OBJECTIVES:

• Compare overall survival in patients with locally advanced, metastatic, or recurrent colorectal cancer treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab vs capecitabine, oxaliplatin, and bevacizumab.
• Compare progression-free survival and time to treatment failure in patients treated with these regimens.
• Compare the response of patients with measurable disease treated with these regimens.
• Compare toxicity rates of these regimens in these patients.
• Compare patient-reported functional status and convenience of therapy in patients treated with these regimens.
• Correlate germline polymorphisms of DNA repair (e.g., ERCC-1, XRCC1, GST-P1, XPD, and ribonucleotide reductase), target enzymes (e.g., thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase), angiogenesis (e.g., vascular endothelial growth factor), and growth factors (e.g., epithelial growth factor receptor) with survival, progression-free survival, and toxicity from chemotherapy in patients treated with these regimens.
• Correlate tumor mRNA expression levels of similar DNA repair enzymes as well as enzymes involved in angiogenesis with survival and progression-free survival in patients treated with these regimens.
• Correlate tumor mRNA expression levels of similar target enzymes before treatment with survival, progression-free survival, and toxicity in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to Zubrod performance status (0 or 1 vs 2) and prior adjuvant therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46-48 hours beginning on day 1. Patients are further randomized to receive bevacizumab or placebo* IV over 30-90 minutes on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *As of 11/15/04, placebo is no longer part of treatment plan; all patients receive bevacizumab.

• Arm II: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine on days 1-15. Patients are further randomized to receive bevacizumab or placebo* as in arm I. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *As of 11/15/04, placebo is no longer part of treatment plan; all patients receive bevacizumab.

Patients are followed every 3 months until disease progression. After disease progression, patients are followed every 6 months for 2 years and then annually for up to 4 years after study entry.

PROJECTED ACCRUAL: A total of 2,200 patients (1,100 per treatment arm) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed locally advanced, recurrent, or metastatic colorectal adenocarcinoma

  • Not curable by surgery or amenable to radiotherapy with curative intent

  • Previously resected colorectal cancer with new evidence of metastasis does not require separate histologic or cytologic confirmation unless one of the following is true:

    • More than 5 years has elapsed between primary surgery and development of metastatic disease
    • Primary tumor was T1-T2, N0, M0
• Site of primary lesion must be or have been in the large bowel as determined by endoscopy, radiology, or surgery
• Measurable or evaluable disease
• No known brain or leptomeningeal disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• No history of hemorrhagic or thrombotic disorders
• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic

• Bilirubin no greater than 2.0 times upper limit of normal (ULN)
• SGOT no greater than 2.5 times ULN (5 times ULN for patients with liver involvement)
• Alkaline phosphatase no greater than 2.5 times ULN (5 times ULN for patients with liver involvement or 10 times ULN for patients with bone involvement)
• INR no greater than 1.5
• PTT no greater than ULN

Renal

• Creatinine no greater than 1.5 times ULN
• Creatinine clearance at least 50 mL/min
• Proteinuria less than 1+* OR
• Protein less than 500mg/24 hours* NOTE: *Proteinuria caused by ureteral stents and not due to nephropathy allowed

Cardiovascular

• No uncontrolled hypertension

  • Hypertension must be well-controlled (i.e., less than 160/90) and on a stable regimen of antihypertensive therapy
• No unstable angina
• No symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmia
• No New York Heart Association class III or IV heart disease

Pulmonary

• No symptomatic pulmonary fibrosis

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission
• No active or uncontrolled severe infection

• No contraindication to oral medications (e.g., severe dysphagia)

  • G-tubes or J-tubes allowed
• No peripheral neuropathy greater than grade 1
• No serious non-healing wound, ulcer, or bone fracture
• No significant traumatic injury within the past 28 days
• No other severe acute or chronic medical condition or laboratory abnormality that would preclude study participation
• No psychiatric condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bevacizumab

Chemotherapy

• No prior oxaliplatin

• No prior chemotherapy for advanced colorectal cancer

  • Prior adjuvant therapy for resected stage II-III disease allowed provided at least 12 months have elapsed between completion of therapy and diagnosis of recurrent disease

Endocrine therapy

• Not specified

Radiotherapy

• At least 28 days since prior radiotherapy and recovered

Surgery

• See Disease Characteristics
• More than 28 days since prior major surgical procedure or open biopsy
• More than 7 days since prior fine needle aspiration or core biopsy
• No concurrent major surgery

Other

• More than 10 days since prior full-dose aspirin (325 mg)
• No concurrent antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, or cilostazol)
• No other concurrent investigational agents

• No concurrent therapeutic anticoagulation

  • Prophylactic anticoagulation of central venous lines allowed
  • Low-dose prophylactic enoxaparin or heparin allowed
• No concurrent cimetidine
• No concurrent sorivudine or its related analogs (e.g., brivudine)
• No concurrent use of a cold cap or iced mouth rinses