D2 Gastrectomy With or Without Para-Aortic Lymph Node Dissection After Chemoimmunotherapy for Gastric Cancer (PAN-SELECT)

Inclusion Criteria:

• Age 18 to 75 years.
• Histologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma limited to Siewert type III or Siewert type II disease not requiring a transthoracic combined operation.
• Human epidermal growth factor receptor 2 (HER2)-negative disease, defined as immunohistochemistry 0 or 1+, or immunohistochemistry 2+ with negative fluorescence in situ hybridization, or HER2 status unknown.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• At initial diagnosis, thin-section contrast-enhanced computed tomography shows at least one No. 16a2 and/or No. 16b1 lymph node with a short-axis diameter of at least 10 mm and metastatic morphology, such as a round shape, irregular border, central necrosis, clustering, or abnormal enhancement, confirmed by two radiologists or gastric cancer multidisciplinary team physicians with relevant experience.
• Regional lymph node metastases are permitted, but imaging shows no peritoneal, hepatic, pulmonary, osseous, or other distant metastasis apart from the eligible No. 16a2 and/or No. 16b1 lymph nodes.
• Completion of 2 to 8 cycles of an immune checkpoint inhibitor combined with chemotherapy as routine clinical care before randomization, with the agents, doses, modifications, and number of cycles determined by the multidisciplinary team and completely documented.
• At the first reassessment after completion of the planned preoperative systemic therapy, all previously suspicious No. 16a2 and No. 16b1 lymph nodes have a short-axis diameter of less than 10 mm.
• No disease progression according to RECIST version 1.1 and clinical assessment, and no new distant metastasis at the post-treatment reassessment.
• The gastric primary tumor and regional disease are considered resectable with curative intent and an R0 resection is expected; the participant is considered medically and technically eligible for either assigned operation.
• Toxicities related to the last preoperative systemic therapy have recovered to Common Terminology Criteria for Adverse Events version 5.0 grade 1 or lower or to the pretreatment baseline. Controlled immune-related endocrine events requiring only stable replacement therapy are permitted.
• Adequate major organ function, cardiopulmonary reserve, and acceptable anesthetic risk for gastrectomy and possible para-aortic lymph node dissection.
• Ability and willingness to complete study follow-up and provide written informed consent after post-treatment eligibility is confirmed.

Exclusion Criteria:

• Disease progression, a new distant metastasis, or any suspicious para-aortic lymph node with a short-axis diameter of 10 mm or greater at the post-treatment reassessment.
• Curative-intent R0 resection is not considered feasible, or the participant cannot tolerate both assigned surgical strategies.
• Previous radical gastric cancer surgery or para-aortic operation expected to substantially alter the planned lymphadenectomy, or severe intra-abdominal adhesions or another condition that prevents safe completion of the assigned surgery.
• Uncontrolled active infection, severe cardiac, pulmonary, hepatic, or renal dysfunction, coagulopathy, or another disease that materially increases perioperative risk.
• Preoperative treatment toxicity has not recovered to the allowed level, or an unstable immune-related adverse event requires high-dose systemic immunosuppression.
• Pregnancy or breastfeeding, or inability to comply with clinically required contraception or follow-up.
• Another active malignancy within the previous 5 years, except a cured malignancy with a low risk of recurrence as determined by the investigator and applicable ethics requirements.
• Concurrent participation in another interventional study that may interfere with evaluation of the primary outcome.
• Any other condition that, in the investigator's judgment, makes participation inappropriate.