SCI
26 July 2024
Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial
（Lancet; if=98.4）
Kato K, Machida R, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, Kojima T, Abe T, Bamba T, Watanabe M, Kawakubo H, Shibuya Y, Tsubosa Y, Takegawa N, Kajiwara T, Baba H, Ueno M, Takeuchi H, Nakamura K, Kitagawa Y; JCOG1109 investigators
Correspondence: kenkato@ncc.go.jp
Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC.
新辅助治疗是局部晚期食管鳞状细胞癌（OSCC）患者的标准治疗方法。然而，预后仍然很差，可能需要更强化的新辅助治疗来改善患者的预后。因此，我们旨在比较新辅助双联化疗、三联化疗和双联化疗加放疗对既往未经治疗的局部晚期OSCC患者的疗效和安全性。
In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete.
在这项随机、开放标签的 3 期试验中，日本全国 44 个中心招募了年龄在 20-75 岁之间、既往未接受过治疗的局部晚期 OSCC 患者，这些患者的ECOG（Eastern Cooperative Oncology Group）评分为 0 或 1。患者被随机分配（1:1:1）通过网络系统集中接受新辅助双联化疗（两个疗程的氟尿嘧啶[每天800mg/m2，第1-5天静脉注射]和顺铂[每天80mg/m2，第1天]，间隔3周[NeoCF]）、三联化疗（三个疗程的氟尿嘧啶[每天750mg/m2，第1-5天]、顺铂[每天70mg/m2，第1天]、 每 3 周重复一次[NeoCF+D]），或双联化疗（两个疗程的氟尿嘧啶[每天 1000 mg/m2，第 1-4 天]和顺铂[每天 75 mg/m2，第 1 天]，间隔 4 周）加 41-4 Gy 放射治疗[NeoCF+RT]），然后进行食道切除术和区域淋巴结清扫术。随机分配按 T 阶段和机构进行分层。参与者、研究人员和评估结果的人员均未被告知分组情况。主要终点是总生存期，按意向治疗进行分析。安全性分析包括所有接受过至少一个疗程化疗的患者，手术并发症分析包括接受过手术的患者。该研究已在日本临床试验注册中心（Japan Registry of Clinical Trials）注册，编号为 jRCTs031180202，试验已完成。
A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group.
2012年12月5日至2018年7月20日期间，共随机分配了601名患者（男性529人，女性72人），其中NeoCF组199人，NeoCF+D组202人，NeoCF+RT组200人。与NeoCF组相比，在中位随访期50-7个月（IQR 23.8-70.7）期间，NeoCF+D组的3年总生存率显著更高（72.1% [95% CI 65.4-77.8] vs 62.6% [55.5-68.9]；危险比[HR] 0.68，95% CI 0.50-0.92；P=0.006），而新CF+RT组则没有（68.3% [61.3-74.3]；HR 0.84，0.63-1.12；P=0.12）。在193例新辅助治疗组患者中，有2例（1%）发生了3级或3级以上发热性中性粒细胞减少症；在196例新辅助治疗组患者中，有32例（16%）发生了3级或3级以上发热性中性粒细胞减少症；在191例新辅助治疗组患者中，有9例（5%）发生了3级或3级以上发热性中性粒细胞减少症。导致终止新辅助治疗的治疗相关不良事件在NeoCF+D组（202名参与者中有18名[9%]）比在NeoCF+RT组（200名参与者中有12名[6%]）和NeoCF组（199名参与者中有8名[4%]）更常见。在新辅助治疗期间，NeoCF 组有 3 例（2%）治疗相关死亡病例，NeoCF+D 组有 4 例（2%）死亡病例，NeoCF+RT 组有 2 例（1%）死亡病例。据报道，在185例患者中，NeoCF组分别有19例（10%）、19例（10%）和28例（15%）患者出现术后2级或2级以上肺炎、吻合口漏和喉返神经麻痹；在183例患者中，NeoCF+D组分别有18例（10%）、16例（9%）和19例（10%）患者出现术后2级或2级以上肺炎、吻合口漏和喉返神经麻痹；在178例患者中，NeoCF+RT组分别有23例（13%）、23例（13%）和17例（10%）患者出现术后2级或2级以上肺炎、吻合口漏和喉返神经麻痹。手术后的院内死亡病例包括：NeoCF 组 3 例死亡，NeoCF+D 组 2 例死亡，NeoCF+RT 组 1 例死亡。
Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy.
与双联化疗相比，新辅助三联化疗后进行食道切除术可显著提高总生存率，这可能是日本治疗局部晚期OSCC的新标准。与双联化疗相比，新辅助双联化疗加放疗对生存率的改善并不明显。
