Combination Chemotherapy and Bevacizumab Before or 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 adjuvant combination
chemotherapy and bevacizumab after hepatic resection with vs without neoadjuvant
combination chemotherapy and bevacizumab (Bevacizumab treatment closed as of
11/15/2010).

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 I (postoperative): Patients undergo hepatic resection. Beginning 31-56 days after
surgery, patients receive mFOLFOX6 or FOLFIRI chemotherapy on day 1. Beginning in
course 2, patients also receive bevacizumab IV over 30-90 minutes on day 1(bevacizumab
treatment closed as of 11/15/2010). Treatment repeats every 2 weeks for 12 courses.

- Arm II (pre- and postoperative): Patients receive mFOLFOX6 or FOLFIRI chemotherapy and
bevacizumab IV over 30-90 minutes on day 1 (bevacizumab treatment closed as of
11/15/2010). Treatment repeats for every 2 weeks for 6 courses (patients do not receive
bevacizumab in course 6). Patients then undergo hepatic resection. Beginning 31-56 days
after surgery, patients receive an additional 6 courses of mFOLFOX6 or FOLFIRI
chemotherapy and bevacizumab (patients start bevacizumab in course 2) (bevacizumab
treatment closed as of 11/15/2010).

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.