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. 2022 Feb;22(1):65-74.
doi: 10.1007/s10238-021-00727-7. Epub 2021 Jun 19.

Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis

Antonio Giovanni Solimando #  1   2 , Nicola Susca #  1 , Antonella Argentiero  2 , Oronzo Brunetti  2 , Patrizia Leone  1 , Valli De Re  3 , Rossella Fasano  2   4 , Markus Krebs  5 , Elisabetta Petracci  6 , Irene Azzali  6 , Oriana Nanni  6 , Nicola Silvestris  7   8 , Angelo Vacca #  1 , Vito Racanelli #  9
Affiliations

Second-line treatments for Advanced Hepatocellular Carcinoma: A Systematic Review and Bayesian Network Meta-analysis

Antonio Giovanni Solimando et al. Clin Exp Med. 2022 Feb.

Abstract

Background & aims: A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option.

Methods: Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels.

Results: Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50-0.79), cabozantinib (HR = 0.76, 95% CI = 0.63-0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70-0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36-0.52), regorafenib (HR = 0.46, 95% CI = 0.37-0.56), ramucirumab (HR = 0.54, 95% CI = 0.43-0.68), brivanib (HR = 0.56, 95% CI = 0.42-0.76), S-1 (HR = 0.60, 95% CI = 0.46-0.77), axitinib (HR = 0.62, 95% CI = 0.44-0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57-0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients' stratification.

Conclusions: The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Keywords: Hepatocellular carcinoma; Network meta-analysis; Second-line treatment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram
Fig. 2
Fig. 2
A: Forest plot of overall survival. The comparisons were made against the placebo; B: Forest plot of progression-free survival. The comparisons were made against the placebo; C: Forest plot of the discontinuation of active treatment. The comparisons were made against regorafenib
See this image and copyright information in PMC

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