目的

探索具有高复发风险肝细胞癌（肝癌）患者术后酪氨酸激酶抑制剂（TKIs）联合免疫检查点抑制剂（ICIs）治疗的安全性及疗效。

方法

回顾性分析2019年1月至2021年12月在中山大学孙逸仙纪念医院接受肝切除手术的287例具有高复发风险肝癌患者临床资料。本研究符合医学伦理学规定。其中男233例，女54例；年龄23～85岁，中位年龄56岁。53例患者接受术后TKIs联合ICIs靶向免疫辅助治疗（辅助治疗组），234例患者未接受任何辅助治疗（对照组）。采用1∶2 倾向性评分匹配（PSM）减少混杂因素和选择偏倚的影响。主要研究终点是无复发生存期（RFS），次要终点为总体生存期（OS）、治疗相关不良事件的发生率和严重程度。生存分析采用Kaplan-Meier法和Log-rank检验。使用Cox比例风险模型分析RFS影响因素。

结果

采用1∶2 PSM后，辅助治疗组41例，对照组72例。辅助治疗组与对照组的中位RFS分别为23.7、15.7个月，辅助治疗组RFS较对照组明显延长（HR=0.601，95%CI：0.367～0.986；P=0.041）；而两组OS差异无统计学意义（HR=0.661，95%CI：0.240～1.823；P=0.421）。亚组Cox分析显示，年龄≤50岁、男性、HBsAg阳性、无肝硬化、Child-Pugh分级A级、AFP＞400 μg/L、合并MVI、Edmondson分级Ⅲ～Ⅳ级、合并大血管癌栓、合并两个以上高复发风险因素患者可以从靶向免疫辅助治疗中到得更明显的RFS获益（HR=0.454，0.554，0.586，0.449，0.582，0.423，0.399，0.474，0.213，0.376；P＜0.05）。81%（43/53）患者发生了治疗相关不良反应，无4级及以上治疗相关不良反应发生。常见的治疗相关不良反应为血小板降低（42%）、高血压（40%）、中性粒细胞减少（25%）、GGT升高（21%）、贫血（13%）等。常见的3级治疗相关不良反应依次为高血压（4%）、中性粒细胞减少（4%）、血小板降低（2%）等。

结论

对于具有高复发风险肝癌患者，术后采用TKIs联合ICIs治疗可以延长患者的RFS，且不良反应安全可控。

Objective

To evaluate the safety and efficacy of postoperative targeted immunotherapy of tyrosine kinase inhibitors （TKIs） combined with immune checkpoint inhibitors （ICIs） in patients with high-risk hepatocellular carcinoma （HCC） recurrence.

Methods

Clinical data of 287 HCC patients with high-risk recurrence after undergoing hepatectomy in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively analyzed. The local ethical committee approval was received. Among them，233 patients were male and 54 female， aged from 23 to 85 years， with a median age of 56 years. 53 patients received postoperative targeted immunotherapy of TKIs combined with ICIs （adjuvant therapy group）， and 234 patients did not receive any adjuvant therapy （control group）. The influence of confounding factors and selection bias was minimized using 1:2 propensity score matching （PSM）. The primary end point of this study was recurrence-free survival （RFS）， and the secondary end point was overall survival （OS）， and the incidence and severity of treatment-related adverse events. Survival analysis was conducted by Kaplan-Meier method and Log-rank test. The influencing factors of RFS were analyzed by Cox proportional hazard model.

Results

After 1:2 PSM analysis， 41 patients were assigned into the adjuvant therapy group and 72 cases in the control group. After PSM analysis， the median RFS in the adjuvant therapy and control groups was 23.7 and 15.7 months， and the RFS in the adjuvant therapy group was significantly longer than that in the control group （HR=0.601； 95%CI: 0.367-0.986； P=0.041）. There was no significant difference in OS between two groups （HR=0.661； 95%CI: 0.240-1.823； P=0.421）. Subgroup Cox analysis showed that patients aged ≤50 years old， male， HBsAg positive， non-cirrhosis， Child-Pugh class A， AFP＞400 μg/L， MVI，Edmondson grade Ⅲ-Ⅳ， complicated with macrovascular tumor thrombus and two or more risk factors of high-risk recurrence could obtain more benefits from targeted immunotherapy （HR=0.454， 0.554， 0.586，0.449， 0.582， 0.423， 0.399， 0.474， 0.213 and 0.376， all P＜0.05）. 81%（43/53） of patients developed treatmentrelated adverse reactions， and no grade 4 or above treatment-related adverse reactions occurred. Common treatment-related adverse reactions included thrombocytopenia （42%）， hypertension （40%）， neutropenia （25%），gamma glutamyl transpeptidase （GGT） elevation （21%） and anemia （13%）， etc. Common gradeⅢ treatmentrelated adverse reactions consisted of hypertension （4%）， neutropenia （4%） and thrombocytopenia （2%）， etc.

Conclusions

For HCC patients with high-risk recurrence， postoperative targeted immunotherapy of TKIs combined with ICIs can prolong postoperative RFS and yield safe and controllable adverse reactions.