Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance Therapy in Treating Patients With Metastatic Colorectal Cancer

OBJECTIVES:

Primary

• Compare disease-control duration in patients with metastatic colorectal cancer receiving FOLFIRI chemotherapy in combination with bevacizumab with or without bevacizumab maintenance therapy.

Secondary

• Determine objective response rate.
• Determine non-hematologic grade 3-4 (except alopecia) toxicity rate.
• Determine overall toxicity rate.
• Determine duration of chemotherapy-free interval.
• Determine progression-free survival.
• Determine overall survival.
• Determine time-to-treatment failure.
• Determine quality of life (EORTC QLQ-C30).
• Complete geriatric evaluation.

OUTLINE: This is a multicenter study. Patients are stratified according to cancer center, primary tumor (resected vs unresected), and Köhne criteria (low vs intermediate vs high). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Chemotherapy treatment repeats every 2 weeks for 12 courses. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks during chemotherapy. Patients then receive bevacizumab maintenance therapy once every 2 weeks during the chemotherapy-free interval.
• Arm B: Patients receive FOLFIRI chemotherapy and bevacizumab as in arm A. Patients receive no treatment during the chemotherapy-free interval.

In all arms, the chemotherapy treatment and the chemotherapy-free interval treatment repeats in the absence of disease progression during the chemotherapy portion or unacceptable toxicity. Patients who progress during the chemotherapy-free interval will receive 12 more courses of chemotherapy.

All patients complete quality of life questionnaires (QLQ-30) and patients ≥ 75 also complete the geriatric questionnaire at baseline and every 8 weeks during study treatment.

After completion of study treatment, patients are followed up every 8 weeks.

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

• Metastatic disease
• Not a candidate for curative surgery
• At least 1 tumor target measurable by RECIST criteria
• No metastasis potentially resectable after receiving chemotherapy
• No occlusive tumors
• No macronodular peritoneal carcinomatosis
• No known or suspected CNS metastases

PATIENT CHARACTERISTICS:

• OMS status 0-2
• Life expectancy ≥ 3 months
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of hepatic metastases)
• Creatinine ≤ 1.5 times ULN
• Proteinuria ≤1 g
• Not pregnant or nursing
• No gastroduodenal ulcer, wound, or fractured bone
• No acute or subacute intestinal occlusion or history of inflammatory bowel disease or large resection of small bowel
• No clinically relevant coronary artery disease or a history of a myocardial infarction within the last 6 months
• No uncontrolled hypertension while receiving chronic medication
• No other malignancy within the past 5 years except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
• No medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study

PRIOR CONCURRENT THERAPY:

• See Patient Characteristics
• No prior chemotherapy for metastatic disease

• Adjuvant chemotherapy allowed provided it was completed > 6 months ago
• No prior irinotecan or other antiangiogenic therapy
• At least 4 weeks since surgery (except for diagnostic biopsy) or irradiation
• No other drugs not allowed for medical reasons
• Concurrent oral anticoagulants (e.g., coumadin, warfarin) allowed provided the INR is closely monitored

• A change of anticoagulants to low-molecular weight heparin is preferred