Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Keywords: Adjuvant; Early stage; Hepatocellular carcinoma; Intermediate stage; Neoadjuvant; Systemic therapy.

Figure 1

Drugs available for systemic therapy classified according to their mechanism of action, indicating by arrows and colors the main drug combinations studied. ¹Immunotherapy. PD1: Programmed cell death protein 1; PDL1: Programmed death-ligand 1; CTLA4: Cytotoxic T-lymphocyte associated protein 4; VEGF: Vascular endothelial growth factor.

Figure 2

Median overall survival shown in clinical trials by drugs approved as first-line systemic therapy, compared with sorafenib. IMbrave150 analyzed atezolizumab + bevalizumab. HIMALAYA investigated durvalumab + tremelimumab.