Preoperative Hypofractionated Radiotherapy With FOLFOX for Esophageal or Gastroesophageal Junction Adenocarcinoma

PRIMARY OBJECTIVE: I. To demonstrate non-inferiority of pathologic complete response (pCR) with hypofractionated radiotherapy and concurrent FOLFOX compared to historical controls. SECONDARY OBJECTIVES: I. Report targeted acute grade ≥ 3 gastrointestinal (GI) toxicity, per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. II. Assess post-operative toxicity for patients undergoing esophagectomy, as determined by the Clavien-Dindo Classification. III. Analyze patient-reported quality of life, per Functional Assessment of Cancer Therapy- Esophageal (FACT-E). IV. Determine the financial toxicity of hypofractionated radiotherapy, using Comprehensive Score for Financial Toxicity (COST-FACIT). V. Report overall survival and progression-free survival. VI. Report long-term toxicity secondary to trimodality therapy. VII. Report event-free survival. VIII. Assess outcomes for patients treated with hypofractionated radiotherapy and FOLFOX but who did not proceed to esophagectomy. IX. Compare toxicity of chemoradiation between patients receiving proton based versus (vs.) photon-based radiotherapy. X. Compare clinical outcomes and pCR for patients receiving hypofractioned radiotherapy but different induction chemo (immuno) therapy regimens: no induction vs. fluorouracil, oxaliplatin, leucovorin, docetaxel (FLOT) vs. FLOT + durvalumab. CORRELATIVE OBJECTIVES: I. Explore the predictive and prognostic role for circulating tumor DNA in esophageal cancer. II. Study the utility of whole exome and germline sequencing to predict chemoradiation treatment response. III. Explore the predictive power of whole exome sequencing regarding chemoradiotherapy toxicity. IV. Implement whole exome and germline sequencing to personalize immunotherapy in esophageal cancer. V. Study the predictive and prognostic role of tumor-derived extracellular vesicles in esophageal cancer. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive 5-FU intravenously (IV) over 24 hours on day 1, leucovorin calcium IV over 10-120 minutes on day 1, oxaliplatin IV over 2-6 hours on day 1, and docetaxel IV over 1 hour on day 1 of each cycle. Treatment repeats every 2 weeks for a total of up to 6 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients also receive durvalumab IV over 1 hour every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of FLOT, patients undergo radiation therapy daily for 3 weeks with 2 concurrent cycles of FOLFOX. FOLFOX: Patients receive oxaliplatin IV over 2-6 hours on day 1, leucovorin calcium IV over 10-120 minutes on day 1, and and fluorouracil IV over 46-48 hours on days 1 and 2. of each cycle. Treatment repeats every 2 weeks for a total of 3 cycles in the absence of disease progression or unacceptable toxicity. Starting at cycle 2, patients undergo radiation therapy daily on Monday through Friday for a total of 15 treatments. Patients undergo esophagogastroduodenoscopy (EGD) and/or endoscopic ultrasound (EUS) during screening and undergo computed tomography (CT)/position emission tomography (PET) scan and CT scan as well as blood and tissue sample collection throughout the study. After completion of study treatment, patients are followed up at 6,12 and 24 months and then up to 5 years.