The study was terminated due to low accrual.

RATIONALE: Drugs used in chemotherapy work in different ways to kill tumor cells or stop them from growing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving combination chemotherapy after surgery may kill any remaining tumor cells. It is not yet known whether giving combination chemotherapy before and after surgery is more effective than giving combination chemotherapy after surgery.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy before and after surgery to see how well it works compared to giving combination chemotherapy after surgery in treating patients with colorectal cancer with liver metastases that could be removed by surgery.

OBJECTIVES:

Primary

• To evaluate the difference in recurrence-free survival (RFS) of patients with potentially resectable hepatic colorectal metastases receiving perioperative (preoperative plus postoperative) adjuvant chemotherapy vs only postoperative adjuvant chemotherapy following liver resection for colorectal metastases.

Secondary

• To compare the proportion of patients between study arms who are R0 or R1 resected, alive, and free of recurrence at 6 months.
• To compare RFS between study arms in the cohort of patients event-free at 6 months.
• To compare overall survival between study arms.
• To evaluate the difference in R0 and combined R0 + R1 resection rates in patients receiving neoadjuvant therapy and those undergoing initial surgical resection.
• To compare the postoperative morbidity profile between study arms.
• To evaluate the safety and toxicity profile of postoperative and perioperative administration of chemotherapy and bevacizumab.

Tertiary

• To evaluate the relationship of baseline circulating tumor cells (CTC) to RFS.
• To evaluate the relationship of baseline CTC to R0 resection.
• To evaluate the relationship of pre-resection CTC in the preoperative therapy group only with RFS and R0 resection.

OUTLINE: This is a multicenter study. Patients are stratified by number of liver metastases (1-3 vs 4+), chemotherapy regimen* (mFOLFOX6 vs FOLFIRI), and synchronous** primary colorectal cancer (yes vs no). Patients are randomized to 1 of 2 treatment arms.

NOTE: *Patients who have not received previous oxaliplatin receive mFOLFOX6 chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1. Patients who have received previous oxaliplatin receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.

NOTE: **Synchronous is defined as the detection (by imaging) of suspicious liver metastases within 90 days before or after the date of histologic diagnosis of the primary colon or rectal cancer.

• Arm 1 (postoperative): Patients undergo hepatic resection. Beginning 31-56 days after surgery, patients receive mFOLFOX6 or FOLFIRI chemotherapy IV on day 1 over 3 hours. Patients receive an additional dose of fluorouracil over 46 hours using a portable pump. Treatment repeats every 2 weeks for 12 courses.
• Arm 2 (perioperative): Patients receive mFOLFOX6 or FOLFIRI chemotherapy IV over 3 hours on day 1. Patients receive an additional dose of fluorouracil over 46 hours using a portable pump. Treatment repeats for every 2 weeks for 6 courses. Patients then undergo hepatic resection. Beginning 31-56 days after surgery, patients receive an additional 6 courses of mFOLFOX6 or FOLFIRI chemotherapy.

Blood and tumor tissue samples may be collected periodically for correlative studies.

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

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal adenocarcinoma

  • Hepatic metastasis (no histologic confirmation required) and no evidence of extrahepatic metastatic disease within the past 4 weeks by one of the following imaging studies*:

    • PET/CT scan with contrast
    • PET scan AND CT scan with contrast
    • PET scan AND MRI with contrast
    • PET/CT scan without contrast AND MRI with contrast NOTE: *If findings noted in imaging study reports are equivocal, the determination of whether or not the findings represent extrahepatic disease will be at the investigator's discretion.

  • No history of or concurrent evidence of extrahepatic metastases

    • Patients with regional nodes that are suspicious on imaging and are associated with the primary colorectal tumor are eligible provided the nodes will be resected with the primary tumor after randomization

  • No radiographic evidence of metastases to portal lymph nodes (node > 1 cm in diameter) unless the node(s) are proven by biopsy to be negative

• No anal, small bowel, or appendiceal carcinoma

• No sarcoma, lymphoma, or carcinoid colorectal malignant diseases

• Within 4 weeks before randomization, the liver metastases must be determined by a hepatic surgeon to be resectable based on meeting both of the following criteria:

  • A complete resection can be performed in a single operation
  • There are ≥ 2 uninvolved contiguous segments of the liver

• Meets one of the following criteria:

  • Primary tumor and regional nodes resected with clear surgical margins and no evidence of extrahepatic disease
  • Unresected primary tumor with plans to resect the primary tumor before randomization
  • Unresected primary tumor with plans to resect the primary tumor and the liver metastases in a single surgical procedure performed after randomization

• No unresected primary tumor in the colon or rectum with significant symptoms related to obstruction or that will require radiotherapy

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Life expectancy ≥ 5 years (excluding the diagnosis of metastatic CRC)

• absolute neutrophil count (ANC) ≥ 1,200/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 10 g/dL

• Total bilirubin ≤ upper limit of normal (ULN)

• aspartate aminotransferase (AST) ≤ 5.0 times ULN

• Alkaline phosphatase ≤ 5.0 times ULN

• Serum creatinine ≤ ULN OR calculated creatinine clearance ≥ 30 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 180 days after completion of study treatment

• Considered a potential candidate for a major hepatic surgical procedure

• No grade 3 or 4 anorexia, grade 3 nausea, or vomiting ≥ grade 2 (per CTCAE v4.0) related to metastatic disease

• No paresthesias, peripheral sensory neuropathy, or peripheral motor neuropathy ≥ grade 2 per Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0 (patients with grade 2 neuropathy who will receive FOLFIRI are eligible)

• No uncontrolled high BP defined as systolic BP ≥ 160 mm Hg OR diastolic BP ≥ 100 mm Hg, with or without antihypertensive medication (patients with initial BP elevations are eligible provided initiation or adjustment of BP medication lowers pressure to meet this criteria)

• Documented history of congestive heart failure requiring chronic medical therapy

• No active inflammatory bowel disease

• No active infection or chronic infection requiring chronic suppressive antibiotics

• No known bleeding diathesis or coagulopathy

• No symptomatic interstitial pneumonitis OR definitive evidence of interstitial pneumonitis described on CT scan, MRI, or chest x-ray in asymptomatic patients

• No other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy ≥ 1 year ago

  • Patients with carcinoma in situ of the cervix, CRC in situ, melanoma in situ, or basal cell or squamous cell carcinoma of the skin diagnosed and treated at any time before study treatment are eligible

• No known Gilbert syndrome

• Not known to be homozygous for the UGT1A1 allele (for patients who will receive FOLFIRI chemotherapy)

• No prior serious hypersensitivity reaction to any of the agents administered as part of study treatment (determination of "serious" is at the investigator's discretion)

• No other serious concurrent medical condition that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to participate in the study, or cause a delay in the initiation of therapy (surgery or chemotherapy) longer than 4 weeks following randomization

• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements

• No pre-existing chronic hepatic disease (e.g., chronic active hepatitis, cirrhosis) that, in the opinion of the investigator and hepatic surgeon, would limit the patient's ability to undergo hepatic metastasectomy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No previous hepatic-directed therapy, including hepatic resection and/or ablation, hepatic arterial infusion therapy, or hepatic radiotherapy

  • Patients who have only had an incision or excisional biopsy are eligible

• No previous chemotherapy or any other systemic therapy for metastatic colorectal cancer (CRC)

• No prior or concurrent portal vein embolization or other hepatic preconditioning techniques

• At least 30 days since prior investigational products

• No intent to use ablation to treat any hepatic lesion

• No concurrent therapeutic doses of coumadin or equivalent