RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, irinotecan, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may be a better way to block tumor growth. Studying the amount of an enzyme found in the tumor may help doctors plan the best treatment.

PURPOSE: This randomized phase II trial is studying giving bevacizumab, oxaliplatin, and irinotecan or giving bevacizumab, oxaliplatin, leucovorin, and fluorouracil in treating patients with metastatic or recurrent colorectal cancer.

OBJECTIVES:

• Compare the response rate (complete and partial), progression-free survival, and overall survival of patients with previously untreated metastatic or locally recurrent colorectal adenocarcinoma with high vs low thymidylate synthase (TS) expression treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab or irinotecan, oxaliplatin, and bevacizumab.
• Compare the toxicity of these regimens in these patients.
• Correlate gene expression with response rates in patients treated with these regimens.
• Correlate gene expression with toxicity of these regimens in these patients.
• Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian excision repair cross complementary protein expression with antitumor response in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to thymidylate synthase (TS) expression levels (high vs low or indeterminate). Patients with high TS expression are randomized to 1 of 2 treatment arms (Arms A or B). Patients with low or indeterminate TS expression are assigned to Arm C.

• Arm A: Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.
• Arm B: Patients receive bevacizumab and oxaliplatin as in arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.
• Arm C: Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm B.

In all arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Patients are followed up every 3 months for 2 years and then every 6 months for 2 years from the date of study registration.

INCLUSION:

• Metastatic or locally recurrent colorectal adenocarcinoma

• Measurable disease

• At least 2 formalin-fixed paraffin embedded core needle biopsies OR fine needle aspirate containing a minimum of 3 clusters of malignant cells and fixed tissue from the previous biopsy

• If no tissue samples are available the patient must be willing to undergo biopsy of a metastatic site

• Age 18 and over

• Eastern Cooperative Oncology Group (ECOG) Performance status 0-2

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 unless patient is receiving full-dose anticoagulants AND the following criteria are met:

  • In-range INR (usually between 2 and 3) AND on a stable dose of warfarin or low molecular weight heparin
  • No active bleeding or pathological condition that is associated with a high risk of bleeding

• Partial thromboplastin time (PTT) < 1.5 times upper limit of normal (ULN)

• Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 3 times ULN

• Bilirubin ≤ 1.5 times ULN

• Creatinine ≤ 1.8 mg/dL

• Meets 1 of the following criteria:

  • Protein negative on urine dipstick
  • Urine protein/creatinine ratio < 1.0
  • Less than 2 g protein on 24-hour urine collection

• Patients with a history of hypertension must meet the following criteria:

  • Blood pressure < 150/90 mm Hg
  • Stable regimen of anti-hypertensive therapy

• More than 28 days since prior major or open surgery

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 3 months after study participation

• Prior non-colorectal malignancies are allowed provided the following criteria are met:

  • No current clinical evidence of persistent or recurrent disease
  • No active therapy for non-colorectal malignancy, including hormonal therapy

EXCLUSION:

• Pregnant or nursing

• Arterial thromboembolic events within the past 6 months, including the following:

  • Transient ischemic attack
  • Cerebrovascular accident
  • Unstable angina pectoris
  • Myocardial infarction

• Symptomatic arrhythmia

• Symptomatic congestive heart failure

• Clinically significant peripheral artery disease

• New York Heart Association class III or IV heart disease

• Serious nonhealing wound, ulcer, or bone fracture within the past 28 days

• Significant traumatic injury within the past 28 days

• Neuropathy ≥ grade 2

• Ongoing or active infection

• Concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

• Prior chemotherapy for metastatic disease. Adjuvant therapy completed at least 12 months before first evidence of metastasis allowed

• Cardiovascular, renal, hepatic, or other nonmalignant systemic disease that would preclude study therapy