A Paradigm Shift in Hepatocellular Carcinoma Treatment: An In-Depth Analysis of Etiology-Stratified First-Line Immunotherapy and Targeted Regimens

Abstract

 Hepatocellular carcinoma (HCC) represents a significant global health burden, with its pathogenesis intricately linked to underlying etiologies such as Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and non-viral factors like non-alcoholic steatohepatitis (NASH). For over a decade, the multi-targeted tyrosine kinase inhibitor (TKI) sorafenib remained the standard first-line systemic therapy, despite offering modest survival benefits and substantial toxicities. The recent introduction of immune checkpoint inhibitors (ICIs) and next-generation TKIs has revolutionized the therapeutic landscape. This paper explores the efficacy and safety of these novel first-line regimens, drawing heavily upon a comprehensive network meta-analysis of 24 randomized controlled trials (RCTs). By examining overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and adverse events, this analysis highlights the superiority of ICI-based combinations over traditional TKIs. Furthermore, it underscores the critical importance of viral etiology in guiding personalized treatment, demonstrating that HBV-related HCC benefits most from specific ICI plus anti-angiogenic combinations (e.g., sintilimab plus bevacizumab biosimilar), HCV-related HCC uniquely favors atezolizumab plus bevacizumab, and non-viral HCC requires dual checkpoint blockade (the STRIDE regimen) to overcome unique metabolic and immunological barriers.