Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the rectum

- Locally advanced disease

- Must have primary T3 or T4 tumor

- Transmural penetration of tumor through the muscularis propria by CT scan plus
endorectal ultrasound or MRI

- An endorectal coil or pelvic MRI is allowed

- Distal border of the tumor must be at or below the peritoneal reflection,
defined as within12 cm of the anal verge by proctoscopic examination

- Tumors that are clinically fixed, clinical stage T4, N0-2, M0 are eligible if it
is believed that the tumors are potentially resectable after chemoradiotherapy,
based on the following:

- Clinically fixed tumors on rectal examination with tumor adherent to the
pelvic sidewall or sacrum

- Sciatica attributed to sacral root invasion with CT scan/MRI evidence
of the lack of clear tissue plane will be considered evidence of
fixation

- Hydronephrosis on CT scan or intravenous pyelogram or ureteric or bladder
invasion as documented by cystoscopy and cytology or biopsy, or invasion
into the prostate

- Vaginal or uterine involvement

- Nonmetastatic disease

- No evidence of tumor outside of the pelvis

- No liver metastases

- No peritoneal seeding

- No metastatic inguinal lymphadenopathy

- Resectable disease, defined as completely resectable disease with negative margins
based on routine examination of the non-anesthetized patient

- A surgeon must prospectively define the tumor as either initially resectable or
potentially resectable after preoperative chemoradiotherapy

- A surgical evaluation must confirm patient's ability to tolerate the proposed
surgical procedure

- Carcinoembryonic antigen must be determined prior to initiation of therapy

- ECOG performance status 0-1

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine clearance ≥ 50 mL/min

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Bilirubin ≤ 1.5 times ULN

- Alkaline phosphatase < 2 times ULN

- SGOT < 2 times ULN

- Urine protein: creatinine ratio < 1

- Patients with a urine protein: creatinine ratio of ≥ 1 must demonstrate < 1 gm
of protein by 24-hour urine collection

- INR ≤ 1.5 unless patient is on full-dose anticoagulants and the following criteria is
met:

- In range INR (usually between 2 and 3)

- On a stable dose of warfarin or on a stable dose of low molecular weight heparin

- Must not have active bleeding or a pathological condition that is associated
with a high risk of bleeding

- Caloric intake > 1,500 kilocalories/day

- Albumin > 2 gm/dL

- No known dihydropyrimidine dehydrogenase deficiency

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
discontinuing bevacizumab

- No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction,
unless diverting colostomy has been performed

- No active inflammatory bowel disease

- No history of cerebrovascular accident/transient ischemic attack

- No myocardial infarction or unstable angina within the past 12 months

- No peripheral neuropathy > grade 1

- No clinically significant peripheral vascular disease

- Patients with a history of hypertension must have a blood pressure of < 150/90 mm Hg
and be on a stable regimen of antihypertensive therapy

- No New York Heart Association class II-IV congestive heart failure

- No evidence of bleeding diathesis/coagulopathy

- No serious nonhealing wound or bone fracture

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 28 days

- No significant traumatic injury within the past 28 days

- No other malignancy within the past 5 years except for in situ carcinomas that were
completely removed

- No known allergy to study drugs

- No other serious medical illness or disease that might limit the patient's ability to
receive protocol therapy

- At least 28 days since prior major surgical procedure or open biopsy

- At least 7 days since prior core biopsy

- No prior chemotherapy for rectal cancer

- No prior pelvic irradiation

- No prior intra-operative radiotherapy (IORT) or brachytherapy treatment to the pelvis

- No concurrent intensity-modulated radiotherapy

- No concurrent full-dose anticoagulants