Brief Summary: This phase II trial tests how well preoperative (prior to surgery) radiation therapy with fluorouracil, oxaliplatin, and leucovorin calcium (FOLFOX) works for the treatment of stage I-III esophageal or gastroesophageal junction adenocarcinoma. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Fluorouracil stops cells from making deoxyribonucleic acid (DNA) and it may kill tumor cells. Leucovorin is not a chemotherapy medication but is given in conjunction with chemotherapy. Leucovorin is used with the chemotherapy medication fluorouracil to enhance the effects of the fluorouracil, in other words, to make the drug work better. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill tumor cells. Giving preoperative hypofractionated radiation with fluorouracil and oxaliplatin may kill more tumor cells in patients with stage I-III esophageal or gastroesophageal junction adenocarcinoma.

Detailed Description: 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 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. 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: Patients receive oxaliplatin intravenously (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. 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 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.