淋巴细胞_单核细胞比值及其动态变化与PD-1抑制剂治疗晚期非小细胞肺癌的疗效分析.pdf

药物治疗学摘要目的：探讨PD-1抑制剂治疗前外周血淋巴细胞和单核细胞比值（lymphocyte-to-monocytesratios，LMR）及治疗后的动态变化与PD-1抑制剂治疗晚期非小细胞肺癌患者（non-small cell lungcancer，NSCLC）疗效及预后的关系。方法：回顾性分析芜湖市第二人民医院肿瘤内科、肿瘤放疗科及肿瘤介入科自2019年6月至2022年7月收治的83例晚期NSCLC患者的临床病例资料。收集所有患者治疗前及治疗后的血常规 LMR 数值，根据ROC曲线计算临界值，并将LMR分为治疗前和治疗后高低两组。分析比较各组患者的客观缓解率（ORR）、疾病控制率（DCR），以及无进展生存期（progression-free survival，PFS）、总生存期（overallsurvival，OS）的差异，分析LMR值及治疗后的动态变化对PD-1抑制剂治疗NSCLC患者疗效及预后的价值。结果：根据 ROC 曲线计算 LMR 临界值为1.8，将 LMR 分为基线低 LMR 组（LMRB/S1.8）、高LMR 组（LMRB/S1.8）及治疗后低 LMR 组（LMRafter1.8）、治疗后高 LMR 组（LMRafter1.8）。治疗前高LMRB/S组免疫治疗后的ORR和DCR均高于低LM-RB/S组（P=0.037；P=0.002 5）。治疗前低LMRB/S患者中，在治疗后LMRafter1.8组的DCR优于LMRafter1.8组（P=0.005）。治疗前高LMR患者中，治疗后LM-Rafter1.8 组的 DCR 优于 LMRafter1.8 组（P=0.034）。Kaplan-Meier分析显示，治疗前高LMRB/S组的PFS、OS均比低LMRB/S组延长；且在治疗前低LMRB/S组中，治疗后LMRafter1.8的患者PFS、OS均比LMRafter3分；（2）合并有免疫系统疾病；（3）合并心肺功能不全。共计纳入83例患者进入本项研究。1.2疗效评价根据WHO实体瘤疗效评定标准，分为完全缓解（CR）、部分缓解（PR）、疾病稳定（SD）和疾病进展（PD）。CR+PR率为客观缓解率（ORR），CR+PR+SD 率为疾病控制率（DCR）。无进展生存期（progression-free survival，PFS）定义为从首次抗PD-1 治疗到因任何原因出现疾病进展或死亡的时间；总生存期（overall survival，OS）定义为首次开始抗PD-1 治疗到任何原因出现死亡的时间。1.3随访通过查阅患者住院病历、门诊病历、影像资料以及电话随访等方式对所有患者进行定期随访。随访内容包括患者肿瘤的治疗情况以及预后生存情况。随访时间截至2023年6月30日，随访过程中若出现失访，则末次随访时间为终点时间。1.4统计学分析采用SPSS 22.0 软件对数据进行统计学分析。建立患者工作特征（ROC）曲线，计算并记录ROC曲线下面积（AUC）并定义了对于生存价值的最佳临界值12-13。基于LMR临界值，将患者分为治疗前高 LMRB/S组（LMRB/S1.8）和低LMRB/S组（LMRB/S1.8），以及治疗后低 LMRafter组（LMRafter1.8）和高 LMRafter组（LMRafter1.8）。计数资料采用率（%）进行描述统计，组间比较采用2检验进行统计推断。生存分析采用Kaplan-Meier法，各组间生存率比较采用Log-rank检验。采用单因素和多因素 Cox 回归模型分析进行风险比（HR）估算。P0.05为差异具有统计学意义。2结果2.1患者基线特征研究共收集83例应用PD-1治疗的 NSCLC 患者，患者中位年龄 65（3782）岁，60岁50例，60岁33例，男性58例，女性25例，其中鳞癌40例，腺癌43例，LMRB/S1.8 54例，LMRB/S1.8 29例，见Tab.1。Tab.1Baseline characteristics of 83 patients(n,%)IndicatorSexAgePathologyStageSmokingECOGLMRB/SCharacteristicsMaleFemale6060LUADLUSCBYesNo0-12LMR1.8LMR1.8N(n=83)5825335043402261384534492954Ratio(%)69.930.129.760.251.848.226.573.545.854.241.059.034.965.1ECOG:Eastern Cooperative Oncology Group;LMR:lymphocyte-to-monocytes ratios;LUAD:lung adenocarcinoma;LUSC:lungsquamous carcinoma.570中国临床药理学与治疗学 2024 May;29(5)2.2LMR最佳临界值根据患者生存状态绘制LMR的ROC曲线，计算并记录ROC AUC和95%置信区间（Fig.1）。根据ROC曲线和约登指数（Youdenindex），计算出LMR的最佳临界值为1.8，根据该临界值将患者分为治疗前高LMRB/S组（LMRB/S1.8）和低LMRB/S组（LMRB/S1.8），以及治疗后低LMRafter组（LMRafter1.8）和高LMRafter组（LMRafter1.8）。1.00.80.60.40.20.00.0 0.2 0.4 0.6 0.8 1.0ROC of LMRSensi?vityAUC=0.642(0.518-0.776)1-SpecificityFig.1ROC of lymphocyte-to-monocytes ratios(LMR)2.3LMR与治疗疗效的关系83例患者经PD-1抑制剂治疗后，12例患者（14.5%）获PR，44例患者（53.0%）达到 SD，27 例患者（32.5%）发生 PD，ORR 12例（14.5%），DCR 56例（67.5%），见Tab.2。高 LMRB/S组的 ORR 和 DCR 分别为 20.4%和75.9%，低 LMRB/S组治疗后的 ORR 和 DCR 分别为3.4%和51.7%，分析显示高LMRB/S组的ORR和DCR均高于低LMRB/S组（2=0.229，P=0.037；2=5.035，P=0.002 5），见Tab.3。Tab.2Efficacy of PD-1 inhibitor treatment in patientsIndicatorCRPRSDPDORRDCRn01244271256Ration(%)0.014.553.032.514.567.5CR:complete response;PR:partial response;SD:stable disease;PD:progressive disease;ORR:objective response rate;DCR:dis-ease control rate.Tab.3The relationship between LMRB/Svalue and the efficacy of PD-1 inhibitorsLMRB/S1.81.8n2954ORRn111%3.420.420.229P0.037DCRn1541%51.775.925.035P0.0025LMR:lymphocyte-to-monocytes ratios;ORR:objective response rate;DCR:disease control rate.2.4治疗前后 LMR 的变化与治疗疗效的关系为了分析治疗前后LMR值的变化与治疗疗效的关系，分别统计治疗前54例高LMRB/S患者及治疗前29例低LMRB/S患者中，治疗后LMR值的变化对其疗效的影响。结果显示治疗前低LMRB/S患者中，在治疗后 LMRafter1.8 的患者有 16 例，LM-Rafter1.8 的患者有 13 例，LMRafter1.8 组的 DCR 优于 LMRafter1.8 组（2=7.744，P=0.005）。治疗前高LMR 患者中，在治疗后 LMRafter1.8 的患者有 44例，LMRafter1.8 的患者有 10 例，LMRafter1.8 组的DCR 优 于 LMRafter1.8 组（2=4.153，P=0.034），见Tab.4。Tab.4The relationship between LMRaftervalue and the efficacy of PD-1 inhibitorsLMRB/S1.81.8LMRafer1.81.81.81.8n13161044ORRn01110%0.06.310.022.720.1730.123P0.3590.367DCRn312536%23.175.050.081.827.7444.153P0.0050.034LMR:lymphocyte-to-monocytes ratios;ORR:objective response rate;DCR:disease control rate.571Chin J Clin Pharmacol Ther 2024 May;29(5)2.5LMR与患者PFS、OS的关系Kaplan-Meier分析显示，基线高LMRB/S组中位PFS、OS均高于低LMRB/S组（14个月vs.6 个月，P=0.004；26个月vs.15个月，P=0.011），见Fig.2A-B。分析治疗后LMR值对于患者生存状态的影响，如Fig.3A-B所示，在基线低LMRB/S组中，治疗后LMRafter1.8组的中位PFS、OS均高于LMRafter1.8组（10个月vs.5 个月，P=0.047；20个月vs.9个月，P=0.007）；如Fig.3C-D所示，在基线高LMRB/S组中，在治疗后LMRafter1.8组的中位PFS、OS与LMRafter1.8组无统计学差异（18个月vs.8个月，P=0.076；27个月vs.15个月，P=0.184）。单因素和多因素Cox回归分析显示，临床分期、ECOG评分、治疗前基线LMR水平是影响患者PFS和OS的独立预后因素。从Tab.5-6中可以看出，与高LMR值组相比，低LMR值组的PFS 95%CI：2.304（1.26-4.211），P=0.007 及OS 95%CI：3.019（1.211-7.523），P=0.018 均显著降低。1.00.80.60.40.20.00 5 10 15 20 25 30MonthsAHR=8.424PFS(%)Log-rank P=0.04LMR1.8LMRU1.81.00.80.60.40.20.0B0 5 10 15 20 25 30MonthsOS(%)HR=6.425LMR1.8LMRU1.8Log-rank P=0.011Fig.2The impact of LMRB/Svalue on patient survival statusA:PFS curves for patients in the high LMRB/S group and the low LMRB/S group;B:OS survival curves for patients in the high LMRB/Sgroup and the low LMRB/S group.PFS:progression-free survival;OS:overall survival;LMR:lymphocyte-to-monocytes ratios.LMRa?er1.8LMRa?erU1.81.00.80.60.40.20.0PFS(%)HR=3.937Log-rank P=0.047A0 5 10 15 20MonthsLMRa?er1.8LMRa?erU1.81.00.80.60.40.20.0OS(%)HR=7.217Log-rank P=0.007B0 5 10 15 20 25 30MonthsLMRa?er1.8LMRa?erU1.81.00.80.60.40.20.0PFS(%)HR=3.143Log-rank P=0.076C0 5 10 15 20 25 30MonthsLMRa?er1.8LMRa?erU1.81.00.80.60.40.20.0OS(%)HR=1.763Log-rank P=0.184D0 5 10 15 20 25 30 35MonthsFig.3The impact of LMRaftervalue on patient survival statusA-B:PFS and OS survival curves for patients in the LMRB/S1.8 group,divided into LMRafter1.8 group and LMRafter1.8 group after treat-ment;C-D:PFS and OS survival curves for patients in the LMRB/S1.8 group,divided into LMRafter1.8 group and LMRafter1.8 group af-ter treatment.PFS:progression-free survival;OS:overall survival;LMR:lymphocyte-to-monocytes ratios.572中国临床药理学与治疗学 2024 May;29(5)Tab.5Cox regression analysis of the LMRB/Svalues as prognostic factors for PFS in two groups of patientsIndicatorAgeSexHistologySmokingStageECOGLMRB/SUnivariate analysisHR1.060.6321.0941.6312.8372.8172.30495%CI0.574-1.9550.336-1.1890.601-1.9920.877-3.0351.245-6.4631.412-5.6191.260-4.2110.8530.1550.7680.1220.0130.0030.007Multivariate analysisHR-2.6002.6512.20795%CI-1.118-6.0431.322-5.3171.199-4.063-0.0260.0060.011LMR:lymphocyte-to-monocytes ratios;ECOG:Eastern Cooperative Oncology Group;HR:hazard ratio.Tab.6Cox regression analysis of the LMRB/Svalues as prognostic factors for OS in two groups of patientsIndicatorAgeSexHistologySmokingStageECOGLMRB/SUnivariate analysisHR0.7850.5321.3570.4084.5083.1593.01995%CI0.315-1.9550.213-1.3290.545-3.3770.147-1.1331.029-19.7390.286-34.8521.211-7.5230.6030.1770.5110.0850.0460.0090.018Multivariate analysisHR-4.2382.8682.71695%CI-0.92-19.5180.259-31.7311.061-6.954-0.0640.0130.037LMR:lymphocyte-to-monocytes ratios;ECOG:Eastern Cooperative Oncology Group;HR:hazard ratio;OS:overall survival.3讨论随着免疫治疗的发展，癌症治疗的手段也更加丰富，其中一个主要进展是ICI的研发，它在多种实体肿瘤中产生了持久的疗效，并提高了患者的生存率。然而，由于在临床应用中相当数量的接受ICI治疗的患者没有达到预期疗效14，因此有必要确定患者对ICI治疗敏感性的预测性生物标记物，通过对标记物的监测筛查并动态随访制定个体化治疗方案，从而期望获得更好的临床疗效。目前已有大量研究报道炎症与肿瘤的进展或转移之间的关系，一直为大家所关注，因此与炎症相关的指标常被用作判断与监测癌症患者预后的客观生物标志物15。然而，将LMR作为生物标记物判断癌症治疗预后的研究相对较少，LMR最初是在血液系统恶性肿瘤中被确定为判断预后的指标，随后越来越多的研究表明它与包括肺癌、胃癌、乳腺癌和黑色素瘤在内的众多实体瘤的预后相关16。有研究报道在使用伊匹单抗治疗的黑色素瘤患者中，发现高水平的单核细胞对该药物治疗的敏感性降低17。同样，在使用派姆单抗治疗后，治疗前淋巴细胞绝对值的基线水平越高的患者，其OS越长18。LMR是指淋巴细胞与单核细胞的比值，反映人体抗肿瘤免疫和肿瘤负荷的强弱。一方面淋巴细胞数量不足是导致肿瘤免疫反应激活不全的一个重要因素19，另一方面，单核细胞能够参与肿瘤的生长、侵袭和转移，通过在浸润肿瘤过程中单核细胞发展为肿瘤相关巨噬细胞，并产生相关趋化因子从而起到促进肿瘤生长作用20。有研究报道肿瘤相关巨噬细胞可以通过作用于PD-1/PD-L1信号通路，进一步抑制细胞毒性T细胞的功能，从而介导肿瘤患者的不良预后21。因此，LMR被认为可以作为反映机体免疫状态的观察指标，并有可能作为免疫检查点抑制剂的疗效预测标志物。本研究分析了治疗前血清中LMR值在评价PD-1抑制剂对晚期NSCLC患者治疗效果的预后价值。结果显示，高LMR组，在经过PD-1抑制剂治疗后的疗效优于低LMR组。进一步分析LMR值与PFS和OS之间关系，结果发现，血清低LMR值是影响患者PFS和OS，导致患者预后不良的独立危险因素，低LMR的患者组PFS和OS均低于高LMR组，573Chin J Clin Pharmacol Ther 2024 May;29(5)表现出更差的生存结局，这一研究结果与之前的报道一致。此外考虑到机体的炎症指标是一个动态变化的过程，本研究更进一步探讨了治疗前高LMR患者及治疗前低LMR患者中，治疗前后LMR值变化对其疗效的影响，结果发现治疗前低LMR患者中，LMR值升高组的有效率优于LMR值降低组。本研究结果表明，尽管治疗前患者的LMR值较低，但接受PD-1抑制剂治疗后部分患者可能重新动员体内的免疫反应，提高机体的LMR值，从而增强对PD-1抑制剂的敏感性。因此在临床应用中，有必要动态监测患者治疗前后LMR值的变化，制定更为适合的个体化治疗方案。在肿瘤患者病情的不同阶段，通过使用准确有效的检测指标评估疗效和预测预后尤为重要。血清LMR指标检测操作简单易获取，为临床医生提供了一种简便快捷的判断方法。必须指出，本研究为单中心回顾性分析，纳入的样本量较少，研究结果尚需设计严谨的大样本、多中心、前瞻性的临床研究进一步证实。参考文献1 Sung H,Ferlay J,Siegel RL,et al.Global Cancer Statis-tics 2020:GLOBOCAN Estimates of Incidence andMortality Worldwide for 36 Cancers in 185 CountriesJ.CA Cancer J Clin,2021,71(3):209-249.2 Siegel RL,Miller KD,Fuchs HE,et al.Cancer statistics,2022J.CA Cancer J Clin,2022,72(1):733.3 Ji J,Zhang C,Peng L,et al.Research progress,benefitgroups,treatment cycle and efficacy prediction ofneoadjuvant immunotherapy for non-small cell lungcancerJ.Zhong Guo Fei Ai Za Zhi,2022,25(2):92-101.4Liu J,Blake SJ,Yong MC,et al.Improved efficacy ofneoadjuvant compared to adjuvant immunotherapyto 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relationship between the ratio and dynamic changes of lympho-cytes/monocytes and the efficacy of PD-1 inhibitors in the treatmentof advanced non-small cell lung cancerHE Ye1,WANG Yinhua1,GENG Biao2,BAO Xing31Department of Radiotherapy,The Second Peoples Hospital of Wuhu,Wuhu 241001,Anhui,China;2Depart-ment of Respiratory,The First Affiliated Hospital of Wannan Medical College(Yijishan Hospital of WannanMedical College),Wuhu 241001,Anhui,China;3School of Pharmacy,Wannan Medical College,Wuhu241002,Anhui,ChinaABSTRACTAIM:To investigate the relationshipbetween the dynamic changes of Lymphocyte-to-monocytes ratios(LMR)before PD-1 inhibitor treat-ment and the efficacy and prognosis of PD-1 inhibi-tor treatment in patients with advanced non-smallcell lung cancer(NSCLC).METHODS:The clinicalcase data of 83 patients with advanced non-smallcell lung cancer admitted to the Cancer Hospital ofWuhu Second Peoples Hospital from June 2019 toJuly 2022 were retrospectively analyzed.The rou-tine blood LMR values of all patients before and af-ter treatment were collected,the cut-off value wascalculated according to the ROC curve,and theLMR was divided into two groups:high and low be-fore treatment and after treatment.The differenc-es of ORR,DCR,PFS and OS among the patients ineach group were analyzed and compared,and thevalue of LMR value and dynamic changes aftertreatment on the efficacy and prognosis of patientswith PD-1 inhibitors in the treatment of NSCLC pa-tients was analyzed.RESULTS:According to theROC curve,the critical value of LMR was 1.8,andthe LMR was divided into the low LMR group atbaseline(LMRB/S1.8)，the high LMR group at base-line(LMRB/S1.8)and the low LMR group aftertreatment(LMRafter1.8)and the high LMR group af-ter treatment(LMRafter1.8).The ORR and DCR afterimmunotherapy in the high LMRB/Sgroup were high-er than those in the low LMRB/Sgroup(P=0.037;P=0.002 5).Among the patients with low LMRB/Sbe-fore treatment,the DCR of the LMRafter1.8 groupwas better than that of the LMRafter1.8 group aftertreatment(P=0.005).Among the patients with highLMR before treatment,the DCR of the LMRafter1.8group was better than that of the LMRafter1.8group(P=0.034).Kaplan-Meier analysis showedthat PFS and OS were longer in the high LMRB/Sgroup than in the low LMRB/Sgroup before treat-ment.In the low LMRB/Sgroup before treatment,PFS and OS were longer in patients with LMRafter1.8 than those with LMRafter1.8(P=0.047;P=0.007).Multivariate Cox regression model analysis showedthat high LMRB/Svalue before treatment was an in-dependent risk factor for PFS and OS in NSCLC pa-tients(P=0.006;P=0.033).CONCLUSION:High LMRvalue of patients before immunotherapy may im-prove the efficacy of PD-1 inhibitors,improve theprognosis of patients,and prolong the survivaltime.Moreover,the increase of LMR value aftertreatment may increase the efficacy of patientswith low LMR before treatment and improve theprognosis of patients.KEYWORDSlymphocyte-to-monocytes ratios;non-small cell lung cancer;PD-1 inhibitor;biomarker575