循环肿瘤细胞用于监测非小细胞肺癌新辅助免疫综合治疗疗效的临床研究

Clinical study of circulating tumor cells in monitoring the efficacy of neoadjuvant immunotherapy for non-small cell lung cancer

目的:探讨非小细胞肺癌(NSCLC)新辅助免疫综合治疗过程中循环肿瘤细胞(CTCs)变化以及其与临床疗效的相关性。方法:采用回顾性病例对照研究,收集2018年6月至2019年12月在湘雅三医院接受新辅助免疫综合治疗后进行手术治疗的23例晚期NSCLC患者的资料,年龄范围35~76岁,中位数年龄52岁,其中男性患者13例,女性患者10例。针对患者的治疗前、新辅助免疫综合治疗后手术前以及手术后的CTCs值、实体瘤疗效评价标准(RECIST)评价结果以及术后病理组织病理缓解(MPR)结果进行分析,并对不同RESICT结果和MPR结果的CTCs进行比较。采用 SPSS21.0统计软件,CTC数量不符合正态分布,计量资料以中位数(四分位数间距)表示,两组间比较用Mann-Whitney U检验,关联样本比较采用Wilcoxon检验,多样本间比较用Kruskal-Wallis检验。 结果:CTCs值与肿瘤的分期呈正相关,即Ⅱb组CTCs值为10.69(3.87)FU/3 ml,Ⅲa组为12.90(2.24)FU/3 ml,Ⅲb组为16.04(3.43)FU/3 ml,组间比较差异有统计学意义(χ^(2)=7.829, P=0.020)。治疗前CTCs值为12.90(3.82)FU/3 ml,新辅助免疫综合治疗后CTCs下降为7.60(4.79)FU/3 ml( Z=4.197, P=0.000),肺癌根治手术后CTCs值下降为6.22(2.80)FU/3 ml( Z=-2.950, P=0.005)。RECIST结果中,治疗前CR组CTCs值为12.90(3.79)FU/3 ml,PR组为12.52(3.96)FU/3 ml,SD组为13.58(5.11)FU/3 ml,组间比较无统计学差异(χ^(2)=1.806, P=0.405);新辅助免疫综合治疗后,与治疗前相比,CR组CTCs值下降为6.22(3.87)FU/3 ml( Z=-4.950, P=0.000),PR组下降为7.32(4.31)FU/3 ml( Z=-3.180, P=0.001),SD组下降为11.19(4.37)FU/3 ml( Z=-2.023, P=0.043),但治疗后CR组和PR组无统计学差异( Z=-0.838, P=0.402)而SD组与CR/PR组差异有统计学意义( Z=-1.922, P=0.050);肺癌根治术后,CR组和PR组的CTCs值分别下降为6.09(3.43)FU/3 ml 和6.40(1.82)FU/3 ml,与术前相比差异无统计学意义( Z=-0.764, P=0.619;Z=-2.411, P=0.160),但SD组下降为9.20(5.16)FU/3 ml,差异有统计学意义( Z=-2.023, P=0.043);术后CR组和PR组差异无统计学意义( Z=-1.134, P=0.257),SD组与CR/PR组差异有统计学意义( Z=-1.624, P=0.014)。MPR结果中,治疗前MPR组和非MPR组的CTCs值为11.98(4.14)FU/3 ml和13.54(4.76)FU/3 ml,组间差异无统计学意义( Z=-1.354, P=0.176);新辅助免疫综合治疗后,MPR组和非MPR组CTCs值分别下降为6.36(2.65)FU/3 ml和10.88(2.80)FU/3 ml,与治疗前相比差异有统计学意义( Z=-2.934, P=0.001;Z=-2.840, P=0.003),并且两组间比较差异有统计学意义( Z=-3.693, P=0.000),以及两组治疗前后CTCs变化值差异也具有统计学意义( Z=-2.770, P=0.006);肺癌根治术后,MPR组CTCs值下降为5.40(1.33)FU/3 ml,与术前相比差异无统计学意义( Z=-0.533, P=0.594);非MPR组CTCs值下降为7.05(3.80)FU/3 ml,与术前相比差异有统计学意义( Z=-2.734, P=0.030);术后两组间比较差异有统计学意义( Z=-1.900, P=0.011)。 结论:CTCs值与NSCLC新辅助免疫综合治疗的疗效(RESICT和MPR)呈负相关,可能用于临床NSCLC新辅助免疫综合治疗疗效的评价。

Objective To investigate the changes of CTCs and the correlation between the changes of CTCs and the clinical efficacy of neoadjuvant immunotherapy for non-small cell lung cancer(NSCLC).Methods A retrospective case-control study was conducted to collect the data of 23 patients with NSCLC who received neoadjuvant immunotherapy in the Third Xiangya Hospital from June 2018 to December 2019.They were 35-76 years old with a median age of 52 years old,including 13 male patients and 10 female patients.The CTCs value,evaluation results from response evaluation criteria in solid tumor(RECIST)and major pathological response were evaluated before treatment,after neoadjuvant immunotherapy and after operation.Mann Whitney U test was used for the comparison between the two groups,Wilcoxon test was used for the comparison of association samples,and Kruskal Wallis test was used for the comparison between multiple samples.Results The CTCs value was positively correlated with tumor progression,that the CTCs value ofⅡB group,ⅢA group andⅢB group was 10.69(3.87)FU/3 ml,12.90(2.24)FU/3 ml and 16.04(3.43)FU/3 ml,and the difference was statistically significant(χ^(2)=7.829,P=0.020).Then CTCs decreased to 7.60(4.79)FU/3 ml significantly(Z=4.197,P=0.000),and decreased to 6.22(2.80)FU/3 ml significantly again after surgery(Z=-2.950,P=0.005).In RECIST results,the CTCs value of CR group,PR group and SD group was 12.90(3.79)FU/3 ml,12.52(3.96)FU/3 ml and 13.58(5.11)FU/3 ml,and no significant difference before treatment(χ2=1.806,P=0.405).After neoadjuvant immunotherapy,the CTCs of CR group decreased to 6.22(3.87)FU/3 ml significantly(Z=-4.950,P=0.000),and also PR group to7.32(4.31)FU/3 ml(Z=-3.180,P=0.001)or SD group to(Z=-2.023,P=0.043).There was no significant difference between CR group and PR group(Z=-0.838,P=0.402),but significant difference between SD group and CR/PR group(Z=-1.922,P=0.050).After operation,the CTCs of CR,PR and SD group decreased to 6.09(3.43)FU/3 ml,6.40(1.82)FU/3 ml and 9.20(5.16)FU/3 ml,and there was no significant difference to preparation in CR group and PR group,but significant difference in SD group(Z=-2.023,P=0.043).There was no significant difference between CR group and PR group(Z=-1.134,P=0.257),but significant difference between SD group and CR/PR group(Z=-1.624,P=0.014).Before treatment,CTCs of MPR group and non-MPR group were 11.98(4.14)FU/3 ml and 13.54(4.76)FU/3 ml,and there was no significant difference between them(Z=-1.354,P=0.176).After neoadjuvant immunotherapy,the CTCs of MPR group decreased to 6.36(2.65)FU/3 ml significantly(Z=-2.934,P=0.001)and also in non-MPR group to 10.88(2.80)FU/3 ml(Z=-2.840,P=0.003);but there was significant difference between MPR group and non-MPR group(Z=-3.693,P=0.000),and also the change of CTCs between two groups(Z=-2.770,P=0.006).After operation,the CTCs of MPR group decreased to 5.40(1.33)FU/3 ml insignificantly(Z=-0.533,P=0.594)but significantly to 7.05(3.80)FU/3 ml in non-MPR group(Z=-2.734,P=0.030),and significant difference between them(Z=-1.900,P=0.011).Conclusion The value of CTCs is negatively correlated with the efficacy(RECIST and MPR)of neoadjuvant immunotherapy for NSCLC,which can be used for clinical efficacy evaluation of neoadjuvant immunotherapy.