Long-Term Prognosis of Intracorporeal Versus Extracorporeal Anastomosis in Stage II/III Colorectal Cancer (INEX Study): Study Protocol for a Multicenter Randomized Controlled Trial in Japan

Background Intracorporeal anastomosis (IA) for colon cancer has garnered attention owing to its minimally invasive nature and compatibility with advanced robot-assisted surgery. IA offers advantages such as smaller incisions, reduced postoperative pain, and quicker recovery. However, concerns persist in basic research regarding the increased risk of tumor cell dissemination due to IA, which may lead to peritoneal recurrence as a result of exposure of the intestinal lumen under high intra-abdominal pressure. Evidence regarding the long-term oncological outcomes of IA is limited, with no randomized controlled trials (RCTs) addressing this issue. Furthermore, no ongoing RCTs focus on long-term outcomes as a primary endpoint regarding two anastomosis techniques, and clinical guidelines do not currently recommend a preferred anastomotic method. This multicenter RCT aims to assess the non-inferiority of IA compared with EA in the surgery of colon cancer. Methods This multicenter, open-label RCT will enroll 1,400 patients with clinical stage II or III colon cancer undergoing laparoscopic or robot-assisted colectomy across 47 institutions in Japan. Eligible patients must have tumors located in the cecum, ascending, transverse, or descending colon. Participants will be randomized to receive either EA or IA. Each participating institution must have a board-certified endoscopic surgeon to ensure surgical quality. Colon resection will include D2 or D3 lymph node dissection, in accordance with the Japanese Classification of Colorectal Carcinoma. The primary endpoint is relapse-free survival, with long-term follow-up planned. Discussion This trial will be the first RCT to evaluate long-term oncological outcomes as the primary endpoint when comparing IA and EA during minimally invasive colon cancer surgery. If IA is non-inferior to EA in relapse-free survival, the choice of anastomotic technique can be tailored to the expertise of individual institutions and surgeons. Conversely, if IA fails to demonstrate non-inferiority, EA will remain the standard treatment. Given the current lack of long-term outcome data comparing IA and EA in colon cancer, this study will provide valuable insights that may influence future surgical standards and guideline recommendations. Trial registration jRCT1032240435