| Background:Immunotherapy represented by programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1)blockade has gradually become the significant component of systematic therapy for unresectable hepatocellular carcinoma(HCC).However,it is worth being studied whether prescribing combination immunotherapy perioperatively has the potential to reduce tumor activity,while increasing the resection rate and improving prognoses in unresectable HCC patient.Furthermore,studies have suggested that the level of PD-1/PD-L1 in tumor could effectively predict the prognosis of HCC patients.However,the correlation between sPD-1/sPD-L1(the soluble status of PD-1/PD-L1)level and prognosis of HCC patient is still unclear.This study investigated the efficacy and safety of preoperative combination immunotherapy for patients with initially unresectable HCC,and the prognostic value of sPD-1/sPD-L1 level in HCC patients.Methods:This retrospective,real-world study involved patients with initially unresectable HCC receiving combined immunotherapies based on PD-1/L1 blockade before surgery.Tumor treatment responses and resectability were assessed by Response Evaluation Criteria in Solid Tumors version 1.1(RECIST v1.1)and modified RECIST(mRECIST).Pathological manifestations in postoperative specimens and overall survival(OS)were evaluated.Data were compared between groups by X2 test,Fisher test,independent samples t-test,nonparametric rank sum test,Cox regression,logistic regression,Kaplan-Meier(KM)survival curves,and log rank survival analysis.Treatment-related adverse events(AEs)were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE,version 4.0).Moreover,we searched several electronic databases from database inception to October 7,2021,Eligible studies were included according to screening criteria.Meta-analyses were performed separately for OS and disease-free survival(DFS)/recurrence-free survival(RFS)/time to progression(TTP)/tumor-free survival(TFS).Random effects were introduced to this meta-analysis.The correlation between sPD-1/sPD-L1 level and prognosis of HCC patient was evaluated using hazard ratios(HRs)with 95%confidence intervals(95%CIs).Results:In the clinical exploration of combination immunotherapy,we consecutively included 54 initially unresectable HCC patients and 34 patients were evaluated the safety,efficacy and possibility of subsequent radical surgery.Finally,14 patients received surgical resection.Of these,57.1%(n=8)receiving combination immunotherapy before surgery achieved a partial response(PR),which highlighted at least a 30%reduction in tumor size.Pathological evaluation of postoperative specimens confirmed that 21.4%(n=3)achieved complete responses.78.6%(n=11)achieved partial responses.All patients experienced at least one kind of AEs,and 28.6%(n=4)encountered grade 3 or 4 AEs out of 14 patients.The main AEs included fatigue(n=11;78.6%),leukocytopenia(n=8;57.1%,)and aspartate aminotransferase(AST)elevation(n=6;42.9%).In the analysis of sPD-1/sPD-L1 levels for the prognosis of HCC patients,a total of 11 studies(1291 patients)were eligible,including 7 on sPD-L 1,2 on sPD-1 and 2 about both factors.The pooled results showed that high sPD-L 1 level was associated with worse OS(HR=2.46,95%CI 1.74-3.49,P<0.001;I2=31.4,P=0.177)and DFS/RFS/TTP/TFS of patients with HCC(HR=2.22,95%CI 1.47-3.35,P<0.001;I2=66.1,P=0.011),irrespective of method of detection,study type,treatment,cut-off value and followup time.In contrast,the level of sPD-1 was not correlated to the OS(HR=1.19,95%CI 0.552.56,P=0.657)and DFS/TFS of patients with HCC(HR=0.94,95%CI 0.36-2.49,P=0.906).Conclusions:After the application of combination immunotherapy,patients should be comprehensively evaluated whether they meet the criteria for surgical resection.This surgical resection following by combination immunotherapy might effectively control tumor progression,increase the resection rate of initial unresectable HCC and improve the prognosis of HCC patients.Furthermore,sPD-L1 rather than sPD-1 could be a good predictor of recurrence and survival after treatment for HCC.More high-quality prospective studies are warranted to assess the efficacy and safety of preoperative combination immunotherapy and the prognostic value of sPD-1/sPD-L1 for HCC patients. |
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