Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer

This randomized phase III trial studies oxaliplatin, leucovorin calcium, fluorouracil, and bevacizumab to see how well they work compared to oxaliplatin, leucovorin calcium, and fluorouracil in treating patients who have undergone surgery for stage II colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer.

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in 3-year disease-free survival for high-risk stage II colon cancer patients randomly assigned to 5-FU (fluorouracil), leucovorin (leucovorin calcium), oxaliplatin versus 5-FU, leucovorin, oxaliplatin and bevacizumab.

SECONDARY OBJECTIVES:

I. To compare overall survival between the regimens. II. To further define the toxicity profiles of the regimens. III. To prospectively determine the impact of tumor biological characteristics on the survival of patients with stage II colon cancer.

IV. To assess the association between oxaliplatin exposure, allelic variants in candidate genes, and neurotoxicity. (Pharmacogenetic ancillary objective)

OUTLINE: Patients with high-risk disease are randomized to 1 of 2 treatment arms (Arms A and B). Patients with low-risk disease are assigned to Arm C.

ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in Arm A and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses in the absence of disease progression or unacceptable toxicity.

ARM C: Patients undergo observation.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 10 years.

Eligibility Criteria:
Inclusion Criteria:

* STEP 1: INITIAL REGISTRATION
* The distal extent of the tumor must be \>= 12 cm from the anal verge on endoscopy; if this distance was not confirmed on endoscopy pre-operatively, then the distal extent of the tumor must be \>= 12 cm from the anal verge as determined by surgical examination; colonoscopy should be performed postoperatively for those unable to have a preoperative colonoscopy to guarantee there are no synchronous lesions; (if tumor is located beyond sigmoid colon and centimeter distance unavailable, include anatomic region of colon, e.g. right colon, transverse colon, hepatic flexure descending colon, cecum etc.)
* Patients must have paraffin-embedded tumor specimen available for evaluation of microsatellite instability and loss of heterozygosity at 18q, to determine high risk versus low risk

  * High-risk patients will be randomized to treatment Arms A or B
  * Low-risk patients will be registered to Arm C for observation

    * NOTE: Every effort should be made to submit blocks (tumor and normal mucosa) to the Principal Coordinates Analysis (PCO) immediately; blocks CANNOT be accepted after day 50 (post surgery) in order to allow for molecular assessment
    * Specific laboratory requirements for Step 2 must be obtained within 2 weeks prior to Step 2 randomization
* Patients must not have synchronous tumors
* Patients must not have appendiceal tumors
* Patients must not have a history of inflammatory bowel disease (IBD)
* Patients with hereditary non-polyposis colorectal cancer (HNPCC) are eligible
* Patients must have no history of isolated, distant, or non-contiguous intra-abdominal metastases, even if restricted
* Patients must have histologically confirmed adenocarcinoma of the colon that meets the criteria below:

  * Stage II adenocarcinoma (pT3/pT4a/pT4b pN0 M0 according to the definitions of the American Joint Committee on Cancer, 7th Edition, 2010): the tumor invades through the muscularis propria into pericolic tissues (pT3), penetrates to the surface of the visceral peritoneum (pT4a), or directly invades other organs or structures (pT4b); patients with mesenteric tumor deposits or satellites without identifiable residual lymph node in the absence of lymph node involvement are now designated pN1c, rather than pT3; patients with such tumor deposits are not eligible for E5202; patients must have had a complete resection (R0 resection)
* Patients must have \>= 8 lymph nodes evaluated and reported
* Patients must not have presented with clinical complete obstruction or perforation of the bowel
* Patients must not have had any systemic or radiation therapy initiated for this malignancy
* Patients must not have a previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:

  * Non-melanoma skin cancer, in situ cervical cancer, or breast cancer in situ
  * Prior malignancy completely excised or removed and patient has been continuously disease free for \> 5 years
  * Patients with completely excised or removed breast cancer and disease free \> 5 years, regardless of the continuation of hormonal therapy
  * Patients with previous radiation therapy (RT) to the pelvic region will be ineligible
* Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* STEP 2: RANDOMIZATION (HIGH RISK PATIENTS - ARMS A AND B ONLY)
* Within 2 weeks prior to randomization, postoperative absolute granulocyte count (AGC) must be \>= 1500/mm\^3 (or \< 1500/mm\^3, if in the opinion of the investigator, this represents an ethnic or racial variation of normal)
* Within 2 weeks prior to randomization, the postoperative platelet count must be \>= 100,000/mm\^3
* Within 2 weeks prior to randomization, there must be postoperative evidence of adequate hepatic function; bilirubin must be =\< upper limit of normal (ULN) unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin
* Within 2 weeks prior to randomization, there must be postoperative evidence of adequate hepatic function; alkaline phosphatase must be \< 2.5 x ULN
* Within 2 weeks prior to randomization, there must be postoperative evidence of adequate hepatic function; aspartate transaminase (AST) must be \< 1.5 x ULN
* Within 2 weeks prior to randomization, there must be postoperative evidence of adequate renal function; serum creatinine =\< 1.5 x ULN
* Within 2 weeks prior to randomization, there must be postoperative evidence of adequate renal function; urine protein/creatinine (UPC) ratio of \< 1.0; patients with a UPC ratio \>= 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate \< 1 gm of protein in order to participate
* Patients with any significant bleeding that is not related to the primary colon tumor within 6 months prior to study entry are not eligible
* Patients with gastroduodenal ulcer(s) determined to be active by endoscopy are not eligible
* Patients with a history of hypertension must measure \< 150/90 mmHg and be on a stable regimen of anti-hypertensive therapy
* Patients must not have a serious or non-healing wound, skin ulcers or bone fracture
* Patients experiencing clinically significant peripheral neuropathy at the time of step 2 randomization (defined in the National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events version 4.0 \[CTCAE 4.0\] as grade 2 or greater neurosensory or neuromotor toxicity) are not eligible
* Patients must not have had invasive procedures, defined as follows:

  * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization
  * Core biopsy or other minor procedure, excluding placement of a vascular access device, within 7 days prior to randomization
  * Or anticipate the need for major surgical procedure(s) during the course of the study
* Patients must begin adjuvant treatment no less than 28 days and no more than 60 days from surgery
* Eligible patients of reproductive potential (both sexes) must agree to use an accepted and effective method of contraceptive during study therapy and for at least 3 months after the completion of bevacizumab; women must not be pregnant or breast-feeding; all females of childbearing potential must have a serum pregnancy test to rule out pregnancy within 2 weeks prior to step 2 randomization
* Patients with prothrombin time (PT) (international normalized ratio \[INR\]) \> 1.5 are not eligible, unless the patient is on full-dose anticoagulants; if so, the following criteria must be met for enrollment:

  * The subject must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or on a stable dose of low molecular weight heparin
  * The subject must not have active bleeding or a pathological condition that is associated with a high risk of bleeding
* Patients with non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study therapy drugs are not eligible; specifically excluded are the following conditions:

  * New York Heart Association (NYHA) class III or IV congestive heart failure
  * Current symptomatic arrhythmia
  * Any non-malignant systemic disease
* Patients with a history of transient ischemic attack (TIA) or cerebrovascular accident (CVA) are not eligible
* Patients with a history of the following within twelve months of study entry are not eligible:

  * Arterial thromboembolic events
  * Unstable angina
  * Myocardial infarction
* Patients with symptomatic peripheral vascular disease are not eligible
* Patients with psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude them from meeting the study requirements are not eligible
* Patients must not have a known allergy to platinum compounds
* STEP 2: REGISTRATION (LOW-RISK PATIENTS - ARM C)
* Patients determined to be low risk are eligible