Therapeutic Management of Advanced Hepatocellular Carcinoma: An Updated Review

Abstract

Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child-Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy.

Keywords: cirrhosis; hepatocellular carcinoma; prognosis; treatment.

Figure 1

Tyrosine kinase inhibitors and molecular pathways in hepatocellular carcinoma.

Figure 2

(A). Anti-VEGF and monoclonal antibody (ramucirumab) inhibit angiogenesis in tumor cell (B). Activated T-cells express P-1 that binds to its specific ligand PD-L1 on antigen presenting cell which inhibits T-cell activity (C). Anti PD-1 (Nivolumab) and anti-PD-L1 (Atezolizumab) prevent this binding and increase T-cell activation which allows apoptosis of tumor cells.

Figure 3

Historical timeline of systemic therapies approved in advanced hepatocellular carcinoma management [9,11,12,15,27,28].

Figure 4

Forest plots of hazard ratio (HR) of overall survival (OS) in phase III-studies on advanced HCC [9,11,12,13,14,15,18,27,28].

Figure 5

Algorithm proposition for therapeutic management of advanced hepatocellular carcinoma in patients with Child–Pugh A liver function. TBM: tumor board meeting.