Hepatocellular Carcinoma Chemoprevention with Generic Agents

Abstract

Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis. Hepatitis B- and hepatitis C-related HCC incidences have been substantially reduced by the new antivirals, but HCC risk can persist over a decade even after successful viral treatment, highlighting the need for HCC-preventive measures also in these patients. Experimental and retrospective studies have suggested potential utility of generic agents such as lipophilic statins and aspirin for HCC chemoprevention given their well-characterized safety profile, although anticipated efficacy may be modest. In this review, we overview recent clinical and translational studies of generic agents in the context of HCC chemoprevention under the contemporary HCC etiologies. We also discuss newly emerging approaches to overcome the challenges in clinical testing of the agents to facilitate their clinical translation.

Fig. 1. Framework of HCC prevention.

HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.

Fig. 2. Levels of evidence for preventive interventions.

(A) Domains to describe evidence. (B) Grades of evidence level and corresponding recommendations by USPSTF. USPSTF, U.S. Preventive Services Task Force.

Fig. 3. Potential use of HCC risk biomarker to refine design of chemoprevention clinical trial

(A) Monitoring of on-treatment pharmacological response to experimental intervention. (B) Determination of biomarker-based HCC risk modulation as surrogate endpoint to infer reduction of future HCC incidence based on previously conducted longitudinal cohort studies. (C) Selection of participants with elevated HCC risk in chemoprevention trial. Because anticipated HCC incidence is higher than that of general cirrhosis population, expected chemopreventive effect will be detected with smaller sample size and shorter follow-up time compared to all-comer enrollment.