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

Angelo Vacca,Patrizia Leone,Valli De Re,Antonio Giovanni Solimando,Oronzo Brunetti,Antonella Argentiero,Irene Azzali,Elisabetta Petracci,Vito Racanelli,Rossella Fasano,Oriana Nanni,Nicola Susca,Nicola Silvestris,Markus Krebs

doi:10.1007/s10238-021-00727-7

Abstract

Background & AimsA 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.MethodsPubmed, 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.ResultsFourteen 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.ConclusionsThe results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common cancers and the fourth leading cause of cancer-related death worldwide [1][2]
According to the Barcelona Clinic Liver Cancer (BCLC) staging, advanced hepatocellular carcinoma (HCC) is classified as C-HCC and includes vascular involvement/extrahepatic spread, physical impairment, and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1–2 [7]
A significantly prolonged progression-free survival (PFS) compared to placebo was determined for cabozantinib (HR 0.44, 95% confidence interval (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) (Table 2; Fig. 2B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers and the fourth leading cause of cancer-related death worldwide [1][2]. Encouraging antitumor activity was obtained using a combination of anti-antiangiogenic agents with immunotherapy This has led to the approved use of atezolizumab plus bevacizumab as a first-line treatment for patients with unresectable HCC. 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.

Methods

Results

Conclusion