Standard treatment for patients with early stage gastric cancer consists of perioperative chemotherapy and surgical resection. If radiation therapy is administered in the adjuvant setting, the radiated area is often large and associated with significant toxicity.

In this study, the investigators propose the addition of short course radiation therapy (SCRT) to chemotherapy in the neoadjuvant setting. The investigators hypothesize that this regimen of Total Neoadjuvant Therapy (TNT) will result in a higher rate of complete response (both pathologic and clinical), with less toxicity.

Inclusion Criteria:

• Newly diagnosed histologically or cytologically gastric adenocarcinoma. (Siewert III acceptable: the bulk of tumor should be in stomach; gastric tumors with extension to the gastroesophageal junction are permitted.) Patients with T1-4N0-3 are eligible.

• Known T-stage defined by EUS. Must have had CT of the chest/abdomen/pelvis with IV contrast (or PET/CT if unable to receive iodinated contrast).

• Medically eligible to receive SOC chemotherapy.

• At least 18 years of age.

• ECOG performance status ≤ 2.

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Creatinine clearance > 50 mL/min by Cockroft Gault calculation

• The effects of the various chemotherapy agents used in this study on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and one month after completion of the study.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior surgery, radiation, or chemotherapy for gastric or esophageal cancer.
• Prior surgery to the esophagus or stomach.
• Siewert I-II GE junction tumor.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently receiving any other investigational agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to the SOC chemotherapy used in the study.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia that are considered clinically significant as determined by the treating physician.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of study entry.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.