Testing the Addition of Radiotherapy to the Usual Treatment (Chemotherapy) for Patients with Esophageal and Gastric Cancer that has Spread to a Limited Number of Other Places in the Body

Inclusion Criteria

• Patient must be >= 18 years of age
• Patient must have histologically confirmed HER2 negative metastatic esophageal or gastric adenocarcinoma (American Joint Committee on Cancer [AJCC] 8th edition) with known PDL1 Combined Positive Score (CPS) expression
• Patient must have received 3-6 months of first-line systemic therapy for advanced disease within 4 weeks of the date of protocol randomization. Patient must have at least stable disease, with no evidence of disease progression on first-line systemic therapy to be eligible
• Patient must have oligometastatic disease at the time of diagnosis of metastatic disease and prior to initiation of the first-line systemic therapy, which is defined as the following: * One to five (1-5) radiologically visible metastatic lesions (not sites), in addition to the primary site. CT or MRI scans will be performed for staging purposes. Patients with oligometastatic sites that are only detected with positron emission tomography (PET)/CT will be eligible for participation. Malignant lymph node must be at least 1 cm in short axis or biopsy proven involved by disease * Anatomically defined lymphadenopathy will be considered as 1 metastatic lesion. For example, 2 enlarged paraaortic lymph nodes will be considered as one lesion, and 2 additional lesions will be allowed to meet protocol definition of oligometastatic disease. However, if supraclavicular or cervical nodes are involved for distal esophageal tumors or gastric tumors, these are counted separately from intrathoracic nodes. For upper thoracic/cervical esophageal tumors, the involvement of celiac nodes are counted separately from intrathoracic nodes. Intrathoracic nodes, defined as hilar and mediastinal nodes, will be collectively counted as one * Patients with radiologically evident peritoneal metastasis are not eligible.
• Patient must have received at least 2 chemotherapy agents during their first-line treatment.
• Consultation with radiation oncology must be performed to confirm eligibility. Patient must not have any contraindications to radiation therapy. Prior palliative or definitive radiation or chemoradiation to the primary site is allowed
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patient must not be pregnant or breast feeding due to the potential harm to unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. * A patient of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 14 days prior to randomization * A patient of childbearing potential is defined as someone, regardless whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in this study. Patients of childbearing potential must continue contraception measures for 5 months after the last dose of protocol treatment. Investigators must counsel all patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy
• Hemoglobin ≥ 8 g/dL (obtained within 28 days prior to randomization)
• Platelets ≥ 75,000/uL (obtained within 28 days prior to randomization)
• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (obtained within 28 days prior to randomization)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3.0 x institutional upper limit of normal (ULN) (obtained within 28 days prior to randomization)
• Bilirubin ≤ 1.5 x institutional ULN (unless suspected Gilbert's disease per treating physician) (obtained within 28 days prior to randomization)
• Serum creatinine ≤ 1.5 x institutional ULN or creatinine clearance ≥ 30 mL/min (estimated using Cockcroft and Gault formula or measured) (obtained within 28 days prior to randomization)
• Patient must be able to understand and willing to sign and date the written voluntary informed consent form prior to any protocol-specific procedures. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this protocol
• Patients who had prior definitive treatment for early stage EGA are eligible for participation as long as recurrent disease developed at least 6 months after completion of all prior therapies * NOTE: Patients previously treated with radiosensitizing 5-FU and oxaliplatin will be eligible for participation as long as adequate time has elapsed from past treatments. For prior definitive treatments with curative intent, recurrent disease must be diagnosed at least 6 months after treatment completion * NOTE: Patients who received systemic chemotherapy or immunotherapy as part of the treatment for their locoregional disease (for example, induction therapy before chemoradiation or adjuvant therapy after resection) are eligible for participation, as long as all definitive therapy has been completed at least 6 months prior to developing recurrent disease
• Any major surgery must have been completed ≥ 4 weeks prior to randomization
• Patient must not have any known central nervous system (CNS) metastasis
• Patient must not have any uncontrolled intercurrent illness including, but not limited to ongoing or active infection requiring treatment, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patient must not have had live vaccines within 4 weeks prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette Guerin (BCG), and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and coronavirus disease 2019 (COVID-19) (Note: intranasal influenza vaccines, such as Flu-Mist® are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events)