| Objective:To compare the effectiveness and safety of first-line drug treatments in patients with advanced unresectable hepatocellular carcinoma by this network meta-analysis.By integrating and ranking first-line drug treatment measures,it provides a reference for patients to choose the best treatment option and provides a basis for future clinical trial design.Methods:We searched the Embase,Cochrane,and Pubmed databases,as well as international conference abstracts including the American Society of Clinical Oncology(ASCO)and the European Society of Medical Oncology(ESMO),until October 6,2022.We included studies that were randomized controlled trials(RCTs)including at least one of the following outcomes: overall survival(OS),progression free survival(PFS),time to progression(TTP),and grade ≥3 The incidence of adverse events.We used the Risk of Bias assessment tool in Review Manager 5.3 software to assess the quality of the literature;in a Bayesian framework,we used R software to perform a network metaanalysis of the collected data with subgroup analysis for different etiologies,different regions,and the presence or absence of vascular invasion and or extrahepatic metastases of the disease;finally,we ranked the treatment measures for effectiveness and safety according to the cumulative ranking curve(surface under the cumulative ranking,SUCRA).Results:A total of 16 RCTs(containing 11,209 patients)and 17 drug regimens(including placebo)were included in this study.Compared with sorafenib monotherapy,sintilimab plus bevacizumab generic(sintilimab+IBI305,SIN+IBI)and camrelizumab plus rivoceranib(camrelizumab+rivoceranib,CAM+RIV)significantly improved OS in patients with advanced unresectable hepatocellular carcinoma(SIN+IBI.HR 0.57,95% CI 0.43-0.75;CAM+RIV: HR 0.62,95% CI 0.49-0.79)and PFS(HR 0.56,95% CI 0.45-0.69;HR 0.52,95% CI 0.41-0.66)in patients with advanced unresectable hepatocellular carcinoma.But CAM+RIV was inferior in safety to sorafenib(HR 3.86,95% CI 2.66-5.73),with the highest safety profile for nivolumab(OR 0.29,95% CI 0.21-0.4).For the hepatitis B population in patients with advanced unresectable hepatocellular carcinoma,cabozantinib plus atezolizumab(cabozantinib + atezolizumab,CAB + ATE)(HR 0.53,95% CI0.32-0.86),SIN + IBI(HR 0.58,95% CI 0.44-0.77)and atezolizumab plus bevacizumab(atezolizumab+bevacizumab,ATE+BEV)(HR 0.58,95% CI 0.4-0.84)showed a significant OS advantage;for those with vascular invasion and or extrahepatic metastases,the most significant improvements in OS were SIN+IBI(HR 0.6,95% CI 0.45-0.8)and ATE+ BEV(HR 0.64,95% CI0.49-0.84);for Asian patients,SIN+IBI(HR 0.57,95% CI 0.43-0.75)and ATE+BEV(HR 0.62,95%CI 0.42-0.92)were the most effective in improving OS;for those without vascular invasion or extrahepatic metastases,SIN+ IBI(HR 0.43,95% CI 0.19-0.97)showed a significant OS superiority;for those with hepatitis C,the best improvement in OS was associated with ATE+BEV(HR 0.43,95% CI 0.25-0.74).Conclusion:Our study showed that both SIN+IBI and CAM+RIV had similar efficacy in the treatment of unresectable advanced hepatocellular carcinoma,prolonging patients’ OS and PFS,and did not show statistically significant differences by indirect comparisons.For those with hepatitis B,vascular invasion and or extrahepatic metastases,and in Asian regions,SIN+IBI and ATE+BEV were associated with the best OS;CAB+ATE was also associated with the best OS in the hepatitis B subgroup with similar efficacy to SIN+IBI and ATE+BEV.For those with hepatitis C,ATE+BEV was associated with the best OS;for those without vascular invasion or extrahepatic metastases,SIN+IBI significantly improved OS.The combination of drug use raised safety risks and are more likely to result in grade 3 or higher adverse reactions.Nivolumab and durvalumab were non-inferior to conventional sorafenib treatment in terms of efficacy and had a higher safety profile. |
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