Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Lancet. 2024 Jul 6;404(10447):55-66. doi: 10.1016/S0140-6736(24)00745-1. Epub 2024 Jun 11.
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.
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/m per day intravenously on days 1-5] and cisplatin [80 mg/m per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m per day on days 1-5], cisplatin [70 mg/m per day on day 1], and docetaxel [70 mg/m per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m per day on days 1-4] and cisplatin [75 mg/m 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.
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.
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.
Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.
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，预后仍然较差，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在未经治疗的局部晚期 OSCC 患者中的疗效和安全性。
在这项随机、开放标签、III 期临床试验中，从日本 44 个中心招募了年龄在 20-75 岁之间、未经治疗的局部晚期 OSCC 和东部合作肿瘤学组体能状态 0 或 1 的患者。患者通过基于网络的系统进行 1:1:1 随机分组，分别接受新辅助双联化疗（两个疗程的氟尿嘧啶[800mg/m 每日静脉滴注，第 1-5 天]和顺铂[80mg/m 每日，第 1 天]，间隔 3 周[NeoCF]）、三联化疗（三个疗程的氟尿嘧啶[750mg/m 每日静脉滴注，第 1-5 天]、顺铂[70mg/m 每日]和多西紫杉醇[70mg/m 每日]，每 3 周重复[NeoCF+D]）或双联化疗（两个疗程的氟尿嘧啶[1000mg/m 每日静脉滴注，第 1-4 天]和顺铂[75mg/m 每日]，间隔 4 周）加 41.4Gy 放疗[NeoCF+RT]），然后行食管切除术和区域淋巴结清扫。随机分组按 T 分期和机构分层。参与者、研究者和评估结局的人员对分组情况不知情。主要终点是总生存，采用意向治疗进行分析。安全性分析包括接受至少一个疗程化疗的所有患者，手术并发症分析包括接受手术的患者。本研究在日本临床试验注册中心（jRCTs031180202）注册，试验已完成。
2012 年 12 月 5 日至 2018 年 7 月 20 日期间，共有 601 名患者（529 名男性和 72 名女性）被随机分组，其中 199 名患者接受 NeoCF 治疗，202 名患者接受 NeoCF+D 治疗，200 名患者接受 NeoCF+RT 治疗。与 NeoCF 组相比，中位随访 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]；风险比[HR]0.68，95%CI 0.50-0.92；p=0.006），但 NeoCF+RT 组差异无统计学意义（68.3%[61.3-74.3]；HR 0.84，95%CI 0.63-1.12；p=0.12）。NeoCF 组 193 名患者中有 2 名（1%）发生 3 级或以上发热性中性粒细胞减少症，NeoCF+D 组 196 名患者中有 32 名（16%），NeoCF+RT 组 191 名患者中有 9 名（5%）。NeoCF+D 组（18[9%]例）比 NeoCF+RT 组（12[6%]例）和 NeoCF 组（8[4%]例）更常见与新辅助治疗相关的治疗相关不良事件导致治疗终止。NeoCF 组有 3 例（2%）治疗相关死亡，NeoCF+D 组有 4 例（2%），NeoCF+RT 组有 2 例（1%）。NeoCF 组有 19 例（10%）、19 例（10%）和 28 例（15%）患者分别发生 2 级或以上术后肺炎、吻合口漏和喉返神经麻痹，NeoCF+D 组分别有 18 例（10%）、16 例（9%）和 19 例（10%），NeoCF+RT 组分别有 23 例（13%）、23 例（13%）和 17 例（10%）。手术后院内死亡包括 NeoCF 组 3 例、NeoCF+D 组 2 例和 NeoCF+RT 组 1 例。
与双联化疗相比，新辅助三联化疗联合手术可显著提高总生存率，可能成为日本条件良好的局部晚期 OSCC 的新治疗标准。新辅助双联化疗加放疗与双联化疗相比，生存改善不显著。
日本医学研究与发展署和国家癌症中心研究与发展基金。
