Short-Course Chemoradiotherapy Followed by Chemotherapy for the Treatment of Resectable Gastric Adenocarcinoma

This phase Ib trial investigates the side effects and how well a shorter course of chemotherapy and radiation treatment (chemoradiotherapy) for 2 weeks instead of 5 weeks followed by standard chemotherapy works in treating patients with gastric cancer who are scheduled to have treatment and then surgery to remove the tumor. Chemotherapy drugs, such as capecitabine and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy sources to kill tumor cells and shrink tumors. Giving short-course chemo-radiotherapy before chemotherapy and surgery may help to control the disease.

PRIMARY OBJECTIVE:

I. To assess the safety and tolerability of preoperative short-course chemoradiotherapy (CXRT) in patients with potentially resectable gastric adenocarcinoma.

SECONDARY OBJECTIVES:

I. To assess the rate of pathologic complete response (pathCR) in patients treated with preoperative short-course CXRT.

II. To assess the rate of perioperative complications after gastrectomy in patients treated with preoperative short-course CXRT.

III. To assess overall survival from the date of diagnosis in subjects treated with short course CXRT.

OUTLINE:

Patients receive CXRT consisting of radiation therapy 5 days a week (Monday through Friday) for 2 weeks (10 treatments) and standard of care chemotherapy consisting of capecitabine orally (PO) twice daily (BID) or fluorouracil intravenously (IV) continuous Monday to Friday of each radiation week. About 2 weeks later, patients receive standard of care chemotherapy for up to 2 months in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery 3-8 weeks post-chemotherapy completion.

After the completion of study treatment, patients are followed up every 6 months for 5 years.

Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Patients with a biopsy-confirmed diagnosis of adenocarcinoma of the stomach
* No evidence of distant metastatic disease based on standard of care preoperative imaging evaluation
* Evidence of T2 stage or greater primary tumor, or any T stage with node positive disease based on endoscopic ultrasound or standard of care imaging
* Leukocytes \>= 3,000/ul
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 60,000/UI
* Glomerular filtration rate \>= 60 mL/min/1.73 m\^2. The estimated glomerular filtration rate (eGFR) is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The eGFR declines with age. eGFR \< 60 mL/min/1.73 m2 is considered as "decreased". This equation should only be used for patients 18 and older. According to the National Kidney Foundation's Kidney Disease Outcome Quality Initiative (KDOQI) classification and 2012 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline, the stage of CKD should be categorized based on estimated GFR

Exclusion Criteria:

* Presence of metastatic disease on staging with standard of care imaging, with or without diagnostic laparoscopy. Subjects not able to undergo staging laparoscopy due to previous surgery will not be excluded from this trial, and the determination of absence of metastatic disease will be decided solely on imaging consistent with our current standard of care
* Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract
* Infections such as pneumonia or wound infections that would preclude protocol therapy
* Women with a positive urine or serum pregnancy test are excluded from this study; women of childbearing potential (defined as those who have not undergone a hysterectomy or who have not been postmenopausal for at least 12 consecutive months) must agree to refrain from breast-feeding and practice adequate contraception as specified in the informed consent. Adequate contraception consists of oral contraceptive, implantable contraceptives, injectable contraceptives, barrier methods, or abstinence. Contraception for males consists of barrier methods or abstinence
* Subjects with unstable angina or New York Heart Association grade II or greater congestive heart failure
* Subjects deemed unable to comply with study and/or follow-up procedures
* Subjects with a known hypersensitivity to protocol systemic chemotherapy that was life threatening, required hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability or incapacity
* Prior radiotherapy to the same field
* Comorbid conditions (examples - collagen vascular diseases, certain genetic conditions that predispose to secondary malignancies) that are prohibitive to preoperative therapy, or contraindications to radiotherapy