Surgery:

• See Disease Characteristics