Kelly A. Benante

Hepatocellular carcinoma (HCC) is a lethal cancer with an increasing burden. Few clinical trials have evaluated preventive strategies for HCC in high-risk patients with liver cirrhosis. Observational studies show that statins are associated with a reduced HCC risk although a causal link has yet to be established. This multicenter randomized double-blinded, placebo-controlled phase II trial of 40 mg/day oral simvastatin to reduce the likelihood of hepatocarcinogenesis was conducted at four sites in the United States. The primary outcome was the change in serum α-fetoprotein (AFP)-L3% from baseline to 6 months. Secondary biomarker endpoints include changes in serum AFP, serum IL6, serum deoxycholic acid, liver stiffness, Model for End-Stage Liver Disease score, and Fibrosis-4 index score. Comparisons were made using paired t tests or the Wilcoxon rank-sum test. Forty-five participants completed the intervention and final study assessments [mean age, 58 years; female, 42%; Asian, 2.2%; Black or African American, 11%; White, 87%; Hispanic or Latino, 51%; Child-Pugh (CP) A, 69%; CP B, 16%]. Of 45 participants, 10 (22%) had detectable AFP-L3%, which did not differ between the intervention arms. Serum IL6 levels, detectable in all participants, decreased significantly in the simvastatin group compared with the placebo group (P = 0.02). The number and grade of adverse events did not differ between groups. In this randomized controlled trial, simvastatin was well tolerated in patients with liver cirrhosis but did not result in a decrease in AFP-L3%, potentially owing to the low number of participants with detectable AFP/AFP-L3%. Simvastatin did result in a decrease in IL6, offering one potential anticancer mechanism of simvastatin in the setting of cirrhosis. Prevention Relevance:Increasing liver cancer incidence parallels cirrhosis related to nonalcoholic steatohepatitis. Statins have the potential to arrest cirrhosis progression and prevent liver cancer. In a phase IIB trial randomizing patients with cirrhosis to simvastatin versus placebo, we found that simvastatin decreased the inflammation biomarker IL6, but not the primary endpoint of AFP-L3.

Supplemental Table 1. Study Participants Representativeness.

Hepatocellular carcinoma (HCC) is a lethal cancer with an increasing burden. Few clinical trials have evaluated preventive strategies for HCC in high-risk patients with liver cirrhosis. Observational studies show that statins are associated with a reduced HCC risk although a causal link has yet to be established. This multicenter randomized double-blinded, placebo-controlled phase II trial of 40 mg/day oral simvastatin to reduce the likelihood of hepatocarcinogenesis was conducted at four sites in the United States. The primary outcome was the change in serum α-fetoprotein (AFP)-L3% from baseline to 6 months. Secondary biomarker endpoints include changes in serum AFP, serum IL6, serum deoxycholic acid, liver stiffness, Model for End-Stage Liver Disease score, and Fibrosis-4 index score. Comparisons were made using paired t tests or the Wilcoxon rank-sum test. Forty-five participants completed the intervention and final study assessments [mean age, 58 years; female, 42%; Asian, 2.2%; Black or African American, 11%; White, 87%; Hispanic or Latino, 51%; Child-Pugh (CP) A, 69%; CP B, 16%]. Of 45 participants, 10 (22%) had detectable AFP-L3%, which did not differ between the intervention arms. Serum IL6 levels, detectable in all participants, decreased significantly in the simvastatin group compared with the placebo group (P = 0.02). The number and grade of adverse events did not differ between groups. In this randomized controlled trial, simvastatin was well tolerated in patients with liver cirrhosis but did not result in a decrease in AFP-L3%, potentially owing to the low number of participants with detectable AFP/AFP-L3%. Simvastatin did result in a decrease in IL6, offering one potential anticancer mechanism of simvastatin in the setting of cirrhosis. Prevention Relevance: Increasing liver cancer incidence parallels cirrhosis related to nonalcoholic steatohepatitis. Statins have the potential to arrest cirrhosis progression and prevent liver cancer. In a phase IIB trial randomizing patients with cirrhosis to simvastatin versus placebo, we found that simvastatin decreased the inflammation biomarker IL6, but not the primary endpoint of AFP-L3.

Supplemental Methods 1: Clinical Trial Protocol

Supplemental Table 3: Study Participants Representativeness Table

Supplemental Table 2: Adverse Events, N = 13 Participants

Accumulation of the DNA adduct γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is associated with hepatocellular carcinoma development. Theaphenon E—a green tea polyphenol extract dosed according to mg of epigallocatechin gallate—suppresses the formation of γ-OHPdG and reduces hepatocellular carcinoma development in preclinical models. This study aimed to evaluate the safety of Polyphenon E (Theaphenon E equivalent) and its effect on liver γ-OHPdG levels in patients with cirrhosis. This phase I trial used a 3 + 3 dose-escalation design with five planned Polyphenon E (epigallocatechin gallate) dose levels: 400, 800, 1,200, 1,600, and 2,000 mg daily, administered orally for 24 weeks. Each dose cohort was monitored for “discontinue therapy” criteria for 4 weeks before additional participants were enrolled in the next cohort. Participant liver samples were assessed for γ-OHPdG levels using LC/MS-MS and vibration-controlled transient elastography; endogenous catechin pharmacokinetic data were analyzed. Grade 1 and 2 treatment-related adverse events were observed in 38% of the participants. Liver γ-OHPdG levels declined after treatment in most participants. There was a decrease in the vibration-controlled transient elastography–controlled attenuation parameter in some participants. After Polyphenon E dosing, catechin pharmacokinetic clearance patterns were equivalent for all doses except 1,600 mg. Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. Therefore, the recommended starting dose for a phase II trial in a cirrhotic population is 1,200 mg. We observed promising Polyphenon E suppression of liver γ-OHPdG levels.Prevention Relevance:In this phase I dose-escalation trial, Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. We observed promising Polyphenon E suppression of liver γ-OHPdG levels and recommend 1,200 mg dose for a future phase II trial in a cirrhotic population.

Supplemental Table 1: Baseline Liver Characteristics by Dose Cohort, N = 13 Participants

Accumulation of the DNA adduct γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is associated with hepatocellular carcinoma development. Theaphenon E—a green tea polyphenol extract dosed according to mg of epigallocatechin gallate—suppresses the formation of γ-OHPdG and reduces hepatocellular carcinoma development in preclinical models. This study aimed to evaluate the safety of Polyphenon E (Theaphenon E equivalent) and its effect on liver γ-OHPdG levels in patients with cirrhosis. This phase I trial used a 3 + 3 dose-escalation design with five planned Polyphenon E (epigallocatechin gallate) dose levels: 400, 800, 1,200, 1,600, and 2,000 mg daily, administered orally for 24 weeks. Each dose cohort was monitored for “discontinue therapy” criteria for 4 weeks before additional participants were enrolled in the next cohort. Participant liver samples were assessed for γ-OHPdG levels using LC/MS-MS and vibration-controlled transient elastography; endogenous catechin pharmacokinetic data were analyzed. Grade 1 and 2 treatment-related adverse events were observed in 38% of the participants. Liver γ-OHPdG levels declined after treatment in most participants. There was a decrease in the vibration-controlled transient elastography–controlled attenuation parameter in some participants. After Polyphenon E dosing, catechin pharmacokinetic clearance patterns were equivalent for all doses except 1,600 mg. Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. Therefore, the recommended starting dose for a phase II trial in a cirrhotic population is 1,200 mg. We observed promising Polyphenon E suppression of liver γ-OHPdG levels. Prevention Relevance: In this phase I dose-escalation trial, Polyphenon E was well tolerated in participants with cirrhosis at a dose up to and including 1,600 mg/day. We observed promising Polyphenon E suppression of liver γ-OHPdG levels and recommend 1,200 mg dose for a future phase II trial in a cirrhotic population.

Table S8 Comparisons of pre- (Week 0) to post-treatment (Week 9) changes in endpoint biomarkers for continuous aspirin vs. intermittent aspirin arm