Efficacy And Safety Analysis Of Radiotherapy Combined With Targeted Therapy And Immune Checkpoint Inhibitors In The Treatment Of Unresectable Hepatocellular Carcinoma

Background:Hepatocellular carcinoma(HCC)is the main type of liver malignancies with poor prognosis.The 5-year survival rate of patients with advanced HCC is as low as2.5%[1].Due to the insidious onset of HCC,patients often have reached the middle and late stage of the disease when diagnosed,and the opportunity for surgical cure is lost[2].According to the latest NCCN guidelines,patients with advanced HCC who cannot undergo radical surgery should be systematically treated.The first choice of first-line treatment is Atrilizumab combined with bevacizumab,but this regimen is only suitable for Child-Pugh class A population.In addition,radiotherapy is also a common treatment for HCC patients with metastases.In the context of current targeted therapy and immune checkpoint inhibitors(ICIs)combination therapy regimen,whether active combination with radiotherapy can prolong the survival of patients with unresectable HCC remains controversial.The purpose of this study was to investigate whether unresectable HCC patients who have developed extrahepatic metastasis or relapse after radical surgery have better survival benefits after radiotherapy combined with targeted therapy and ICIs and the safety of combined therapy.Materials and Methods:Clinical data of unresectable HCC patients admitted to the First Hospital of Jilin University from October 2018 to December 2022 were retrospectively included,and patients receiving radiotherapy combined with targeted therapy and ICIs were screened out.In combination therapy,targeted therapy was synchronized throughout the treatment cycle,with no more than 2 months between the time of receiving the ICIs and the start or end date of radiotherapy.Results:A total of 35 patients were enrolled until February 27,2023,the last day of follow-up.The primary endpoint was death or the end of follow-up.Of the 35 patients,16(48.5%)survived,17(51.5%)died,and 2 patients were lost to follow-up by the end of follow-up.median overall survival(m OS)was 26.1 months(95%CI10.775-41.425).median progression-free survival(m PFS)was 19 months(95%CI2.212～ 35.855).The m OS and m PFS were 19.2 months and 6.8 months,respectively,significantly longer than previous studies that explored only receiving targeted therapy and ICIs in advanced HCC.The one-year OS rate was 66.8%,one-year PFS rate was 54.1%,two-year OS rate was 52.9%,and two-year PFS rate was 38.6%.The overall objective response rate(ORR)was 36.4%(95%CI 20.4%-54.9%).The disease control rate(DCR)was 72.7%(95%CI 54.5%-86.7%).For treatment-related adverse events(TRAE)in the safety analysis,16 patients(48.5%)experienced at least one TRAE.Most are grade 1 or 2 and are remitting with clinical intervention.The most common TRAE of any grade are nausea(40%),and decreased appetite(40%).Grade3/4 TRAE occurred in four patients,resulting in treatment interruption.No patient deaths were attributed to treatment.The safety is tolerable.In univariate analysis,the risk of death in patients with reduced AFP after targeted therapy and ICIs was significantly lower than that in patients with increased AFP,and the risk of death in patients with reduced AFP was 0.294 times higher than that in patients with increased AFP(HR = 0.294,95%CI 0.082-1.049,P = 0.059).In multi-factor analysis,AFP is an independent factor affecting OS.The risk of death in patients with reduced AFP after targeted therapy and ICIs was significantly lower than in patients with increased AFP,and the risk of death in patients with reduced AFP was 0.271 times greater than that in patients with increased AFP(HR = 0.271,95%CI 0.068-1.075,P = 0.063).In univariate analysis,there was no significant prognostic factor for PFS.Multivariate analysis of AFP showed that the risk of disease progression was significantly lower in patients with reduced AFP after targeted therapy and ICIs than in patients with increased AFP,and the risk of disease progression was 0.293 times higher in patients with reduced AFP than in patients with increased AFP(HR = 5.969,95%CI0.083-1.026,P = 0.055).Subgroup analysis showed that baseline AFP levels were predictive of unresectable HCC with an AUC of 0.738(95%CI 0.536-0.939,P =0.053).Conclusion:1.The m OS and m PFS of unresectable HCC patients receiving radiotherapy combined with targeted therapy and ICIs were significantly longer than previous studies exploring targeted therapy and ICIs alone in advanced HCC.2.ORR and DCR were 36.4% and 72.7%,respectively.3.The safety of radiotherapy combined with targeted therapy and ICIs is tolerable.4.Changes in AFP after targeted therapy and ICIs is an independent prognostic factor affecting OS,and patients with low baseline AFP before treatment may have better disease control effects.