【作者】 陈群；

【导师】 欧阳学农；

【作者基本信息】 福建医科大学 ， 内科学（消化）（专业学位）， 2018， 硕士

【摘要】 目的:探讨在亚洲人群中抗生素使用与抗PD-1抗体治疗晚期肝细胞癌及非小细胞肺癌的疗效的相关性。方法:1、收集2016年5月至2017年12月期间在多个合作医院接受抗PD-1抗体(Pembrolizumab/Nivolumab)治疗的晚期肝细胞癌(HCC)和非小细胞肺癌(NSCLC)患者的抗生素使用情况、一般临床资料、疗效及生存随访资料进行回顾性分析。2、按照实体瘤疗效评价标准1.1(RECIST 1.1)评价治疗效果,观察抗PD-1抗体在晚期肝细胞癌和非小细胞肺癌患者中的疗效;按照美国国家癌症研究所不良事件常见毒性标准4.0版(NCI-CTCAE v4.0)评估治疗相关的不良反应。3、根据接受抗PD-1抗体患者治疗前2月及治疗后1月期间有无使用抗生素(使用时间≥3天)将病人分为两组,分别比较两组患者的客观缓解率(ORR)、疾病控制率(DCR)、无进展生存时间(PFS)和总生存时间(OS),并采用单因素和多因素生存分析探究影响患者预后的相关因素。4、所得数据均采用IBM SPSS 23.0软件进行统计学分析。结果:1、共纳入61例患者,33例晚期HCC患者接受Nivolumab治疗,28例晚期NSCLC患者接受Pembrolizumab或Nivolumab治疗(11例患者接受Nivolumab治疗,17例患者接受Pembrolizumab治疗)。61例患者接受抗PD-1抗体治疗后,均未发生因药物而导致死亡的事件,其中,22例患者出现1-2级AE(Adverse Event,不良事件),表现为粒细胞减少、转氨酶升高;4例患者出现3级以上AE,主要表现为转氨酶升高、肺炎。在接受抗PD-1抗体治疗前2月及治疗后1月期间,14例HCC患者、13例NSCLC患者因肺炎、感染等原因口服或静脉使用抗生素。2、在33例晚期HCC患者中,使用抗生素组与未用抗生素组的ORR(7.1%vs10.5%,P=1.000)、DCR(28.6%vs 57.9%,P=0.158)均无统计学差异;中位PFS(2.0个月vs 3.7个月,P=0.293)、中位OS(3.3个月vs 4.0个月,P=0.757)均无统计学差异。3、在28例晚期NSCLC患者中,使用抗生素组与未用抗生素组的ORR(7.7%vs 13.3%,P=1.000)、DCR(38.5%vs 33.3%,P=1.000)均无统计学差异;中位PFS(1.5个月vs 2.1个月,P=0.046)、中位OS(3.6个月vs 15.2个月,P=0.014)均有统计学差异。单因素分析显示,年龄、抗生素与OS具有相关性(P<0.05),Cox回归多因素分析显示,使用抗生素(P=0.029)是影响NSCLC患者预后的独立危险因素。4、61例患者中,使用抗生素组与未用抗生素组的中位PFS(1.8个月vs 2.8个月,P=0.036)、中位OS(3.6个月vs 4.8个月,P=0.046)均有统计学差异。结论:使用抗生素可影响抗PD-1抗体治疗实体瘤的疗效;其次使用抗生素可能是抗PD-1抗体治疗的新型的独立预后因素。更多还原

【Abstract】 Objective:We aim to investigate the relationship between the use of antibiotics and the efficacy of PD-1–based immunotherapy against advanced hepatocellular carcinoma and non-small cell lung cancer in Asian populations.Methods:1.The patients with advanced hepatocellular carcinoma(HCC)and non-small cell lung cancer(NSCLC)admitted between May 2016 and December 2017 in our cooperative hospitals,who have treated with anti-PD-1 antibody(Pembrolizumab/Nivolumab),with complete records of antibiotic use,treatment outcomes,adverse events and survival data,were studied retrospectively.2.The efficacy of the PD-1–based immunotherapy in advanced hepatocellular carcinoma and non-small cell lung cancer was evaluated according to Response Evaluation Criteria in Solid Tumors1.1(RECIST 1.1).And the adverse events were in accordance with the National cancer institute-common toxicity criteria adverse events version 4.0(NCI-CTCAE 4.0).3.Patients were divided into two groups according to whether they used antibiotics(use time ≥3 days)during the time of 2 months before treatment and 1 month after treatment.The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),and overall survival(OS)were compared between the two groups.And the factors influencing the prognosis were analysed by the univariate and multivariate survival analyses.4.Statistical analysis was performed by IBM SPSS software version 23.0.Results:1.A total of 61 patients were admitted to the study cohort,including 33 cases of advanced HCC patients treated with Nivolumab,11 cases of advanced NSCLC patients treated with Nivolumab and 17 cases of NSCLC patients treated with Pembrolizumb.During the treatment,none of the 61 patients had died of adverse drug reaction.The grade 1~2 adverse events had happened in 22 patients,including granulocytopenia and transaminase elevation.4 patients had experienced grade 3~4 toxic effects of elevated transaminases and pneumonia.During the time of 2 months before and 1 month after receiving anti-PD-1 antibody treatment,antibiotics were used mostly for pneumonia and infection in 14 patients with HCC and 13 patients with NSCLC.2.Among 33 patients with advanced HCC,there was no statistical difference in ORR(7.1% vs 10.5%,P=1.000),DCR(28.6% vs 57.9%,P=0.158),median PFS(2.0 months vs.3.7 months,P=0.293)and median OS(3.3 months vs.4.0 months,P = 0.757)between the antibiotic group and the non-antibiotic group.3.Among 28 patients with advanced NSCLC,there was no statistical difference in ORR(7.7% vs 13.3%,P=1.000)and DCR(38.5% vs 33.3%,P=1.000)between the antibiotic group and the non-antibiotic group.While there was significant statistical difference in median PFS(1.5 months vs.2.1 months,P = 0.046)and median OS(3.6 months vs.15.2 months,P = 0.014).The univariate analysis indicated that age and the use of antibiotics were significantly associated with overall survival.The multivariate analysis of the COX proportional hazards model confirmed that the use of antibiotics(P=0.029)was an independent factor that influenced the prognosis of NSCLC patients.4.Of all 61 patients,there was significant statistical difference in median PFS(1.8 months vs.2.8 months,P = 0.036)and median OS(3.6 months vs.4.8 months,P = 0.046).Conclusions:Antibiotics use can influence the response to anti-PD-1 immunotherapy in solid tumors in Asian populations.And antibiotics use may sever as a novel prognostic factors for PD-1–based immunotherapy.更多还原