基于真实世界数据的食管鳞癌在新辅助治疗联合PD-1/PD-L1抑制剂的安全性及疗效分析

Safety and efficacy analysis of neoadjuvant therapy for esophageal squamous cell carcinoma combined with PD-1/PD-L1 inhibitors based on real-world data

目的:免疫检查点抑制剂联合化疗在食管癌的治疗中具有较好的疗效,然而免疫治疗在局部晚期食管癌围手术期的应用尚缺乏共识。本研究通过分析真实世界的数据,为免疫检查点抑制剂在食管癌新辅助治疗中的临床应用提供借鉴和依据。方法:本研究分析2020年3月至2021年8月就诊于河北医科大学第四医院,经病理证实为食管鳞癌的局部晚期患者,经评估建议行新辅助治疗联合免疫检查点抑制剂,后接受规范的食管癌根治手术,共纳入患者152例。观察终点为病理完全缓解(pathologic complete response,pCR)率,主要病理缓解(major pathologic response,MPR)率,显微镜下无残留(R0)切除率、术后并发症、肿瘤退缩分级、无病生存(disease-free survival,DFS)率,并探索最优的新辅助化免联合治疗的周期数。结果:R0切除94.1%(143/152),术后病理评估发现按照美国病理学家协会(CAP)肿瘤退缩分级标准,0级、1级、2级、3级的比例分别为29.6%、11.2%、25.7%、33.5%;pCR率25%。16.4%出现新辅助治疗相关不良反应;术后降期率62.5%。术后并发症:90天术后死亡率为0,发生术后并发症25%,吻合口瘘的发生率7.8%,肺炎发生率9.2%。术前免疫周期数为2~3次的患者,术后病理类型为CAP分级0~2级的占比92.1%,而其他周期数的患者术后病理类型为CAP分级0~2级的占比7.9%(P=0.007)。全组患者中位随访时间16.4(15.0~7.8)个月,1年DFS率96.7%,2年DFS率87.5%。结论:程序性细胞死亡因子-1/配体-1(programmed death-1/programmed cell death-ligand 1,PD-1/PD-L1)抑制剂在局部晚期食管鳞癌患者的新辅助治疗中安全可行,R0切除率满意,pCR率满意,新辅助化疗联合免疫检查点抑制剂治疗明显达到降期的目的。多数患者术后治疗受限,建议辅助治疗尽可能放到术前。术前2~3个周期患者可能有更高的病理缓解率。

Objective:While immune checkpoint inhibitors combined with chemotherapy have displayed good efficacy in esophageal cancer treatment,to date,no consensus on the application of immunotherapy in the perioperative phase of locally advanced esophageal cancer has been achieved.This study provides a reference and basis for the clinical application of immune checkpoint inhibitors in the neoadjuvant treatment of esophageal cancer by analyzing accumulated patient data.Methods This study collected locally advanced patients with esophageal squamous cell carcinoma who were diagnosed by pathology at The Fourth Hospital of Hebei Medical University from March 2020 to August 2021.After evaluation,it was recommended to undergo neoadjuvant therapy combined with immune checkpoint inhibitors,and then undergo standardized esophageal cancer radical surgery.A total of 152 patients were included.The observed endpoints were pathologic complete response(pCR)rate,major pathologic response(MPR)rate,R0 resection rate,postoperative complications,tumor regression grade,and disease-free survival(DFS)rate.The optimal number of cycles of neoadjuvant combination therapy was explored.Results:A total of 152 patients were enrolled in this study.R0 resection was performed in 143 patients(94.1%),and postoperative pathological evaluation revealed pCR in 45 patients(29.6%).The respective percentages of patients with College of American Pathologists(CAP)grades 0,1,2,and 3 were 29.6%,11.2%,25.7%,and 33.5%.pCR was 25%,and 16.4%developed neoadjuvant therapy-related adverse events.The postoperative downstaging rate was 62.5%.No deaths occurred within 90 days after surgery,and postoperative complications occurred in 25%,including anastomotic fistula 7.8%and pneumonia 9.2%.The proportion of patients with CAP grade 0~2 after surgery was 92.1%in patients with 2~3 immune-cycles before surgery,while 7.9%in patients with other immune-cycles(P=0.007).The median follow-up time for the whole group was 16.4(15.0-17.8)months,with a 1-year DFS rate of 96.7%and a 2-year DFS rate of 87.5%.Conclusions:PD-1/PD-L1 inhibitors are safe,and neoadjuvant treatment is feasible for patients with locally advanced esophageal squamous cell carcinoma with satisfactory R0 resection and pCR rates.Neoadjuvant chemotherapy,in combination with immune checkpoint inhibitor therapy,achieves stage reduction.Postoperative treatment is limited in most patients,and it is recommended that adjuvant therapy be placed preoperatively when possible.Patients with 2~3 preoperative cycles seem to achieve higher rates of pathological remission.