This pilot phase II trial studies how well giving bevacizumab and combination chemotherapy together before surgery works in treating patients with locally advanced esophageal or stomach cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery.

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