Evolving Strategies in the Management of Intermediate-Stage HCC

Overview

This lecture by Dr. Gaddy Lager explores the evolving therapeutic landscape for intermediate-stage hepatocellular carcinoma (HCC), focusing on patient selection, sequencing of locoregional versus systemic therapy, combination strategies, and the role of clinical staging tools in guiding treatment decisions.

Key Clinical Topics

• Epidemiology and prognosis of HCC globally and in the United States
• BCLC staging system and its role in therapeutic decision-making
• The ALBI grade as a liver function assessment tool in HCC
• Defining and managing the heterogeneous BCLC intermediate stage (Stage B)
• Criteria for selecting locoregional (TACE) versus systemic therapy
• The up-to-seven criteria as a tumor burden threshold for treatment selection
• Role of combination therapy (TACE plus systemic agents)
• Portal vein tumor thrombus and its implications for staging
• Overview of ongoing and recent clinical trials in intermediate-stage HCC

Key Learning Points

• BCLC staging system: Endorsed by major international guidelines; integrates tumor burden, liver function, and performance status to guide both prognosis and therapy
• ALBI grade: A continuous score derived from albumin and bilirubin; particularly useful for distinguishing functional status among compensated patients where the Child-Pugh score has limited resolution
• Intermediate stage (BCLC B): Defined by absence of portal vein invasion and extrahepatic spread, but encompasses a heterogeneous population ranging from transplant-eligible patients on extended criteria to those requiring systemic therapy
• Up-to-seven criteria: Sum of the number of tumors plus the diameter of the largest tumor; patients within up-to-seven are preferred candidates for TACE, while those beyond up-to-seven may derive greater benefit from systemic therapy
• TACE-related decompensation: Approximately one-fifth to one-sixth of patients experience hepatic decompensation per TACE session; this compromises eligibility and outcomes with subsequent systemic therapy
• Liver function preservation: ALBI grade deterioration (Grade 1 to Grade 2) eliminates the survival benefit of systemic therapy, as demonstrated in post-hoc analysis of the IMbrave150 dataset
• TACE variants: DEB-TACE, cTACE, and TAE are considered broadly equivalent; selection should be individualized
• Combination rationale: Locoregional therapy may convert immunologically "cold" tumors to "hot" tumors via immunogenic necrosis, neoantigen release, and pro-inflammatory cytokine production; ischemia also upregulates VEGF, supporting combination with TKIs and anti-VEGF antibodies
• TACE plus TKI combinations: A decade of trials showed improvements in progression-free survival (PFS) but no overall survival (OS) benefit, with increased toxicity

Clinical Data & Study Results

• Global HCC incidence and mortality: Incidence rate of 3–15 per 100,000; mortality closely parallels incidence, highlighting poor overall outcomes
• 5-year survival: Approximately 22% in the US; below 20% globally; projected 60% increase in cases by 2040
• Up-to-seven criteria — Korean cohort: Complete response to TACE dropped from 59% within to 14% beyond up-to-seven criteria
• Kudo group retrospective study (n=90): Patients with tumors beyond up-to-seven treated with systemic therapy (lenvatinib) demonstrated superior OS compared to TACE
• ABC-HCC trial: Phase III; atezolizumab/bevacizumab (atezo/bev) versus TACE in unresectable HCC including VP1–VP2 portal vein thrombus; positive for time to treatment failure; OS data immature
• EMERALD-1: TACE plus durvalumab plus bevacizumab versus TACE alone; positive for PFS; benefit concentrated in patients with preserved liver function and higher tumor burden; OS data pending 2025
• LEAP-012: TACE plus lenvatinib and **pembrolizumab