评估免疫检查点抑制剂为基础的联合治疗在原发性肝癌患者中肝损伤发生情况的真实世界研究

Real-world study evaluating the incidence of liver damage conditions in patients with primary liver cancer using immune checkpoint inhibitor-based combination therapy

目的在原发性肝癌患者中评估以免疫检查点抑制剂为基础的联合治疗引起的肝功能损伤发生情况。方法回顾性分析2018年1月1日至2021年3月31日在重庆医科大学附属第二医院感染病科住院,并接受程序性死亡蛋白其配体(PD-1/PD-L1)抗体治疗的65例原发性肝癌患者的临床资料。根据CTCAE V5.0标准评估治疗前后肝损伤的级别。根据性别、年龄段、是否有肝硬化、基线Child-Pugh评分、BCLC分期和治疗方案对患者进行分组,比较不同情况下患者肝损伤的发生率。多组间比较采用χ^(2)检验或秩和检验。结果根据CTCAE V5.0标准,46例(70.77%)患者在治疗观察期间发生了任意级别的肝损伤,规范化抗乙型肝炎病毒(HBV)治疗的6例患者均发生肝损伤;10例(15.38%)患者发生1级肝损伤,15例(23.08%)患者发生2级肝损伤,19例(29.23%)患者发生3级肝损伤,2例(3.08%)患者发生4级肝损伤。男性患者与女性患者的肝损伤发生率差异无统计学意义(发生率分别为68.33%和100%,P=0.180);肝损伤的发生率在各年龄组间差异无统计学意义(P=0.245);肝硬化组患者的肝损伤发生率为72.22%,非肝硬化组发生率为63.64%(P=0.370);基线Child-Pugh评分为A级、B级和C级的患者肝损伤发生率分别为71.43%、61.11%和100%,差异无统计学意义(P=0.878);肝损伤发生率在不同的BCLC分期下差异无统计学意义(P=1.000);PD-1/PD-L1抗体单药治疗组肝损伤发生率为60.00%,PD-1/PD-L1抗体联合靶向药物治疗组为67.85%,PD-1/PD-L1抗体联合经肝动脉栓塞化疗术/射频消融治疗组为86.67%,各治疗方案之间肝损伤发生率差异无统计学意义(P=0.480)。结论在原发性肝癌患者中,免疫检查点抑制剂治疗引起的肝功能损伤较为常见,严重危及患者生命安全的肝损伤罕见;患者的性别、年龄、是否合并肝硬化、基线肝功能、BCLC分期和免疫治疗方案对免疫相关性肝损伤的发生率尚无影响。

Objective To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer.Methods Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death ligand 1(PD-1/PD-L1)antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1,2018 to March 31,2021 were retrospectively analyzed.The degree of liver injury before and after treatment was assessed according to CTCAE v5.0.Patients were grouped according to gender,age,presence or absence of cirrhosis,baseline Child-Pugh score,BCLC stage,and treatment regimen to compare the incidence of liver injury under different conditions.The χ^(2) test or rank-sum test was used for comparison among multiple groups.Results 46 cases(70.77%)had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period.All 6 cases who received standardized anti-hepatitis B virus(HBV)treatment developed liver damage.10(15.38%),15(23.08%),19(29.23%),and 2(3.08%)cases had grade 1,2,3,and 4 liver damage respectively.There was no statistically significant difference in the incidence of liver damage between male and female patients(68.33%and 100%,0.180).There was no statistically significant difference in the incidence of liver damage among different age groups(P=0.245).The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%,and 63.64%(P=0.370),respectively.The incidence of liver damage in patients with baseline Child-Pugh class A,B,and C were 71.43%,61.11%and 100%,respectively,and the diFFerence was not statistically significant(P=0.878).The incidence of liver damage was not statistically significantly different under difFerent BCLC stages(P=1.000).The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy,PD-1/PD-L1 antibody combined with targeted drug therapy,and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%,67.85%,and 86.67%,respectively.There was no statistically significant difference in the incidence of liver damage between the treatment regimen(P=0.480).Conclusion Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer;however,it rarely severely endangers the patient's life.Additionally,patient's gender,age,presence or absence of cirrhosis,baseline liver function,BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.