Regorafenib in Treating Patients With Locally Advanced Cancer of the Esophagus or Gastroesophageal Junction Who Have Completed Chemoradiation Therapy and Surgery

• Histological confirmation of node positive (any T stage N1-3) proximal esophageal, distal esophagus or gastroesophageal (GE) junction adenocarcinoma (Siewert I, II, or III) after completing preoperative chemoradiation and surgery; supporting pathology report sufficient for registration; available tumor tissue from endoscopic biopsies prior to preoperative chemotherapy (chemo)/radiation therapy (RT), and tumor from surgical specimens will be submitted to Academic and Community Cancer Research United (ACCRU), but not be required prior registration; Note: if tissue is depleted, patient will still be eligible after discussion with the physician
• Imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) =\< 28 days of study registration negative for disease recurrence
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Absolute neutrophil count (ANC) >= 1500/mm\^3
• Platelet count >= 100,000/mm\^3
• Total bilirubin =\< 1.5 x the upper limits of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer)
• Alkaline phosphatase limit =\< 2.5 x ULN (=\< 5 x ULN for subjects with liver involvement of their cancer)
• Lipase =\< 1.5 x the ULN
• Serum creatinine =\< 1.5 x the ULN
• International normalized ratio (INR)/partial thromboplastin time (PTT) =\< 1.5 x ULN; Note-subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT are stable; close monitoring (day 1 of each cycle) is mandatory; if either of these values is above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until they are stable
• Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only
• Provide informed written consent
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
• Able to swallow and retain oral medications and begin therapy within 6 to 12 weeks post-surgery
• Provide blood samples for the mandatory correlative research purposes

Exclusion Criteria:

• Presence of metastatic or recurrent disease
• R1 or R2 resection
• Patients who have not recovered from serious adverse events (as determined by treating doctor of medicine [MD]) related to surgery
• Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management per physician discretion

• Active or clinically significant cardiac disease including:

  • Congestive heart failure - New York Heart Association (NYHA) > class II
  • Active coronary artery disease
  • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
  • Unstable angina (anginal symptoms at rest), new-onset angina \< 3 months before randomization, or myocardial infarction within 6 months before randomization
• Evidence or history of bleeding diathesis or coagulopathy
• Any hemorrhage or bleeding event >= National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 grade 3 =\< 4 weeks prior to registration
• Prior cancers \< 3 years, with the exception of in-situ cervical cancer, low grade prostate cancer and basal or squamous cell skin cancers
• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism =\< 6 months prior to registration
• Receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); use of strong or moderate inhibitors are prohibited =\< 7 days to registration
• Receiving any medications or substances that are inducers of CYP3A4; use of inducers are prohibited =\< 7 days prior to registration