Abstract:

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.

Key words: Carcinoma,hepatocellular, High recurrence risks, Hepatectomy, Adjuvant therapy, Tyrosine kinase inhibitors (TKIs), Immune checkpoint inhibitor (ICIs), Survavl analysis, Safety, Adverse reactions