Atorvastatin for Liver Cancer Risk in Fibrosis

(TORCH Trial)

Recruiting at 1 trial location

Overseen By Yujin Hoshida, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Raymond Chung

Must not be taking: Statins

Disqualifiers: HIV, Untreated HCV, Uncontrolled HBV, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 48 weeks

60 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but if you are taking a statin, you must stop it and undergo a 90-day washout period before starting the trial.

What data supports the idea that Atorvastatin for Liver Cancer Risk in Fibrosis is an effective drug?

The available research shows that Atorvastatin, a type of statin, is effective in reducing the risk of liver cancer in people with liver diseases. One study found that statin use, including Atorvastatin, was linked to a 44% reduction in the development of liver scarring and a 49% reduction in new liver cancer cases among patients with hepatitis C. Another study highlighted that Atorvastatin was particularly effective in reducing high-risk patterns associated with liver cancer development. These findings suggest that Atorvastatin is a potent option for lowering liver cancer risk in patients with viral and metabolic liver diseases. ^{1 2 3 4 5}

What safety data exists for atorvastatin in liver cancer risk and fibrosis treatment?

Atorvastatin is generally well tolerated, but there are concerns about hepatotoxicity, with some cases of liver injury reported. Statins, including atorvastatin, have been associated with idiosyncratic liver injury in 1.9%-5.5% of patients. Most patients recover after stopping the drug, though there have been rare cases of severe liver injury. Despite these risks, statins are being studied for their potential benefits in liver conditions, including cirrhosis and hepatocellular carcinoma prevention. ^{1 6 7 8 9}

Is the drug Atorvastatin a promising treatment for reducing liver cancer risk in people with liver fibrosis?

Yes, Atorvastatin shows promise in reducing liver cancer risk, especially in patients with liver diseases like hepatitis C and nonalcoholic fatty liver disease. It has been associated with a lower risk of developing liver cancer and slowing down liver damage. ^{2 3 6 10 11}

What is the purpose of this trial?

Prospective randomized, multi-center, double blind placebo-controlled trial to assess the chemopreventive impact of atorvastatin (20 mg oral) vs placebo in up to 60 adults with advanced fibrosis at high risk of developing HCC.

Research Team

Raymond Chung, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults over 18 with advanced liver fibrosis or cirrhosis at high risk for developing liver cancer (HCC) can join. They must be able to take medication as directed and complete study visits. Women who can have children must use birth control, and participants need recent liver imaging. People with other major illnesses, certain chronic liver diseases, uncontrolled infections like HIV or hepatitis B, a history of drug abuse, or those on statins recently cannot join.

Inclusion Criteria

I can follow the medication schedule and attend all study visits.

The subject must be able to comply with the instructions for taking the study drug and be able to complete the study schedule of assessments.

My scans show a liver condition with increased blood pressure in the portal vein.

Exclusion Criteria

ALT > 10 x ULN

Known positivity for HIV infection

I have been diagnosed with a chronic liver disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atorvastatin or placebo daily for 48 weeks to assess chemopreventive impact on HCC risk

48 weeks

Regular visits every 4 weeks, with additional visits at weeks 12, 24, 36, and 48

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a 5-year observational study to examine HCC incidence

5 years

Treatment Details

Interventions

• Atorvastatin
• Placebo

Trial Overview The trial is testing if Atorvastatin (20 mg daily pill) prevents liver cancer better than a placebo in people with serious scarring of the liver due to disease. It's a controlled test where neither doctors nor patients know who gets the real medicine versus a fake pill to ensure unbiased results.

Participant Groups

Group I: Group A: Atorvastatin 20 mg Experimental Treatment 1 Intervention

Atorvastatin 20mg will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

Group II: Group B: Placebo to Match (PTM) Placebo Group 1 Intervention

PTM will be administered daily via oral route for 48 consecutive weeks on an outpatient basis.

Atorvastatin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

Raymond Chung

Lead Sponsor

Trials

3

Recruited

100+

University of Texas Southwestern Medical Center

Collaborator

Trials

1,102

Recruited

1,077,000+

Findings from Research

In a study of over 73,000 patients with newly diagnosed cirrhosis, higher cholesterol levels were linked to better liver function and lower mortality rates, suggesting that hyperlipidemia may have protective effects in these patients.

Each additional year of statin use was associated with an 8.0%-8.7% reduction in mortality for patients with cirrhosis, indicating that statins can be beneficial and should not be avoided due to concerns about liver toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis. Kaplan, DE., Serper, MA., Mehta, R., et al.[2019]

In a study of 9,135 patients with chronic hepatitis C, statin use was linked to a 44% reduction in the development of cirrhosis and a 49% reduction in hepatocellular carcinoma (HCC), indicating significant protective effects against liver disease progression.

The effectiveness of statins was dose-dependent, with atorvastatin and fluvastatin showing the most pronounced antifibrotic effects, suggesting that higher doses may provide greater benefits in managing fibrosis and reducing cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Simon, TG., Bonilla, H., Yan, P., et al.[2022]

Lipophilic statins, especially atorvastatin, significantly reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis by suppressing high-risk liver gene patterns associated with cancer development.

Atorvastatin uniquely inhibits key pathways (YAP and AKT) involved in liver cancer progression, making it a promising candidate for HCC chemoprevention in patients with liver diseases like hepatitis C and nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Kim, MH., Kim, MY., Salloum, S., et al.[2022]

In a study of 1,036 patients with stage I or II hepatocellular carcinoma (HCC), those using statins had a longer median survival of 23.9 months compared to 18.9 months for nonusers, suggesting a potential benefit.

However, after adjusting for various biases and confounding factors, statin use was not significantly associated with improved survival rates, indicating that statins do not enhance survival in elderly patients with early-stage liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin Use and Survival with Early-Stage Hepatocellular Carcinoma. Jeon, CY., Goodman, MT., Cook-Wiens, G., et al.[2017]

In a study of 1,072 patients with nonalcoholic steatohepatitis (NASH) and advanced liver fibrosis, those with bridging fibrosis (F3) showed no cases of hepatocellular carcinoma (HCC) during follow-up, indicating a low risk for this group.

Among patients with cirrhosis (F4), the annual incidence of HCC was 1.90 per 100 person-years, and statin use was associated with a significantly lower risk of developing HCC, with a 23.6% reduction in risk for each additional year of statin use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis. Pinyopornpanish, K., Al-Yaman, W., Butler, RS., et al.[2022]

Atorvastatin effectively reduced serum cholesterol levels in mice but did not decrease the size or number of chemically induced liver tumors, indicating it does not inhibit hepatocellular carcinoma (HCC) growth.

The study challenges the idea that long-term atorvastatin use may protect against HCC, as it showed no beneficial effects on tumor growth despite changes in drug uptake transporters in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemically induced mouse liver tumors are resistant to treatment with atorvastatin. Braeuning, A., Bucher, P., Hofmann, U., et al.[2022]

Statins, while generally well tolerated, can cause idiosyncratic liver injury in 1.9%-5.5% of patients, particularly with atorvastatin and simvastatin, which have over 50 reported cases of liver damage.

Most patients who experience liver injury from statins recover after stopping the medication, although there have been rare cases leading to severe outcomes like liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatotoxicity of statins and other lipid-lowering agents. Björnsson, ES.[2022]

Statins, known for lowering cholesterol, also have beneficial effects in cirrhosis patients, including anti-inflammatory properties and potential to reduce the risk of liver complications and mortality, based on retrospective studies.

Ongoing clinical trials are expected to provide more insights into the safety and effectiveness of statins in treating cirrhosis, which could influence future treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC. Sharpton, SR., Loomba, R.[2023]

In a study of 42 patients with nonalcoholic steatohepatitis treated with atorvastatin for 12 months, significant improvements were observed in liver injury markers and metabolic profiles, including decreased liver transaminases and triglycerides, and increased beneficial adiponectin levels.

Atorvastatin's effectiveness in improving disease activity is linked to its ability to lower tumor necrosis factor-α levels, suggesting a mechanism by which it alleviates inflammation associated with nonalcoholic steatohepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property. Hyogo, H., Yamagishi, S., Maeda, S., et al.[2022]

In a study involving 94 cases of hepatocellular carcinoma (HCC) and 468 matched controls, statin use was found to be significantly associated with a reduced risk of developing HCC, with an odds ratio of 0.32.

The protective effect of statins against HCC was consistent regardless of the duration of use, indicating that even short-term use may be beneficial in lowering HCC risk in low-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin use and risk of hepatocellular carcinoma in a U.S. population. McGlynn, KA., Divine, GW., Sahasrabuddhe, VV., et al.[2021]

In a study of 16,668 adults with chronic hepatitis B or C, lipophilic statin users had a significantly lower 10-year risk of developing hepatocellular carcinoma (HCC) compared to nonusers, with a risk reduction of 4.8 percentage points.

Both lipophilic and hydrophilic statin users experienced lower 10-year mortality rates, but only lipophilic statins showed a strong association with reduced HCC incidence, suggesting they may be more effective in preventing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Simon, TG., Duberg, AS., Aleman, S., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Statin Use and Survival with Early-Stage Hepatocellular Carcinoma. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Chemically induced mouse liver tumors are resistant to treatment with atorvastatin. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Hepatotoxicity of statins and other lipid-lowering agents. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Statin use and risk of hepatocellular carcinoma in a U.S. population. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. [2021]