Combination Chemotherapy and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

OBJECTIVES:

Primary

• Evaluate the objective response (RECIST criteria) at 6 months associated with FOLFIRI and bevacizumab therapy.
• Evaluate the tolerability (NCI CTC v. 2.0 criteria) of this treatment.

Secondary

• Evaluate progression-free survival and overall survival.
• Determine the time to treatment failure.
• Evaluate the quality of life (EuroQOL EQ5D questionnaire).
• Explore the prognostic factors associated with the tolerability and efficacy of this treatment.

OUTLINE: This is a multicenter study. Patients are stratified according to genotype (UCT1A1*1/ UCT1A1*1 vs UCT1A1*1/ UCT1A1*28).

Patients receive bevacizumab IV over 30-90 minutes, irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 4 courses, and then every 2 months after the completion of study therapy.

After completion of study therapy, patients are followed every 2-3 months.

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic adenocarcinoma of the colon or rectum

• Not curable by surgery
• Genotype UGT1A1*1/UGT1A1*1 or UGT1A1*1/ UGT1A1*28
• Measurable disease
• No original tumor in place
• No secondary cerebral metastases

PATIENT CHARACTERISTICS:

Inclusion criteria

• WHO performance status 0-2
• Life expectancy ≥ 3 months
• Absolute neutrophil count ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 times normal
• Alkaline phosphatase ≤ 2.5 times normal (5 times normal if liver involvement)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients of must use effective contraception

Exclusion criteria

• Progressive gastrointestinal ulcer, hemorrhagic ulcer, or perforation in the past 6 months
• Enteropathy or chronic diarrhea
• Proteinuria > 500 mg/24 hours
• Active cardiac disease
• Uncontrolled hypertension
• Myocardial infarction in the past 12 months
• Angina
• NYHA grade II-IV congestive heart disease
• Severe arrhythmia even with treatment
• Peripheral vascular disease ≥ grade II
• Nonhealing wound, ulcer, or severe bone fracture
• Hemorrhagic diatheses or coagulopathy
• Severe or uncontrolled infection
• Severe or uncontrolled medical condition
• Other malignant disease in the past 5 years except curatively treated basal cell skin cancer or carcinoma in situ of the uterine cervix
• Severe traumatic injury within the past 4 weeks

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy for metastatic disease

• One prior regimen of chemotherapy in the neoadjuvant or adjuvant setting for the original tumor allowed
• At least 6 months since prior chemotherapy
• No prior irinotecan hydrochloride or bevacizumab
• No oral or parenteral anticoagulant therapy within the past 10 days

• Warfarin allowed provided INR < 1.5
• No major surgery or biopsy within the past 4 weeks
• No puncture in the past 7 days
• No planned major surgery
• No concurrent daily or chronic aspirin (> 325 mg/day), anti-inflammatories, or steroids
• No other concurrent anticancer therapy