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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

Ken Kato, Ryunosuke Machida, Yoshinori Ito, Hiroyuki Daiko, Soji Ozawa, Takashi Ogata, Hiroki Hara, Takashi Kojima, Tetsuya Abe, Takeo Bamba, Masaya Watanabe, Hirofumi Kawakubo, Yuichi Shibuya, Yasuhiro Tsubosa, Naoki Takegawa, Takeshi Kajiwara, Hideo Baba, Masaki Ueno, Hiroya Takeuchi, Kenichi Nakamura, Yuko Kitagawa, on behalf of the JCOG1109 investigators*

Lancet June 11, 2024

Background: 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.

背景：新辅助治疗是局部晚期食管鳞癌(OSCC)患者的标准治疗方法。然而，预后仍然很差，可能需要更密集的新辅助治疗来改善患者的预后。因此，我们的目标是比较新辅助化疗、三联化疗和双联化疗加放射治疗在未经治疗的局部晚期食管鳞癌患者中的有效性和安全性。

METHODS: 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/m2 per 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.

方法：在这项随机、开放标签的3期试验中，从日本各地的44个中心招募了20-75岁的患者，这些患者以前没有接受过治疗，局部晚期食管鳞癌，东方合作肿瘤组的表现状态为0或1。患者通过网络系统被随机分配(1：1：1)接受新辅助双重化疗(两个疗程的氟尿嘧啶[第1-5天每天800 mg/m2静脉注射]和顺铂[第1天80 mg/m2每天静脉注射]，间隔3周[NeoCF])，三联化疗(3个疗程的氟尿嘧啶[第1-5天每天750 mg/m2]，顺铂[第1天每天70 mg/m2]，多西紫杉醇[第1天70 mg/m2每天]，每3周重复[NeoCF+D])，二联化疗(氟尿嘧啶1000 mg/m2，第1~4天；顺铂75 mg/m2，第1天，间隔4周)加放射治疗41·4Gy1~4d，食道切除加区域淋巴结清扫。随机分组按T分期和机构进行分层。参与者、调查人员和那些评估结果的人没有被小组分配所掩盖。主要终点是总体存活率，按治疗意向进行分析。安全性分析包括所有接受至少一个疗程化疗的患者，手术并发症分析包括接受手术的患者。这项研究已在日本临床试验登记处注册，jRCTs031180202，试验已经完成。

Findings: 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.

结果：在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)被随机分配，其中NeoCF组199例，NeoCF+D组202例，NeoCF+RT组200例。在中位随访期50·7个月(IQR 23·8~70·7)期间，NeoCF+D组的3年总生存率显著高于NeoCF组(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)，而NeoCF+RT组无显著差异(68·3%[61·3~74·3])；HR为0.84，0.63-1.12；P=0.12)。NeoCF组193例患者中有2例(1%)出现3级或更高程度的发热性中性粒细胞减少，NeoCF+D组196例患者中有32例(16%)，NeoCF+RT组191例患者中有9例(5%)发生发热性中性粒细胞减少。导致新辅助治疗终止的与治疗相关的不良事件在NeoCF+D组(202名参与者中有18例[9%])比NeoCF+RT组(200例中12例[6%])和NeoCF组(199例中8例[4%])更常见。在新辅助治疗期间，NeoCF组有3例(2%)与治疗相关的死亡，NeoCF+D组有4例(2%)死亡，NeoCF+RT组有2例(1%)死亡。术后肺炎、吻合口瘘和喉返神经麻痹发生率，NeoCF组分别为19例(10%)、19例(10%)和28例(15%)，NeoCF+D组分别为18例(10%)、16例(9%)和19例(10%)，NeoCF+RT组分别为23例(13%)、23例(13%)和17例(10%)。手术后院内死亡包括NeoCF组3例死亡，NeoCF+D组2例死亡，NeoCF+RT组1例死亡。

Interpretation: 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.

结论：与双药新辅助化疗相比，新辅助三联化疗和食道切除术后的总体存活率在统计学上显著提高，可能成为日本身体状况良好的局部晚期食管鳞癌患者的新护理标准。与新辅助化疗加放疗相比，新辅助化疗并未显示出明显的生存改善。

目录

1. INTRODUCTION

2. METHODS

    2.1 Patients

    2.2 TRIAL DESIGN AND TREATMENTS (Fig. S1)

    2.3 OUTCOMES AND ASSESSMENTS

    2.4 TRIAL OVERSIGHT

    2.4 Statistical Analysis

3. Results

    3.1 PATIENTS AND TREATMENT SUMMARY (Fig. S2)(Table 1 and Table S1-3)(Fig. S3)(Table S4-5)

    3.2 EFFICACY (Fig. 1)(Fig. S4-8)(Fig. 2)(Fig. S9)(Table S6)(Fig. 3A)(Fig. S10-11)

    3.3 PATIENT-REPORTED OUTCOMES (Fig. 3B)(Table S7)

    3.4 SAFETY AND SURGICAL COMPLICATIONS (Table 2)(Table S8)

4. Discussion

— 图表汇总—

3. Results

Figure 1: Trial profile

NeoCF=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin. NeoCF+D=neoadjuvant triplet chemotherapy consisting of fluorouracil, cisplatin, and docetaxel. NeoCF+RT=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin with radiotherapy.

Supplementary Table S2. Surgical outcomes 

*Proportions included 2 missing values for doublet chemotherapy, 2 for triplet chemotherapy, and 1 for doublet chemotherapy plus radiotherapy. 

**Excluding 2 missing values for doublet chemotherapy, 2 for triplet chemotherapy, and 1 for doublet chemotherapy plus radiotherapy. LN, lymph node; NeoCF, neoadjuvant doublet chemotherapy consisting of 5-fluorouracil and cisplatin; NeoCF+D, triplet chemotherapy consisting of 5-fluorouracil, cisplatin, and docetaxel; NeoCF+RT, doublet chemotherapy consisting of 5-fluorouracil and cisplatin with radiotherapy 

Figure 2. Overall survival and progression-free survival in the intention-to-treat population

Comparison of Kaplan–Meier estimates of (A) overall survival and (B) progression-free survival (as assessed by investigators) in the intention-to-treat population for the NeoCF+D group and the NeoCF group. Symbols indicate censored data. Comparison of Kaplan–Meier estimates of (C) overall survival and (D) progression-free survival (as assessed by investigators) in the intention-to-treat population for the NeoCF+RT group and the NeoCF group. Symbols indicate censored data. HR=hazard ratio. NE=not estimable. NeoCF=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin. NeoCF+D=neoadjuvant triplet chemotherapy consisting of fluorouracil, cisplatin, and docetaxel. NeoCF+RT=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin with radiotherapy. NR=not reached.

Supplementary Table S3. Efficacy of neoadjuvant treatment 

The response to neoadjuvant treatment was evaluated in patients with a measurable lesion using the modified RECIST version 1.1 with the following definitions. Lymph node disease was defined as a short diameter of ≥10 mm and evaluated as a target lesion; those with a short diameter <10 mm or ≥5 mm was defined as non-target lesions if they were clinically judged to have metastasis and those clinically diagnosed as having no metastasis were not defined as lesions. Lesions <5 mm in short diameter were not considered to be lesions. CI, confidence interval; NeoCF, neoadjuvant doublet chemotherapy consisting of 5-fluorouracil and cisplatin; NeoCF+D, triplet chemotherapy consisting of 5-fluorouracil, cisplatin, and docetaxel; NeoCF+RT, doublet chemotherapy consisting of 5-fluorouracil and cisplatin with radiotherapy; TNM, Tumor-Node-Metastasis; UICC, International Union for Cancer Control 

Histologic grade of the primary site was defined according to the 11th edition of the Japanese Classification of Esophageal Cancer. Proportions included 2 missing values for doublet chemotherapy, 2 for triplet chemotherapy, and 1 for doublet chemotherapy plus radiotherapy. The data were missing for 13 patients (no resection 10, ineligible 3) in the NeoCF group, 19 patients (no resection 17, ineligible 2) in the NeoCF+D group, and 23 patients (no resection 22, ineligible 1) in the NeoCF+RT group who did not undergo surgery as per the protocol treatment. NeoCF, neoadjuvant doublet chemotherapy consisting of 5-fluorouracil and cisplatin; NeoCF+D, triplet chemotherapy consisting of 5-fluorouracil, cisplatin, and docetaxel; NeoCF+RT, doublet chemotherapy consisting of 5-fluorouracil and cisplatin with radiotherapy; TNM, Tumor-Node-Metastasis; UICC, International Union for Cancer Control. 

Supplementary Figure S1. Comparison of overall survival between the NeoCF+D to NeoCF+RT arms. 

Figure 3. Overall survival and progression-free survival in the total enrolled population according to treatment group

Comparison of (A) overall survival and (B) progression-free survival between the NeoCF+D and NeoCF+RT groups and the NeoCF group. The forest plot HR and 95% CI data are provided in the appendix (pp 25–27). HR=hazard ratio. LT=lower thoracic primary. MT=middle thoracic primary. NeoCF=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin. NeoCF+D=neoadjuvant triplet chemotherapy consisting of fluorouracil, cisplatin, and docetaxel. NeoCF+RT=neoadjuvant doublet chemotherapy consisting of fluorouracil and cisplatin with radiotherapy. OS=overall survival. PFS=progression-free survival. ECOG PS=Eastern Cooperative Oncology Group performance status. SCC=squamous cell carcinoma. UT=Upper thoracic primary.

Supplementary Table S4. Long-term outcomes 

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