By Prof John Olynyk, Curtin University
Hepatic cirrhosis and hepatocellular carcinoma (HCC) are rapidly increasing causes of premature morbidity and death globally.
In 2021, Deloitte Access Economics reported costs of HCC to the health system, productivity and loss of wellbeing in Australia were $140m, $382m and $4.3b a year, respectively.
HCC is the second most common global cause of years-of-life-lost due to malignancy, and the commonest cause of death in cirrhosis.
Globally, the incidence of HCC is increasing at a far greater rate than all other malignancies. Between 2000 and 2015 the liver cancer death rate increased by 50% in men and women, especially in those of lower socioeconomic groups.
In Australia, HCC is now the second leading cause of cancer-related death in men, and of higher incidence in Aboriginal, regional and culturally and linguistically diverse communities. The peak age of incidence is 70 years.
Over 90% of cases of HCC occur in the setting of established cirrhosis. Chronic viral hepatitis B or C, and the chronic steatotic liver diseases (SLDs), which encompass the spectrum of metabolic-associated (MASLD, previously known as nonalcoholic fatty liver disease) through to alcohol-related liver disease, are the commonest aetiologies leading to the development of cirrhosis and HCC.
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The clinical impact of HCC is devastating – 90% of all individuals who develop HCC die of the disease – the highest mortality rate of all cancers.
Even with the development of cancer surveillance and new treatments, the World Health Organization predicts that the incidence of HCC will increase by 60% over the next 30 years and the mortality will remain approximately 90%.
Clearly, there is a significant gap in the provision of current care, with the only effective way to reduce the future burden of disease being through prevention of HCC in people with cirrhosis.
Aspirin for prevention
Based on compelling epidemiological data there is a strong rationale for a randomised clinical trial to test the benefits of aspirin for prevention of HCC. Low dose aspirin consumption (100mg daily) has been associated with a 50-70% reduction in the incidence of HCC.
The longer the duration of treatment, the greater the reduction in incidence. Similar benefits were observed in men and women.
Cessation of aspirin therapy was associated with a reversion back to the general population risk of HCC, suggesting that aspirin was inducing the protective effect.
The 10-year liver-related mortality was also reduced by 30%. The magnitude of benefit associated with aspirin was significantly stronger in subjects with cirrhosis. Thus, aspirin represents an ideal low-risk agent to systematically evaluate in the prevention of HCC in cirrhotic subjects.
Whilst aspirin was safe, with no increased risk of gastrointestinal bleeding in aspirin-users compared with non-users, concerns remain regarding its safety in routine clinical care.
Putting it to the test
We will conduct a prospective, randomised clinical trial over four years to evaluate the effects of daily aspirin compared with placebo therapy on the incidence of HCC in 890 stable, well-compensated cirrhotic subjects attending hospital outpatient clinics and otherwise receiving standard of care treatment.
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Five large Australian hospitals and two UK sites will participate in the research program.
If successful, our trial will deliver significant health impact through change in practice, providing a clinical indication for aspirin prophylaxis to become standard-of-care for the prevention of HCC in people with cirrhosis, and reduce the incidence and mortality of HCC by at least 50%.
These important outcomes will deliver significant economic impact, saving the Australian economy at least $70m a year in direct health care costs.
Key messages
- Hepatocellular carcinoma is the commonest cause of mortality in people with cirrhosis and the second most common cause of years-of-life-lost due to malignancy after lung cancer world-wide
- Most cases of hepatocellular carcinoma occur in the setting of cirrhosis and are diagnosed at an incurable stage with mortality approximating 90%
- Potential prevention of hepatocellular carcinoma in people who have cirrhosis could reduce the incidence by up to 50%. We will conduct a prospective, placebo-controlled trial of aspirin to determine if this is possible.
Author competing interests – the author is involved in the research described
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