Primary liver cancer is the third leading cause of cancer-related deaths worldwide and the sixth most diagnosed cancer overall. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and a significant global health challenge due to its high mortality rate, the 5-year survival rate is approximately 18%. (1) The prevalence of HCC rises with age and is caused by a confluence of somatic mutations, immune system inactivation, and extended exposure to risk factors. Approximately 80% of HCC cases arise in sub-Saharan Africa and Eastern Asia, aligning with the high number of chronic hepatitis B virus (HBV) carriers in these regions. Overall, the global burden of HCC has increased over time. Understanding the drivers of this increase in incidence and implementing both prevention and treatment strategies are essential to reversing this trend.
Primary Risk Factors Driving Increased Incidence
Chronic HBV infection is a major global health problem with high prevalence, that can lead to cirrhosis as well as to HCC. HBV infection rates have been gradually declining throughout Asia and the world since 1990, due in large part to the implementation of universal infant vaccination programs. Although HBV accounted for more than half of all HCC cases in 1990, the proportion decreased to 42% in 2019. (1)
Chronic hepatitis C virus (HCV) is a primary risk factor for HCC in Pakistan, the United States (US), and the Mediterranean region. (1) Direct-active antiviral therapies (DAAs) have reduced the number of cases of HCC associated with HCV. However, despite the availability of DAAs, many infected individuals remain undiagnosed or untreated, progressing to develop cirrhosis and increasing their risk for development of HCC.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), has emerged as the most rapidly expanding risk factor for HCC. Globally, the estimated proportion of patients with HCC with NAFLD ranges from 1% to 38% in different countries/regions; it is more often seen in countries with high sociodemographic indices, such as the US. Driven by rising obesity, type 2 diabetes and the prevalence of metabolic syndrome, MAFLD now affects about 100 million Americans (roughly 25% to 30% of the US population) and has emerged as the most common chronic liver condition in the US and a leading cause of cirrhosis. Individuals with MASLD, even prior to the onset of cirrhosis, are at risk for development of HCC (2).
Alcohol-related liver disease continues to contribute significantly, particularly following increased alcohol consumption patterns observed during and after the Coronavirus disease 2019 (COVID-19) pandemic. Additionally, the intersection of multiple risk factors compounds the risk for development of HCC, with individuals simultaneously exposed to viral hepatitis, metabolic disease and/or alcoholism demonstrating accelerated disease progression
A substantial barrier to improving outcomes of patients with HCC relates to the advanced stage at which most cases are diagnosed. Approximately 60% of HCC cases are detected at intermediate or advanced stages, limiting treatment options and reducing survival rtes. This delayed detection reflects inadequate screening among at-risk populations, limited awareness of HCC risk among both patients and primary care physicians, and among socioeconomically disadvantaged populations with limited healthcare access.
Addressing HCC requires multifaceted primary prevention efforts. Expanded HBV vaccination programs, particularly targeting adult populations and healthcare workers can prevent new infections. For persons with chronic HCV and cirrhosis, achievement of sustained virologic response with DAAs reduces the risk of HCC by 71 to 79%. Therefore, scaling up HCV screening and increasing access to DDA medications represents a critical public health priority.
Addressing metabolic disease requires population-level interventions including nutrition education, increased physical activity promotion and weight management programs. Healthcare systems must integrate metabolic risk assessment into routine care, identifying individuals with MAFLD before cirrhosis develops.
The escalating incidence of HCC requires coordinated efforts spanning primary prevention through risk factor reduction, enhanced surveillance and early detection programs. Expanding viral hepatitis screening and treatment, scaling up metabolic and alcohol-related liver disease prevention, and improving the rate of routine surveillance for high-risk individuals will help to reverse this trend.
As the global burden of HCC continues to evolve, addressing this growing challenge will require not only stronger prevention and early-detection strategies, but also continued innovation in clinical research. By supporting well-designed, patient-centered trials, oncology CROs, such as Linical, can help accelerate the development of new therapies and bring more effective treatment options to patients worldwide.
Author:
Julie Rosenberg, MD
Linical