Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers.

Keywords: genetic alterations; hepatocellular carcinoma; immunotherapy; molecular targeted therapy.

Figure 1

The estimated number of prevalent cases (5 years) of liver cancer, according to geographical area and etiology, in 2020. Hepatitis B virus (HBV) is the major etiological factor in Asia (except in Japan, where HCV is the major risk factor for liver cancer). HCV is the dominant causative factor in North America and Western Europe. Excessive alcohol intake is an etiological factor in Central and Eastern Europe. The prevalence of metabolic risk factors for HCC, including metabolic syndrome, obesity, type 2 diabetes, and MAFLD/MASH, is increasing worldwide. Estimated number of prevalent cases (5 years) as a proportion in 2020, liver, both sexes, all ages, Copyright (2020). (https://gco.iarc.who.int/en) (accessed on 10 March 2023). Etiology data from [6].

Figure 2

The top 20 genetic mutations in HCC. (https://cancer.sanger.ac.uk/cosmic/browse/tissue?wgs=off&sn=liver&ss=all&hn=carcinoma&sh=hepatocellular_carcinoma&in=t&src=tissue&all_data=n) (accessed on 5 February 2024).

Figure 3

Therapies have been approved for advanced HCC by the Food and Drug Administration (FDA, USA) and the National Medical Products Administration (NMPA, China). This figure shows the therapies and corresponding clinical trials (blue font) that have been approved by the FDA and NMPA China to date.