Radiotherapy, Chemotherapy and Anti-PD-1 Immunotherapy Followed by Surgical Resection in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma: A Prospective, Single Arm, Phase II Trial
The goal of this clinical trial is to evaluate the efficacy and safety of radiotherapy combined with chemotherapy and anti-PD-1 immunotherapy followed by surgery for the primary and metastatic lesions in patients with limited metastatic gastric or gastroesophageal junction adenocarcinoma. The main questions it aims to answer are: 1) If the multimodal treatment which includes anti-PD-1 immunotherapy and local therapies will improve the survival of this group of patients. 2) If the multimodal treatment which includes anti-PD-1 immunotherapy and local therapies can be performed safely in this group of patients. Participants will receive short course hypofractionated radiotherapy (HFRT) for the primary lesion, HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions, combined with systemic chemotherapy and anti-PD-1 immunotherapy. For patients with HER2-positive cancer (defined as IHC 3+ or 2+/ISH+), trastuzumab is used along with chemotherapy and anti-PD-1 antibody. Then, surgical resections of primary and metastatic lesions are performed as much as possible. For patients who need a widely invasive surgical approach or are inoperable, local ablative therapies such as radiofrequency ablation (RFA) and microwave ablation (MVA) can be alternatives. For patients undergoing surgical resections, postoperative treatment includes chemotherapy, which is determined by the researcher, and PD-1 antibody, which will be maintained until one year after surgery.
• Histopathologically confirmed adenocarcinoma of stomach (G) or gastroesophageal junction (GEJ) (excluding Siewert type I).
• Limited metastatic status of disease.
• At least one evaluable lesion in CT/MRI according to RESIST 1.1 is required.
• The status of HER2 is clear.
• pMMR/MSS confirmed by immunohistochemistry or gene test.
• Male or female. Patient age ≥ 18 years and ≤ 75 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• 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.
• No previous surgery or antitumor therapies, including chemotherapy, radiotherapy, or immunotherapy, were administered.
⁃ Adequate hematological function: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count ≥ 100×109/L; hemoglobin level ≥ 90 g/L.
⁃ 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.
⁃ Adequate renal function: serum creatinine ≤ 1.5×ULN; creatinine clearance rate ≥ 60 ml/min.
⁃ Adequate coagulation function: INR/PT ≤ 1.5×ULN; APTT ≤ 1.5×ULN.
⁃ 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.
⁃ Urine test: urine protein\<2+; if the urine protein≥2+, the 24-hour urine protein quantification must be≤1g.
⁃ There is no serious concomitant disease, and the patient's life expectancy is more than 6 months.
⁃ Patients agree to sign written informed consent before recruitment.
⁃ Patients are willing and able to follow the protocol during the study, including receiving treatment and scheduled follow-up and examination.
⁃ Patients are willing to provide samples of blood and tissue.
⁃ Female patients should not be pregnant or breast feeding.
⁃ 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:
• Retroperitoneal lymph node metastases (RPLM) only or at maximum one organ involved with or without RPLM.
• There is no peritoneal seeding on diagnostic laparoscopy (P0).
• 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.
• 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).
• Other metastatic disease locations are considered, limited by the investigator and confirmed by the multidisciplinary team (MDT).