新辅助PD-1抑制剂联合化疗与新辅助化疗治疗可切除Ⅲ期非小细胞肺癌的疗效比较

Comparison of the efficacy of neoadjuvant PD-1 inhibitors combined with chemotherapy and neoadjuvant chemotherapy for resectable stageⅢnon-small cell lung cancer

目的:比较新辅助PD-1抑制剂联合化疗与新辅助化疗治疗可切除Ⅲ期非小细胞肺癌(non-small cell lung cancer,NSCLC)的有效性与安全性,并探讨CD8^(+)和CD103^(+)肿瘤浸润淋巴细胞(tumor-infiltrating lymphocyte,TIL)在新辅助治疗中的作用。方法:回顾性分析2018年08月至2022年03月期间我院诊断为Ⅲ期NSCLC接受新辅助PD-1抑制剂联合化疗(PD-1+化疗组18例)或新辅助化疗(化疗组19例)治疗后进行手术的患者临床资料。比较两组的无病生存期(diseasefree survival,DFS)、客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)、病理缓解率以及药物相关不良反应。同时我们使用免疫组化实验技术检测接受新辅助PD-1抑制剂联合化疗方案患者的肺组织(MPR 6例,non-MPR 6例)中CD8^(+)和CD103^(+)TIL的数量,并分析其与疗效的相关性。结果:截至统计时间,PD-1+化疗组仅收集到1名患者出现疾病复发,因此还无法评估该组的中位DFS,化疗组收集到10名患者出现疾病复发,中位DFS为19.1个月。术前影像学评估,PD-1+化疗组ORR为83.3%,高于化疗组的52.6%,差异有统计学意义(P=0.046)。术后病理结果显示,PD-1+化疗组6名患者出现主要病理缓解(major pathological response,MPR),其中4名患者为病理完全缓解(pathological complete response,PCR),化疗组无病理缓解的患者,差异有统计学意义(P=0.021)。PD-1+化疗组不良反应发生率略高于化疗组,差异无统计学意义(P=0.138)。在免疫组化分析中,MPR患者手术切除的组织中CD8^(+)TIL、CD103^(+)TIL数量明显高于治疗前穿刺组织。与非MPR患者相比,MPR患者手术切除的组织中CD8^(+)TIL、CD103^(+)TIL数量更多。结论:相比新辅助化疗,新辅助PD-1抑制剂联合化疗治疗可切除Ⅲ期NSCLC具有更显著的疗效,可以明显提高患者的ORR、MPR以及PCR。CD8^(+)TIL、CD103^(+)TIL数量的动态改变,可能决定可切除Ⅲ期NSCLC患者接受新辅助PD-1抑制剂联合化疗治疗后的病理反应。

Objective:To compare the efficacy and safety of neoadjuvant PD-1 inhibitor combined with chemotherapy versus neoadjuvant chemotherapy for resectable stageⅢnon-small cell lung cancer(NSCLC)and to explore the role of CD8^(+)and CD103^(+)tumor-infiltrating lymphocytes(TIL)in neoadjuvant therapy.Methods:The clinical data of patients diagnosed with stageⅢNSCLC and treated with neoadjuvant PD-1 inhibitor+chemotherapy(18 cases in the PD-1+chemotherapy group)or neoadjuvant chemotherapy(19 cases in the chemotherapy group)followed by surgery at our hospital between August 2018 and March 2022 were retrospectively analyzed.The disease-free survival(DFS),objective response rate(ORR),disease control rate(DCR),pathological remission rate,and drugrelated adverse effects were compared between the two groups.We also used immunohistochemical experimental techniques to detect the number of CD8^(+)and CD103^(+)TILs in lung tissues from patients receiving neoadjuvant PD-1 inhibitor in combination with chemotherapy regimens(6 cases of MPR and 6 cases of non-MPR)and analyze its correlation with efficacy.Results:As of the time of counting,only 1 patient in the PD-1+chemotherapy group was collected to have a disease relapse,so it was not yet possible to assess the median DFS of this group,and 10 patients in the chemotherapy group were collected to have a disease relapse with a median DFS of 19.1 months.On preoperative imaging assessment,the ORR was 83.3%in the PD-1+chemotherapy group,higher than 52.6%in the chemotherapy group,with a statistically significant difference(P=0.046).The postoperative pathological results showed that the major pathological response(MPR)was 33.3%6 cases in the PD-1+chemotherapy group,among which,4 cases were pathological complete response(PCR),and there was no pathological remission in the chemotherapy group,with a statistically significant difference(P=0.021).The incidence of adverse reactions was slightly higher in the PD-1+chemotherapy group than in the chemotherapy group,and the difference was not statistically significant(P=0.138).In immunohistochemical analysis,the numbers of CD8^(+)TIL and CD103^(+)TIL were significantly higher in surgically excised tissues from MPR patients after treatment than in pre-treatment puncture tissues.The number of CD8^(+)TILs and CD103^(+)TILs was higher in surgically resected tissues from MPR patients compared to non-MPR patients.Conclusion:Compared with neoadjuvant chemotherapy,neoadjuvant PD-1 inhibitor combined with chemotherapy for resectable stageⅢNSCLC has more significant efficacy and can significantly improve patients'ORR,MPR,and PCR.Dynamic alterations in the numbers of CD8^(+)TIL,CD103^(+)TIL may determine the pathological response of patients with resectable stageⅢNSCLC treated with neoadjuvant PD-1 inhibitor combined with chemotherapy.