This phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil followed by surgery and response based concurrent chemotherapy and radiation therapy works in treating patients with cancer of the esophagus, gastroesophageal junction, or gastric cardia. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. Giving chemotherapy followed by surgery and response based chemotherapy and radiation therapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To assess the ability of response adapted adjuvant chemoradiotherapy to improve the 1 year recurrence free survival (RFS) compared to historical data in patients with > 50% remaining viable tumor after induction chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the rates of symptomatic, endoscopic, and pathologic response to induction chemotherapy.

II. To determine the rate of R0 resection after induction chemotherapy. III. To establish the toxicity profile of this tri-modality regimen. IV. To assess the recurrence free survival (RFS) and overall survival (OS) of this trimodality therapy regimen for the entire cohort and in patients who do and do not achieve a pathologic response.

V. To assess patterns of failure and assess the rates of distant metastatic control (DMC) and locoregional control (LRC) of this tri-modality therapy regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the pattern of Ki-67 expression in patients with LRA esophageal cancer before and after induction chemotherapy.

II. To explore the relationship of Ki-67 expression to clinical and pathologic response parameters as well as survival outcomes.

III. To evaluate the relationship between human epidermal growth factor receptor 2 (HER2) overexpression (based on immunohistochemistry) and gene amplification (based on fluorescence in situ hybridization) with clinical and pathologic response parameters and survival outcomes.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 44 hours on days 1-3. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Approximately 4-5 weeks after completion of induction chemotherapy, patients undergo a surgical procedure. The choice of surgical procedure is at the discretion of the operating physician.

ADJUVANT THERAPY: Within 6-12 weeks after surgery, patients undergo radiation therapy for 28 days. Patients with a positive pathological response also receive oxaliplatin, leucovorin calcium, and fluorouracil as in the induction chemotherapy, beginning days 1, 15, and 29 concurrent with radiation therapy. Patients with a negative pathological response receive paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36 in the absence of disease progression or unacceptable toxicity. Patients with locoregional disease only after induction therapy but do not undergo surgery may receive chemoradiotherapy with carboplatin and paclitaxel as determined by the primary oncologist.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 4-5 months for 3 years, and then annually thereafter.

Inclusion Criteria:

• Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, GEJ, or GC based on biopsy material or adequate cytologic exam; tumors of the GC are defined as originating within 5 cm of the GEJ
• Patients must be clinically staged according to the 7th edition (2010) of the American Joint Committee on Cancer (AJCC) staging system and must have either clinical T3-4a, or ≥ N1 disease; staging should include upper endoscopy with endoscopic ultrasound and a fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scan (with diagnostic CT abdomen/pelvis preferred)
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Absolute neutrophil count ≥ 1,500/ul
• Platelet count ≥100,000/ul
• Serum creatinine (Scr) ≤ 1.5mg/dl; if the Scr > 1.5, patients may still be eligible if the calculated glomerular filtration rate (GFR) (Cockroft-Gault) is ≥ 40ml/minute
• Serum total bilirubin ≤ 1.5X the institutional upper limit of normal (ULN)
• Alkaline phosphatase ≤ 3X the institutional ULN
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3X the institutional ULN
• Patients with Gilbert's syndrome are eligible provided the total bilirubin is ≤ 3 and the remainder of the liver function tests (ALT, AST, alkaline phosphatase [ALK Phos]) are within the institutional normal range
• Patients must have a forced expiratory volume in one second (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) > 50% predicted
• Patients or their legal representatives must be able to read, understand, provide and sign informed consent to participate in the trial
• Patients of childbearing potential must agree to use an effective form of contraception during this study and for 90 days following the last dose of chemotherapy; an effective form of contraception is an oral contraceptive or a double barrier method

Exclusion Criteria:

• Patients with any other diagnosis except for adenocarcinoma (squamous cell carcinoma, small cell carcinoma, mixed adenosquamous, lymphoma, sarcoma, etc.) will be ineligible

• Patients with evidence of clinical T4b (unresectable) or M1 (distant metastasis) according to the AJCC 2010 staging system will be ineligible

• No prior chemotherapy, radiation therapy, or surgery for this malignancy will be allowed; prior endoscopic procedures for superficial disease (endoscopic mucosal resection, cryotherapy, photodynamic therapy, etc.) will not exclude a patient; prior dilatation is also allowed

• Patients with another active malignancy will not be eligible except for:

  • Resected basal cell carcinoma and squamous cell carcinoma of the skin, cervical or prostatic intraepithelial neoplasia, and ductal or lobular carcinoma in situ of the breast

  • Patients with localized prostate cancer who have received curative intent therapy are also eligible provided:

    • Surgically treated patients have an undetectable prostate specific antigen (PSA)
    • Patients treated with brachytherapy have a PSA within the institutional normal range
    • Patients who have received pelvic external beam radiotherapy are not eligible

• Patients with a clinically apparent active infection will not be eligible (please note, an isolated elevation in the white blood cell count, by itself, does not constitute evidence of an infection)

• Patients with known hypersensitivity to any component of the chemotherapy regimen will not be eligible

• Patients with a baseline peripheral neuropathy ≥ grade 2 will not be eligible

• Patients who are receiving any other concurrent investigational therapy, or who have received investigational therapy within 30 days of the first scheduled day of protocol treatment (investigational therapy as defined as treatment for which there is currently no regulatory authority approved indication) will not be eligible

• Patients who are pregnant or lactating will not be eligible; pregnant patients are ineligible

• Patients with angina, a cardiac ejection fraction < 50%, or ischemic heart disease are not eligible

• Patients with any other medical condition, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results, will not be eligible

• Patients with any history of solid organ or bone marrow transplant will not be eligible

• Patients with a known history of infection with hepatitis B or hepatitis C virus (active, previously treated, or both) will not be eligible due to the increased risk of hepatotoxicity and viral reactivation associated with systemic chemotherapy

• Patients with known infection with human immunodeficiency virus (HIV) will not be eligible