RATIONALE: Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining monoclonal antibody therapy with chemotherapy and radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bevacizumab when given together with fluorouracil and external-beam radiation therapy in treating patients with stage II or stage III rectal cancer.

OBJECTIVES:

• Determine the maximum tolerated dose of neoadjuvant bevacizumab when administered with fluorouracil and external beam radiotherapy in patients with stage II or III rectal cancer.
• Determine the progression-free survival, local control, and overall survival of patients treated with this regimen.
• Determine the pathological response rate of patients treated with this regimen.
• Determine, preliminarily, the changes in the angiogenic profile of this disease in these patients induced by this regimen.

OUTLINE: This is a multicenter, dose-escalation study of bevacizumab.

Patients receive bevacizumab IV over 30-90 minutes on day 1 (courses 1-4). Beginning with course 2, patients also receive fluorouracil IV continuously on days 1-14 and undergo external beam radiotherapy on days 1-5 and 8-12. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 7 weeks after completion of chemoradiotherapy.

Cohorts of 6 patients receive escalating doses of bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 20 additional patients are treated at the MTD.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

PROJECTED ACCRUAL: Approximately 4-32 patients will be accrued for this study.

• Biological: bevacizumab
• Drug: fluorouracil
• Procedure: conventional surgery
• Procedure: neoadjuvant therapy
• Radiation: radiation therapy

• Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, Shellito P, Czito BG, Wong TZ, Paulson E, Poleski M, Vujaskovic Z, Bentley R, Chen HX, Clark JW, Jain RK. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009 Jun 20;27(18):3020-6. Epub 2009 May 26.
• Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004 Feb;10(2):145-7. Epub 2004 Jan 25. Erratum in: Nat Med. 2004 Jun;10(6):649.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum

  • Begins within 15 cm of the anal verge by sigmoidoscopy and/or colonoscopy

• Stage II or III disease

  • Clinical T3 or T4 tumors, as indicated by the following:

    • Tethered or fixed tumor on physical exam
    • cT3, cT4, or N+ disease by endorectal ultrasound or surface coil MRI
• No evidence of metastatic disease by physical examination, chest radiograph, and abdominal/pelvic CT scan
• No primary brain tumor or brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 70-100%

Life expectancy

• More than 2 years

Hematopoietic

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No bleeding diathesis or coagulopathy

Hepatic

• Bilirubin normal
• AST/ALT less than 2.5 times upper limit of normal
• INR less than 1.5* NOTE: *For patients receiving warfarin

Renal

• Creatinine normal OR
• Creatinine clearance at least 60 mL/min
• No proteinuria OR
• Protein less than 1 g on 24-hour urine collection

Cardiovascular

• No history of stroke
• No history of deep vein thrombosis

• No clinically significant cardiovascular disease within the past year, including any of the following:

  • Uncontrolled hypertension
  • Myocardial infarction
  • Unstable angina pectoris

• No arterial thromboembolic events within the past 6 months, including any of the following:

  • Transient ischemic attack
  • Cerebrovascular accident
  • Clinically significant peripheral vascular disease
• No history of venous thromboembolic events requiring continuous therapeutic anticoagulation
• No New York Heart Association class II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No grade II or greater peripheral vascular disease within the past year

Other

• Not pregnant
• Not nursing during and for at least 3-4 months after study participation
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3-4 months after study participation

• No known HIV or HIV risk factors

  • HIV testing not required

• No other concurrent active malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix

  • Completed therapy and considered to be at less than 30% risk of relapse at least 5 years after all therapy
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to bevacizumab or other study agents
• No serious non-healing wound, ulcer, or bone fracture
• No evidence of CNS disease (e.g., seizures not controlled with standard medical therapy)
• No significant traumatic injury within the past 28 days
• No active infection requiring parenteral antibiotics
• No other concurrent uncontrolled illness
• No concurrent psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bevacizumab

Chemotherapy

• No prior fluorouracil-based therapy for any malignancy
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy except the following:

  • Steroids for adrenal failure or allergic reactions
  • Hormones for non-disease-related conditions (e.g., insulin for diabetes)
  • Intermittent dexamethasone as an antiemetic

Radiotherapy

• No prior pelvic radiotherapy

Surgery

• More than 6 months since prior vascular surgery, stenting, or angioplasty
• More than 28 days since prior major surgery or open biopsy
• More than 7 days since prior biopsy (except rectal cancer)
• More than 7 days since prior placement of vascular access device
• No other concurrent planned major surgery

Other

• More than 10 days since prior full-dose oral or parenteral anticoagulants or thrombolytic agents (except to maintain patency of preexisting, permanent indwelling IV catheters)
• No prior treatment for this malignancy
• No concurrent full-dose oral or parenteral anticoagulants or thrombolytic agents (except to maintain patency of preexisting, permanent indwelling IV catheters)
• No concurrent chronic aspirin use (more than 325 mg/day)
• No concurrent nonsteroidal anti-inflammatory medications (of the kind known to inhibit platelet function at doses used to treat chronic inflammatory diseases)
• No other concurrent investigational agents