Thoracoscopic versus open oesophagectomy for patients with oesophageal cancer (JCOG1409 MONET): a multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial.	BACKGROUND: Thoracoscopic oesophagectomy, a minimally invasive treatment for oesophageal cancer, is used worldwide. However, no large-scale, multicentre, randomised controlled trial has compared long-term survival as the primary endpoint between thoracoscopic and open oesophagectomy. We aimed to confirm the non-inferiority in overall survival of thoracoscopic oesophagectomy over open oesophagectomy in patients with resectable thoracic oesophageal cancer. METHODS: This multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial was conducted at 31 hospitals across Japan. Patients aged 20-80 years were eligible if they had histologically confirmed oesophageal squamous cell carcinoma, oesophageal adenosquamous carcinoma, or oesophageal basaloid squamous cell carcinoma, which was located in the thoracic oesophagus; an Eastern Cooperative Oncology Group performance status of 0 or 1; clinical stage I, II, or III (but not T4) disease; and had not received previous treatment for oesophageal cancer, except for endoscopic resection of superficial lesions and preoperative chemotherapy (doublet or triplet) per Japanese guidelines. Patients were randomly assigned (1:1) using a web-based system with adjustment factors by clinical stage (IA vs IB, II, or III), age (<76 years vs ≥76 years), and institution, to right open transthoracic oesophagectomy or right thoracoscopic oesophagectomy, both with at least D2 lymphadenectomy. The primary endpoint was investigator-assessed overall survival, analysed in the intention-to-treat population. The non-inferiority margin was 9% for 3-year overall survival (hazard ratio [HR] 1·44). Two formal interim analyses of overall survival were planned: the first after half of the expected number of patients were enrolled and the second after patients had been accrued and protocol treatment completed. The trial would be terminated for efficacy if non-inferiority and superiority in overall survival was shown for thoracoscopic oesophagectomy in the first interim analysis and if non-inferiority in overall survival was shown in the second interim analysis. This trial was registered with UMIN Clinical Trials Registry, UMIN000017628 (follow-up ongoing). FINDINGS: From May 20, 2015, to June 17, 2022, 300 patients were randomly assigned (150 to open oesophagectomy and 150 to thoracoscopic oesophagectomy). 247 (82%) of 300 patients were male and 53 (18%) were female. The median age was 68 years (IQR 64-72). 148 (99%) of 150 patients underwent open oesophagectomy, and all 150 patients underwent thoracoscopic oesophagectomy. In the first interim analysis at a median follow-up of 1·6 years (IQR 0·8-2·5), non-inferiority was not confirmed (HR 0·56 [99·99990046% CI 0·05-5·73]; one-sided p(non-inferiority)=0·002326, greater than the prespecified non-inferiority threshold). At a median follow-up of 2·6 years (IQR 1·4-4·9) for the second interim analysis, 3-year overall survival was 82·0% (95% CI 73·8-87·8) with thoracoscopic oesophagectomy and 70·9% (61·6-78·4) with open oesophagectomy (HR 0·64 [98·8% CI 0·34-1·21]), confirming non-inferiority (one-sided p(non-inferiority)=0·000726, less than the prespecified non-inferiority threshold of 0·00616). The Data and Safety Monitoring Committee then recommended terminating the trial and publishing the results, and the trial was terminated in June 19, 2023. Intraoperative complications (grade ≥3) were similar between study groups (one [1%] of 150 in the thoracoscopic group vs two [1%] of 148 in the open group; all three events were intraoperative bleeding), as were postoperative complications before first discharge (grade ≥3; 63 [42%] vs 65 [44%]). Grade 3 or higher pneumonia occurred in 12 (8%) patients in the thoracoscopic group and in 18 (12%) in the open group; grade 3 anastomotic leakage occurred in 17 (11%) patients in the thoracoscopic group and seven (5%) in the open group. Four treatment-related deaths occurred in the thoracoscopic group and two in the open group. INTERPRETATION: Thoracoscopic oesophagectomy, a standard treatment in Japan, was non-inferior to open oesophagectomy for patients with resectable thoracic oesophageal cancer. FUNDING: Japan Agency for Medical Research and Development and the National Cancer Center Research and Development Fund.	esophagus