Bevacizumab and Combination Chemotherapy Before Surgery in Treating Patients With Locally Advanced Esophageal or Stomach Cancer

PRIMARY OBJECTIVES:

I. To investigate two-year disease-free survival in patients with resectable esophageal and gastroesophageal (GE) junction cancer treated with perioperative bevacizumab and leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX).

SECONDARY OBJECTIVES:

I. To assess, by pathological examination after surgical resection, complete and partial response to neoadjuvant therapy.

II. To characterize overall and progression free survival. III. To compare baseline and post-chemotherapy/bevacizumab tissues for biomarkers predicting response or resistance to this approach.

IV. To investigate safety in this setting.

OUTLINE:

NEOADJUVANT THERAPY: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1. Patients also receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46 hours on days 1-2. Treatment with bevacizumab repeats every 2 weeks for 4 courses and treatment with FOLFOX repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients then undergo planned surgical resection 4-6 weeks after 6 courses of chemotherapy and at least 8 weeks since the last dose of bevacizumab.

ADJUVANT THERAPY: Beginning 8-10 weeks after surgery, patients receive bevacizumab IV, oxaliplatin IV, leucovorin calcium IV, and fluorouracil IV as in neoadjuvant therapy. Treatment repeats every 2 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Inclusion criteria

• Patients must have biopsy proven adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma of the esophagus, GE junction and/or gastric cardia
• Patients must have potentially resectable disease by the thoracic, minimally invasive or transhiatal approach

• No portion of the lesion may be within 5 cm of the cricopharyngeus
• Patient must be considered medically fit for surgery with average or below average risk
• T1-3 or T4 with local invasion confined to diaphragm, pleura or pericardium
• No myocardial infarction within 12 months of enrollment
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• White blood cells (WBC) >= 3,500/mm^3
• Platelet count >= 100,000/mm^3
• Serum creatinine (Cr) =< 1.5 mg and/or creatinine clearance >= 60 cc/min
• 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
• Alkaline phosphatase must be < ULN
• Aspartate aminotransferase (AST) & alanine aminotransferase (ALT) must be < ULN
• Urine protein/creatinine (UPC) ratio of < 1.0 or dipstick for protein of < 2+, Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4) grade < 2; patients with a UPC ratio >= 1.0 or dipstick of 2+ must undergo a 24-hour urine collection and must demonstrate < 1 gm of protein in order to participate
• Patients must give written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent

Exclusion criteria

• Patients with prior chemotherapy for any malignant disorder, thoracic radiotherapy or prior surgical resection of an esophageal tumor are ineligible
• Patients with biopsy-proven invasion of the tracheobronchial tree or tracheo-esophageal fistula are ineligible
• Patients with a history of a curatively treated malignancy must be disease-free for at least two years and have a survival prognosis that is greater than five years
• 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 6 months after the completion of bevacizumab; women must not be pregnant or breast-feeding because the study drugs administered may cause harm to an unborn fetus or breastfeeding child; all females of childbearing potential must have a serum pregnancy test to rule out pregnancy within 7 days prior to registration
• Patients with a history of hypertension must measure < 150/90 mmHg and be on a stable regimen of anti-hypertensive therapy; patients with a history of hypertension who have a blood pressure of 150/90 mmHg, or greater are not eligible; patients with a history of hypertension who have a blood pressure of < 150/90 mmHg but are not on a stable regimen of anti-hypertensive therapy, are not eligible
• Any prior history of hypertensive crisis or hypertensive encephalopathy
• New York Association (NYHA) grade II or greater congestive heart failure
• Patients must not have a serious or non-healing wound, skin ulcers or unhealed bone fracture, or known human immunodeficiency virus (HIV) infection
• Patients with >= grade 2 neuropathy are not eligible
• Patients must not have had significant traumatic injury within 28 days prior to randomization
• Patients with PT (INR) > 1.5 are not eligible; the patient may not be receiving full-dose anticoagulation; prophylactic or full dose anticoagulation are permitted post-resection or for treatment of an intercurrent thrombotic event
• 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: current symptomatic arrhythmia, symptomatic peripheral vascular disease
• Patients with a history of the following within 12 months of study entry are not eligible: arterial thromboembolic events, unstable angina
• Any history of stroke or transient ischemic attack
• Significant vascular disease (i.e. aortic dissection, aortic aneurysm)
• 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
• Distant metastases
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
• Known hypersensitivity to any component of bevacizumab