Thoracoscopic versus open oesophagectomy for patients with oesophageal cancer (JCOG1409 MONET): a multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial.

However, no large-scale, multicentre, randomised controlled trialhas compared long-term survival as the primary endpoint between thoracoscopic and open oesophagectomy.

然而，尚无大规模、多中心、随机对照试验将胸腔镜与开放性食管切除术作为主要终点，比较两者的长期生存率。

We aimed to confirm the non-inferiority in overall survivalof thoracoscopic oesophagectomy over open oesophagectomy in patients with resectable thoracic oesophageal cancer.

我们旨在确认胸腔镜食管切除术在可切除胸段食管癌患者中的总生存非劣效性优于开胸食管切除术。

Methods

This multicentre, open-label, randomised, controlled, phase 3, non-inferiority trial was conducted at 31 hospitals across Japan.

这项多中心、开放标签、随机、对照、第三阶段、非劣效性试验在日本的31家医院进行。

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.

符合条件的患者年龄在20至80岁之间，如果他们有组织学证实的食管鳞状细胞癌、食管腺鳞癌或食管基底样鳞状细胞癌，这些癌症位于胸食管；东部肿瘤协作组表现状态为0或1；临床分期为I、II或III期（但不包括T4），并且除了根据日本指南进行的内镜下浅表病变切除术和术前化疗（双药或三药）外，未接受过食管癌的其他治疗。

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.

患者通过基于网络的系统随机分配（1:1），根据临床分期（IA与IB、II或III期）、年龄（<76岁与≥76岁）和机构进行调整，接受右侧开放式经胸食管切除术或右侧胸腔镜下食管切除术，两者均至少包括D2淋巴结清扫术。

The primary endpoint was investigator-assessed overall survival, analysed in the intention-to-treatpopulation.

主要终点是研究者评估的总生存期，在意向治疗人群中进行分析。

The non-inferiority margin was 9% for 3-year overall survival(hazard ratio[HR] 1·44).

非劣效性边界为3年总生存期的9%（风险比[HR] 1·44）。

Two formal interim analyses of overall survivalwere 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.

计划了两次正式的总生存中期分析：第一次在预计招募患者数的一半后进行，第二次在患者招募完成并完成方案治疗后进行。

The trial would be terminated for efficacy if non-inferiority and superiority in overall survivalwas shown for thoracoscopic oesophagectomy in the first interim analysis and if non-inferiority in overall survivalwas shown in the second interim analysis.

如果在第一次中期分析中显示出胸腔镜食管切除术在总生存方面的非劣效性和优越性，并且在第二次中期分析中显示出总生存的非劣效性，则试验将因效果显著而终止。

This trial was registered with UMIN Clinical Trials Registry, UMIN000017628 (follow-up ongoing).

该试验已注册于UMIN临床试验注册中心，注册号为UMIN000017628（随访正在进行中）。

Results

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.

从2015年5月20日至2022年6月17日，300名患者被随机分配（150名接受开放性食管切除术，150名接受胸腔镜下食管切除术）。300名患者中，247名（82%）为男性，53名（18%）为女性。

The median age was 68 years (IQR 64-72). 148 (99%) of 150 patients underwent open oesophagectomy, and all 150 patients underwent thoracoscopic oesophagectomy.

中位年龄为68岁（四分位数间距64-72岁）。在150名患者中，有148名（99%）接受了开放性食管切除术，所有150名患者均接受了胸腔镜下食管切除术。

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 pnon-inferiority=0·002326, greater than the prespecified non-inferiority threshold).

在首次中期分析中，中位随访时间为1.6年（四分位数间距0.8-2.5年），非劣效性未得到确认（风险比0.56 [99.99990046% 置信区间0.05-5.73]；单侧p非劣效性=0.002326，大于预先设定的非劣效性阈值）。

At a median follow-up of 2·6 years (IQR 1·4-4·9) for the second interim analysis, 3-year overall survivalwas 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 pnon-inferiority=0·000726, less than the prespecified non-inferiority threshold of 0·00616).

在第二次中期分析的中位随访时间为2.6年（四分位数间距1.4-4.9年）时，胸腔镜下食管切除术的3年总生存率为82.0%（95%置信区间73.8-87.8%），而开放性食管切除术的3年总生存率为70.9%（61.6-78.4%）（风险比0.64 [98.8%置信区间0.34-1.21]），确认了非劣效性（单侧p非劣效性=0.000726，低于预先设定的非劣效性阈值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.

数据和安全监测委员会随后建议终止试验并发布结果，试验于2023年6月19日终止。

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%]).

术中并发症（3级或以上）在研究组之间相似（胸腔镜组150人中有1人[1%]，开放组148人中有2人[1%]；所有三起事件均为术中出血），术前首次出院前的术后并发症（3级或以上）也是如此（胸腔镜组63人[42%]，开放组65人[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.

胸腔镜组有12名（8%）患者出现3级或更高级别的肺炎，开放组有18名（12%）；胸腔镜组有17名（11%）患者出现3级吻合口漏，开放组有7名（5%）。

Four treatment-related deaths occurred in the thoracoscopic group and two in the open group.

胸腔镜组中出现了四例与治疗相关的死亡，在开放组中出现了两例。

interpretation

Thoracoscopic oesophagectomy, a standard treatment in Japan, was non-inferior to open oesophagectomy for patients with resectable thoracic oesophageal cancer.

在日本作为标准治疗的胸腔镜食管切除术对于可切除的胸部食管癌患者来说，并不逊色于开放性食管切除术。

funding

Japan Agency for Medical Research and Development and the National Cancer Center Research and Development Fund.

日本医疗研究与开发机构和国家癌症中心研究发展基金。