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

This randomized phase II trial studies how well regorafenib works in treating patients with cancer of the esophagus or gastroesophageal junction that has spread from where it started to nearby tissue or lymph nodes and have completed chemoradiation therapy and surgery. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To compare the disease-free survival (DFS) for patients with resected esophageal and gastroesophageal (GE) junction adenocarcinoma treated with regorafenib vs. placebo in the adjuvant setting.

SECONDARY OBJECTIVES:

I. To compare the safety profile of adjuvant regorafenib vs. placebo in patients with locally advanced resectable esophageal and GE junction adenocarcinoma.

II. To compare the overall survival (OS) for patients with resected esophageal and GE junction adenocarcinoma treated with regorafenib vs. placebo in the adjuvant setting.

III. To compare the DFS in those patients that receive at least 1 cycle of therapy.

IV. To collect tumor samples for future genomic analysis to explore the biology of locally advanced esophageal and GE junction adenocarcinoma.

V. DFS will be compared between the arms from the time of surgery as well.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Within 6-12 weeks after surgery, patients receive regorafenib orally (PO) once daily (QD) on days 1-21.

ARM II: Within 6-12 weeks after surgery, patients receive placebo PO QD on days 1-21.

In both arms, courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and every 6 months for up to 5 years.

Eligibility Criteria:
Inclusion Criteria:

* 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