Radiotherapy + Chemoimmunotherapy Followed by Surgery in Patients With Limited Metastatic Gastric or GEJ Cancer

Inclusion Criteria:

1. Histopathologically confirmed adenocarcinoma of stomach (G) or gastroesophageal junction (GEJ) (excluding Siewert type I).
2. Limited metastatic status of disease.
3. At least one evaluable lesion in CT/MRI according to RESIST 1.1 is required.
4. The status of HER2 is clear.
5. pMMR/MSS confirmed by immunohistochemistry or gene test.
6. Male or female. Patient age ≥ 18 years and ≤ 75 years.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
8. Physical state or organ function can tolerate the planned treatment of the study protocol, including systematic chemotherapy, immunotherapy with anti-PD-1 monoclonal antibody (mAb), primary lesion radiotherapy, metastatic lesion radiotherapy, and surgical resection of primary and/or metastatic lesions.
9. No previous surgery or antitumor therapies, including chemotherapy, radiotherapy, or immunotherapy, were administered.
10. Adequate hematological function: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count ≥ 100×109/L; hemoglobin level ≥ 90 g/L.
11. Adequate hepatic function: total bilirubin ≤ 1.5×upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) \< 2.5 × ULN in the absence of liver metastases, or \< 5 × ULN in case of liver metastases; ALP ≤ 2.5×ULN; ALB ≥ 30 g/L.
12. Adequate renal function: serum creatinine ≤ 1.5×ULN; creatinine clearance rate ≥ 60 ml/min.
13. Adequate coagulation function: INR/PT ≤ 1.5×ULN; APTT ≤ 1.5×ULN.
14. TSH is within the normal range; if TSH is out of the normal range, FT3 and FT4 should be investigated. If the test results of FT3/FT4 cannot be obtained, T3 and T4 can be accepted. 13. If the level of T3/T4 is normal, the patients can be selected.
15. Urine test: urine protein\<2+; if the urine protein≥2+, the 24-hour urine protein quantification must be≤1g.
16. There is no serious concomitant disease, and the patient's life expectancy is more than 6 months.
17. Patients agree to sign written informed consent before recruitment.
18. Patients are willing and able to follow the protocol during the study, including receiving treatment and scheduled follow-up and examination.
19. Patients are willing to provide samples of blood and tissue.
20. Female patients should not be pregnant or breast feeding.
21. Female patients agree to take contraceptive measures during treatment and within 120 days after the last dose of anti-PD-1 mAb or 180 days after the last use of chemotherapy or radiotherapy.

Definition of the limited metastatic disease:

1. Retroperitoneal lymph node metastases (RPLM) only or at maximum one organ involved with or without RPLM.
2. There is no peritoneal seeding on diagnostic laparoscopy (P0).
3. The definition of RPLM includes but is not limited to para-aortal, intra-aorto-caval, parapancreatic or mesenteric lymph nodes. If the duodenum is invaded, retropancreatic nodes are not regarded as M1.
4. The definition of single organ metastasis in the study is as follows: a) Liver: maximum of 5 metastatic lesions that are potentially resectable and the metastases should be limited to one lobe and not involve important blood vessels or bile ducts. b) Lung: unilateral involvement, potentially resectable. c) Ovary: uni- or bilateral Krukenberg tumors in the absence of macroscopic peritoneal carcinomatosis. d) Adrenal gland: uni- or bilateral metastases. e) Extra-abdominal lymph node metastases, such as supraclavicular or cervical lymph node involvement. f) Bone: localized bone involvement (defined as being within one radiation field).
5. Other metastatic disease locations are considered, limited by the investigator and confirmed by the multidisciplinary team (MDT).

Exclusion Criteria:

1. Patients who have previously received surgery, chemotherapy, radiotherapy or immunotherapy for gastric cancer.
2. Patients have a history of cancer in the five years before enrollment except for squamous or basal cell carcinoma of the skin that was effectively treated and superficial bladder cancer, cervical carcinoma in situ and breast cancer in situ that was treated by operation.
3. Pregnant or lactating females or females planning to become pregnant or lactating. Women of childbearing age with a positive pregnancy test or without a pregnancy test in the baseline period. Menopausal women must have stopped menstruating for at least 12 months before being considered to have no chance of pregnancy.
4. Patients who had sexual activity (with the possibility of childbirth) and were unwilling to use contraception during the study period.
5. Patients with a history of allergies to any drugs that may be used in this study, including chemotherapy drugs.
6. History of allogeneic stem cell transplantation or organ transplantation.
7. Vaccinated with live vaccine within 28 days before recruitment.
8. Immunotherapy (interleukin, interferon, thymine) or other experimental treatment was given 28 days before enrollment.
9. History of anti-PD-1, PD-L1, PD-L2 or any other specific T-cell costimulation or checkpoint pathway targeted therapy.
10. History of using steroids (dose \> 10 mg/d prednisone) or other systemic immunosuppressive therapy within 14 days before recruitment, except for patients treated with the following regimen: steroids used for hormone replacement (dose \> 10 mg/d prednisone); local application of steroids with little systemic absorption; short-term (≤ 7 days) use of steroids to prevent allergy or vomiting.
11. Patients with weight loss of more than 20% within 2 months before recruitment.
12. Uncontrolled systemic diseases, including diabetes, hypertension, etc.
13. Uncontrollable pleural effusion, pericardial effusion, or ascites occurred within two weeks before recruitment.
14. Failure of important organs (heart, lung, liver, kidney, etc.).
15. Moderate or severe renal injury \[creatinine clearance ≤ 50 ml/min (according to Cockcroft \& Gault equation)\], or SCR \> ULN.
16. Dipyrimidine dehydrogenase (DPD) deficiency.
17. Patients with central nervous system (CNS) disorders or tumors, including brain metastases, peripheral nervous system disorders or psychiatric diseases.
18. Cerebrovascular accidents occurred within 6 months before recruitment.
19. Patients with peripheral neuropathy of NCI-CTCAE grade 1, except for those with disappearance of the deep tendon reflex.
20. Patients with a known history of uncontrolled or symptomatic angina, uncontrolled arrhythmias and hypertension, congestive heart failure, cardiac infarction or cardiac insufficiency within 6 months prior to study recruitment.
21. Pulmonary embolism occurred within 28 days before enrollment.
22. Patients who had the following history of pulmonary diseases: interstitial lung disease, noninfectious pneumonia, pulmonary fibrosis, or acute lung disease.
23. Patients with gastrointestinal bleeding or a high risk of bleeding within the first 2 weeks of enrollment.
24. Patients who experienced gastrointestinal perforation or fistula within 6 months prior to enrollment.
25. Upper gastrointestinal obstruction, dysfunction or malabsorption syndrome may affect the absorption of oral chemotherapy drugs.
26. Patients who cannot swallow or take medication orally.
27. Patients with a history of active autoimmune disease or refractory autoimmune disease.
28. Severe chronic or active infections requiring systemic antibiotics, antifungal or antiviral therapy, including tuberculosis and AIDS.
29. Known history of human immunodeficiency virus (HIV) infection.
30. Patients with untreated chronic hepatitis B or HBV-DNA exceeding 500 IU/ml or HCV-RNA positive.
31. Alcohol/drug abuse and medical, psychological or social conditions may interfere with patients' participation in the study or have an impact on the evaluation of the study results.