【作者】 李玉；

【导师】 王楠娅；

【作者基本信息】 吉林大学 ， 临床医学硕士（专业学位）， 2025， 硕士

【摘要】 背景:肝细胞癌(hepatocellular carcinoma,HCC)是原发性肝癌最常见的类型,占全球原发性肝癌的90%。我国是HCC高发国家,超过60%的患者初诊时已是中晚期,为不可切除肝细胞癌(unresectable hepatocellular carcinoma,u HCC)。系统治疗成为主要治疗方式,靶向单药治疗是传统标准一线治疗方案。基于靶向治疗与免疫治疗的协同增效机制,近年来,靶向联合免疫治疗已经在临床上广泛实践,并成为一线优选治疗方案。在全球老龄化的背景下,老年肝癌的发病率呈明显的上升趋势,老年u HCC患者常常合并其他疾病,导致治疗耐受性下降、发生治疗相关不良反应的风险增加。对于老年患者,免疫联合治疗的实际应用现状尚未得到充分研究。因此,本项回顾性研究旨在通过对比分析靶向联合免疫治疗和单药靶向治疗老年u HCC患者的有效性和安全性,为临床药物治疗方案的选择提供参考依据。方法:本研究回顾性纳入了中国中青年肝癌协作组(China Liver Cancer Study Group Young Investigators,CLEAP)数据库中来自8家医疗中心2019年3月至2023年7月期间被诊断为u HCC的老年患者(≥65岁)158名,根据治疗方案的不同,分为靶向单药治疗组(包括但不限于索拉非尼、仑伐替尼等)以及靶向联合免疫治疗组(PD-1/PD-L1抑制剂包括但不限于帕博利珠单抗、阿替利珠单抗等;联合药物包括索拉非尼、仑伐替尼、贝伐珠单抗等)。收集两组患者的一般临床资料、实验室检验指标、影像学检查,并随访至死亡或2023年12月31日。依据实体肿瘤疗效评价标准(Response Evaluation Criteria in Solid Tumors 1.1,RECIST1.1)进行客观疗效评价,根据常见不良反应事件评价标准(Common Terminology Criteria for Adverse Events,CTCAE)5.0版记录不良事件(adverse event,AE)的发生情况并进行评估。研究的主要终点是总生存期(overall survival,OS),次要终点是无进展生存期(progression free survival,PFS)、客观缓解率(objective response rate,ORR)和疾病控制率(disease control rate,DCR)。结果:1、共有158名符合标准的患者被纳入本研究,其中56名患者接受了单药靶向治疗,102名患者接受了靶向联合免疫治疗。靶向联合免疫治疗组患者接受局部治疗(76.5%vs.60.7%,P=0.037)和Child-Pugh A级(70.6%vs.39.3%,P=0.001)患者的比例均高于靶向单药治疗组,两组间其他人口统计学和肿瘤特征无显著差异。2、截止末次随访,中位随访时间是24.9个月(95%CI:23.3-26.4)。靶向联合免疫治疗组ORR和DCR均高于靶向单药治疗组,ORR为29.4%vs.3.6%(P=0.001)、DCR为54.9%vs.53.6%(P=0.872)。生存分析显示,靶向联合免疫治疗组中位PFS和中位OS均高于靶向单药治疗组,分别为13.2 vs.7.3个月(P=0.137)、20.0 vs.16.0个月(P=0.140)。3、亚组分析显示,大多数亚组都倾向于靶向联合免疫治疗更受益,不合并腹水和基线甲胎蛋白<400 ng/m L的患者,联合治疗后PFS和OS均有显著改善。然而,合并腹水的老年u HCC患者在靶向单药治疗组中的中位PFS(10.2 vs.8.0个月,P=0.446)和中位OS(15.0 vs.10.0个月,P=0.271)均高于靶向联合免疫治疗组。4、多因素回归分析显示,合并脑血管疾病(HR:0.467,95%CI:0.220-0.992,P=0.048)和既往有手术史(HR:0.500,95%CI:0.252-0.994,P=0.048)是影响老年u HCC患者OS预后的相关因素。5、158例患者中共有85例患者(53.7%)出现不良反应。靶向单药治疗组的不良反应发生率为44.6%,最常见的反应为腹胀(16.6%)。联合治疗组的不良反应发生率为58.8%,其中疲劳(17.6%)最为常见,两组AE的发生率无明显统计学差异(P=0.087)。但靶向联合免疫治疗组因AE导致的停药率明显高于单药治疗组,差异有统计学意义(20.5%vs.8.9%,P=0.005)。结论:1、对于老年uHCC患者,靶向联合免疫治疗组患者的ORR和DCR高于单药靶向治疗组,联合治疗在老年患者中较单药靶向治疗显示出更高的有效率。2、靶向联合免疫治疗组对比单药靶向治疗组的PFS和OS无统计学差异。从曲线上看,靶向联合免疫治疗组的PFS和OS有延长的趋势。3、靶向联合免疫治疗组老年患者AE发生率和因AE导致的停药率高于单药靶向治疗组,但未出现预期之外的不良反应,安全性可控。更多还原

【Abstract】 Background:Hepatocellular carcinoma(HCC)is the most prevalent type of primary liver cancer,accounting for approximately 90%of primary liver cancer cases worldwide.China has a high incidence of HCC,with more than 60%of newly diagnosed patients presenting with advanced-stage disease,classified as unresectable hepatocellular carcinoma(u HCC).Systemic therapy has emerged as the primary treatment modality.In the first-line systemic treatment of u HCC,targeted monotherapy has traditionally been the standard first-line regimen.However,based on the synergistic mechanisms of targeted therapy and immunotherapy,the combination of targeted therapy and immunotherapy has been widely adopted in clinical practice in recent years and has become a preferred first-line treatment option.With the global aging population,the incidence of HCC among elderly population is rising.Elderly patients with u HCC often present with multiple comorbidities,which can compromise treatment tolerance and increase the risk of adverse drug reactions.However,the real-world applicability of combination therapy in elderly patients remains insufficiently studied.Therefore,this study aims to compare the safety and efficacy of targeted monotherapy versus targeted therapy combined with immunotherapy in elderly u HCC patients,providing valuable evidence to guide clinical decision-making in this patient population.Methods:This retrospective study included 158 elderly patients(≥65 years)diagnosed with u HCC from the CLEAP(China Liver Cancer Study Group Young Investigators)database across eight hospitals between March 2019 and July 2023.Based on treatment regimens,patients were divided into two groups:the targeted monotherapy group(with treatment drugs including but not limited to sorafenib,lenvatinib,etc.)and the targeted therapy combined with immunotherapy group(with PD-1/PD-L1 inhibitors including but not limited to pembrolizumab,atezolizumab,etc.and targeted drugs including sorafenib,lenvatinib,and bevacizumab).Clinical data,laboratory test results,and imaging findings were collected for both groups and followed-up until death or December 31,2023.Objective efficacy evaluation was based on the Response Evaluation Criteria in Solid Tumors(RECIST 1.1),while adverse events(AEs)were recorded according to the Common Terminology Criteria for Adverse Events(CTCAE)version 5.0.The primary endpoint of the study was overall survival(OS),while secondary endpoints included progression-free survival(PFS),objective response rate(ORR),and disease control rate(DCR).Results:1.A total of 158 eligible patients were included in this study,56 patients received targeted monotherapy,while 102 patients received targeted therapy combined with immunotherapy.The proportion of patients who received local treatment(P=0.037)and those with Child-Pugh A(P=0.001)was significantly higher in the combination therapy group than in the targeted monotherapy group.No significant differences were observed between the two groups in other demographic and tumor characteristics.2.The median follow-up duration was 24.9 months(95%CI:23.3-26.4).The ORR and DCR were higher in the combination therapy group compared to the targeted monotherapy group,at 29.4%vs.3.6%(P=0.001)and 54.9%vs.53.6%(P=0.872),respectively.Survival analysis indicated that the median PFS and median OS were longer in the combination therapy group than in the targeted monotherapy group,with PFS at 13.2 vs.7.3 months(P=0.137)and OS at 20.0 vs.16.0 months(P=0.140).3.Subgroup analysis suggested that most of them benefited more from the combination therapy.Patients without ascites and those with baseline alpha-fetoprotein(AFP)<400ng/m L showed significant improvements in both PFS and OS after combination therapy.However,in elderly u HCC patients with ascites,the targeted monotherapy group had higher median PFS(10.2 vs.8.0 months,P=0.446)and median OS(15.0 vs.10.0 months,P=0.271)than the combination therapy group.4.Multivariate regression analysis identified cerebrovascular disease(HR:0.467,95%CI:0.220-0.992,P=0.048)and a history of prior surgery(HR:0.500,95%CI:0.252-0.994,P=0.048)as significant prognostic factors affecting OS in elderly u HCC patients.5.A total of 85 patients(53.7%)experienced adverse events(AEs)in 158 patients.The incidence of AEs in the targeted monotherapy group was 44.6%,with the most common being abdominal distension(16.6%).In the combination therapy group,the incidence of AEs was 58.8%,with fatigue(17.6%)being the most common.There was no statistically significant difference in AE incidence between the two groups(P=0.087).However,the discontinuation rate due to AEs was significantly higher in the combination therapy group than in the targeted monotherapy group(20.5%vs.8.9%,P=0.005).Conclusion:1.In elderly u HCC patients,the combination therapy group demonstrated higher ORR and DCR compared to the targeted monotherapy group,indicating superior therapeutic efficacy of the combination therapy in this population.2.The patients in the combination therapy group had numerically higher PFS and OS than the targeted monotherapy group,although there was no statistically significant difference.3.The elderly u HCC patients in the combination therapy group demonstrated higher incidence rates of AE and AE-related treatment discontinuation compared to the targeted monotherapy group.No unexpected toxicities were identified,and the safety profile was consistent with established clinical expectations,remaining within manageable parameters.更多还原