基于真实世界数据的Ⅲ期胃癌免疫检查点抑制剂联合辅助化疗的中期疗效回顾性研究

Enhancing survival outcomes in stageⅢgastric/esophagogastric junction cancer:a retrospective study of immune checkpoint inhibitors and adjuvant chemotherapy based on real-world data

目的探讨免疫检查点抑制剂联合辅助化疗对Ⅲ期胃癌和食管胃结合部癌患者的疗效。方法本研究采用回顾性队列研究方法,基于真实世界的数据,分析2020年1月至2023年12月期间在中山大学肿瘤防治中心胃外科手术并接受术后辅助治疗的403例Ⅲ期胃癌和食管胃结合部癌患者的临床资料,其中ⅢA期患者147例(36.5%),ⅢB期患者130例(32.3%),ⅢC期患者126例(31.3%);人表皮生长因子受体-2(HER-2)阳性患者15例(3.7%);错配修复缺失(dMMR)患者25例(6.2%);EB病毒编码RNA(EBER)阳性患者22例(5.5%)。根据其治疗方案分为免疫抑制剂联合辅助化疗组(免疫治疗组,110例,男性71例,女性39例,中位年龄59岁)和单纯辅助化疗组(单纯化疗组,293例,男性186例,女性107例,中位年龄60岁)。免疫治疗组使用的免疫治疗药物均为程序性细胞死亡蛋白-1(PD-1)及其配体(PD-L1)免疫检查点抑制剂(包括替雷丽珠单抗85例、信迪利单抗10例、特瑞普利单抗8例、纳武利尤单抗4例,卡瑞丽珠单抗2例、帕博丽珠单抗1例);单纯化疗组采用辅助化疗方案包括SOX方案[奥沙利铂+替吉奥(S-1)]132例、XELOX(卡培他滨和奥沙利铂)102例、S-1单药方案44例、其他方案15例。比较两组的3年无病生存率(DFS),并对不同年龄、分子表型、pTNM分期、淋巴结外浸润及肿瘤长径进行亚组分析。结果中位随访20.5(3.1~46.3)个月,全组403例患者3年总体DFS为61.4%,免疫治疗组的3年DFS为82.7%,优于单纯化疗组(58.8%),差异具有统计学意义(P=0.021);多因素分析显示,术后接受免疫治疗是本组患者DFS的保护性因素(HR=0.352,95%CI:0.180~0.685)。亚组分析显示,ⅢC期(HR=0.416,95%CI:0.184~0.940)、年龄≥60岁(HR=0.336,95%CI:0.121~0.934)、淋巴结结外浸润阳性(HR=0.378,95%CI:0.170~0.839)的患者可从免疫联合辅助化疗中获益(均P<0.05)。而在不同MMR状态、HER-2和EBER等亚组中,免疫联合辅助化疗的获益并未显示出统计学意义(均P>0.05)。结论在真实世界状态下,Ⅲ期胃癌及食管胃结合部癌患者或可从术后免疫检查点抑制剂联合辅助化疗中获益。

Objective To explore the efficacy of immune checkpoint inhibitors combined with adjuvant chemotherapy in patients with phase Ill gastric cancer and esophagogastric junction cancer Methods This study used a retrospective cohort study method based on real-world data.Clinical data of 403 patients with stageⅢgastric/esophagogastric junction cancer who underwent gastrectomy followed by adjuvant therapy in the Department of Gastric Surgery at Sun Yat-sen University Cancer Center from January 2020 to December 2023 were retrospectively collected.The study cohort comprised 147(36.5%)patients with stageⅢA,130(32.3%)with stage IIB,and 126(31.3%)with stageⅢC gastric/esophagogastric junction cancer.Of them,15(3.7%)were HER-2 positive,25(6.2%)dMMR,and 22(5.5%)patients Epstein-Barr virus encoding RNA(EBER)positive.Based on treatment plans,the patients were divided into immune checkpoint inhibitor combined with chemotherapy group(immune therapy group,n=110,71 males and 39 females,median age 59 years old)and chemotherapy alone group(chemotherapy group,n=293,186 males and 107 females,median age 60 years old).All patients in the immunotherapy group received immune checkpoint inhibitors targeting the programmed cell death protein-1(PD-1)and its ligand(PD-L1).Of them,85 received pembrolizumab,10 received sintilimab,8 received tislelizumab,4 received camrelizumab,2 received toripalimab,and 1 received pabocizumab.The adjuvant chemotherapy regimens used among the chemotherapy alone group includes Sox regimen(132 cases),XELOX(102 cases),S-1 monotherapy(44 cases),and other regimens(15 cases).The 3-year DFS rate of the two groups was compared,and subgroup analysis was conducted based on different ages,molecular phenotypes,pTNM staging,extranodal infiltration,and tumor length.Results The median follow-up was 20.5 months(range 3.1~46.3),with a 3-year overall DFS rate of 61.4%for the entire 403 patients.The 3-year DFS rate for the immunotherapy group was 82.7%,higher than the chemotherapy alone group(58.8%),with a statistically significant difference(P=0.021).Multivariate analysis showed that postoperative immunotherapy was a protective factor for DFS(HR=0.352,95%CI:0.180~0.685).Subgroup analysis showed that stageⅢC(HR=0.416,95%CI:0.184~0.940),aged≥60 years(HR=0.336,95%CI:0.121~0.934)and extranodal invasion(HR=0.378,95%Cl:0.170~0.839)were associated with benefit from the combined immune adjuvant chemotherapy,while no association was observed for MMR,HER-2 or EBER status.Conclusion StageⅢgastric/esophagogastric junction cancer patients may benefite from postoperative immune checkpoint inhibitor combined with adjuvant chemotherapy in real-world settings.