Comparison Of Different Treatments For Hepatocellular Carcinoma:Systematic Review And Meta-analyses

BackgroundHepatocellular carcinoma(HCC)is the sixth most common cancer,and the fourth leading cause of cancer-related death worldwide.In recent decades,although great advances in liver resection(LR),local ablation(radiofrequency ablation[RFA],microwave ablation[MWA]),liver transplantation,etc.,have improved the systematic curative effect of HCC,the long-term prognosis of HCC remains unsatisfactory.As HCC is often characterised by an insidious onset,intermediate-advanced diseasse is common at the time of HCC diagnosis,resulting in loss of opportunity for radical treatment and poor prognosis.In addition,the high recurrence rate of HCC after radical treatment is also one of the important reasons for the poor long-term prognosis of HCC.Therefore,exploring and optimizing treatment strategies for intermediate-advanced HCC and recurrent HCC is essential to prolong survival for HCC patients.There always has been a great controversy in clinical practice regarding the treatment selection for intermediate-stage HCC.The most widely used Barcelona Clinic Liver Cancer(BCLC)system recommends transarterial chemoembolization(TACE)as the first-line therapy for intermediate-stage HCC.However,the efficacy of TACE monotherapy for intermediate-stage HCC remains unsatisfactory.Recently,many studies have addressed the role of TACE combination therapy in the treatment of intermediate-stage HCC.However,the findings have differed greatly among studies.The cumulative 5-year recurrence rate after curative treatment is up 70%to 80%.LR is the most commonly considered first-line therapy for recurrent HCC.RFA,which is characterized by minimaly invasive,less complication and high repeatability,is widely used in recurrent HCC.For now,the optimal treatment modality for recurrent HCC remains unclear.AimsThe aims of this systematic review and meta-analysis were:(1)to compare the efficacy and safety of different TACE combination therapies with TACE monotherapy for patients with intermediate-stage HCC;(2)to compare the efficacy and safety of LR vs RFA for recurrent HCC.MethodsPubMed,Embase,Web of Science,and the Cochrane Library were searched for studies that compared TACE combination therapy with monotherapy when treating intermediate-stage HCC patients,and studies that compared liver resection with radiofrequency abalation for recurrent HCC.Data were extracted for all studies that met the inclusion criteria.The Cochrane Collaboration’s Tool was used to assess the risk of bias in RCTs.The Newcastle-Ottawa scale(NOS)was used to assess the quality of nonrandomized controlled studies.The meta-analysis was performed with STATA 16.0.The outcomes included overall survival(OS),tumor progression and adverse events.Depending on the level of heterogeneity,either fixed or random effects models were used to pool hazard ratios(HRs),odds ratios(ORs)and their 95%confidence intervals(95%CIs).Subgroup analyses were conducted based on tumor burden,study design and study region.Sensitivity analysis was conducted to evaluate the quality and consistency of the results.Funnel plot,Egger’s test and Begg’s test were used to evaluate publication bias.Results(1)For the meta-analysis of TACE combination versus TACE alone for intermediate-stage HCC:among the twenty-two studies that compared TACE combination therapy vs monotherapy for intermediate-stage HCC,seventeen were included in the meta-analysis.Eight studies compared TACE plus radiofrequency ablation(TACE+RFA)vs TACE alone.The results demonstrated that TACE+RFA significantly prolonged OS(HR=0.58,95%CI=0.50-0.67;ORi-year=0.51,95%CI=0.36-0.73;OR3-year=0.39,95%CI=0.30-0.50;OR5-year=0.25,95%CI=0.15-0.42)without increasing the risk of adverse events.Nine studies compared TACE plus sorafenib(TACE+SOR)vs TACE alone.The pooled HR showed that patients receiving TACE+SOR had significantly better OS than those receiving TACE alone(HR=0.46,95%CI,0.31-0.69;OR1-year=0.56,95%CI=0.44-0.71;OR2-year=0.50,95%CI=0.33-0.77;OR3-year,0.30,95%CI=0.11-0.79).The combined use of sorafenib carried a potential risk of more mild-to-moderate dermatological adverse events,diarrhea and hypertension.In addition,five studies compared TACE+microwave ablation,TACE+orantinib,TACE+apatinib,TACE+131I-metuximab and TACE+S-1 chemotherapy vs TACE monotherapy,respectively.(2)For the meta-analysis about liver resection versus RFA for recurrent HCC:Eighteen studies with 1991 patients with recurrent HCC were included.The pooled hazard ratio(HR)for OS demonstrated that LR had significantly better OS than RFA in recurrent HCC(HR=0.81;95%CI=0.68-0.95).Specifically,LR was associated with higher 2-,3-and 4-year OS rates compared with RFA.The pooled HR for DFS showed no significant difference between LR and RFA during the whole follow-up period(HR=0.90;95%CI=0.76-1.07).However,LR was associated with significantly higher 2-to 5-year DFS rates compared to RFA.LR was also associated with more major complication(p<0.001)and longer hospital stay(p<0.001).Subgroup analyses demonstrated that LR and RFA had similar efficacy in patients with recurrent tumor less than 3 cm or patients presenting three or fewer recurrent nodules.Conclusions(1)TACE combination therapies can provide survival benefits in patients with intermediate-stage HCC.The meta-analysis demonstrated that TACE+RFA and TACE+SOR can significantly improve OS for those patients.(2)LR could provide better long-term survival outcomes than RFA for recurrent HCC patients,while RFA has a higher safety profile.RFA can be a good alternative to LR for patients with small-sized recurrence or patients with a limited number of recurrent nodule.