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Over the past two decades, the management of hepatocellular carcinoma (HCC) has evolved significantly. Multidisciplinary and personalized approach to patient care, improvement in techniques of various locoregional treatments, and most notably, progress occurring in systemic therapies for advanced unresectable HCC have improved prognosis. Since sorafenib was approved in 20081 as the first systemic treatment for advanced HCC, tyrosine kinase inhibitors and immune checkpoint inhibitors with or without anti-vascular endothelial growth factor (anti-VEGF) inhibitors have been rapidly emerging, including lenvatinib,2 atezolizumab plus bevacizumab,3 durvalumab plus tremelimumab,4 and most recently nivolumab plus ipilimumab as first-line treatment.5 Minimally invasive surgery (i.e., robotic and laparoscopic surgery) is increasing based on promising results in overall survival and fewer complications compared to open surgery,6,7 and local ablative techniques have diversified, such as radiofrequency, microwave ablation, cryoablation, and injection of chemicals.8 Transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation therapy (SBRT) are developing into a more targeted and individualized approach such as the drug-eluting beads TACE9 or the personalized dosimetry approach in TARE.10 The combination of different locoregional and systemic treatment modalities such as TACE in combination of sorafenib and immune checkpoint inhibitors or TACE plus SBRT has been shown to improve survival outcomes and is increasingly being explored in recent studies.11,12
In this issue of the Journal of Liver Cancer, Han et al.13 analyzed the trends in epidemiology, etiology, and treatment patterns for HCC in South Korea between 2008 and 2022 using the National Health Insurance database. Overall, there was a decreasing trend in incidence, with the crude rate declining from 23.9 cases in 2008 to 20.4 cases per 100,000 by 2022. However, there was a notable increase in the proportion of elderly (above the age of 70). There was a shift in the etiology of HCC: portion of hepatitis B virus decreased (68.9% of HCC cases in 2008 and 59.7% in 2022) while an increase in metabolic dysfunction associated fatty liver disease (MAFLD) (7.5% in 2008 to 11.8% in 2022) and alcohol-associated liver disease (ALD) (8.9% in 2008 to 15.8% in 2022) were observed. Transarterial therapy was the dominant treatment in 2008, accounting for 49.9% of initial treatments, but decreased to 36.6% in 2022. Surgical resection increased from 12.2% to 21.3%, with a surge in laparoscopic resections, and systemic therapy increased from 0.2% to 9.6% between 2008 and 2022. Sorafenib was the sole systemic therapy of choice earlier, while atezolizumab-bevacizumab became the most widely used in 2022 taking up to 63.1% of patients receiving systemic therapy. Best supportive care also decreased from 31.7% to 21.3%.
Along with the rising prevalence of metabolic syndrome, MASLD is the most rapidly increasing etiology of HCC cases globally, increasing by 39% from 2010 to 2019, and the fastest-growing cause of liver cancer deaths, with a 38% increase, compared to a 21% rise in other causes.14 The rise in global per-capita alcohol consumption has also led to an increase in ALD and alcohol-associated HCC globally, especially during the COVID-19 pandemic.15 South Korea, located in East Asia, is an endemic area to hepatitis B,16 and demonstrated a decrease in hepatitis B virus (HBV)-associated HCC cases from 68.9% to 59.7% between 2008 and 2022, in contrast to the increasing proportion of HCC due to MASLD and ALD. The use of oral antiviral treatment for HBV, such as tenofovir, and the expansion of universal vaccination, especially in newborns and infants, have contributed to a marked decline in prevalence in South Korea and East Asia.17
The proportion of best supportive care as initial treatment has decreased while the proportion of curative treatment for HCC has increased, likely due to improvements in early detection and more widespread surveillance. Additional measures need to be implemented to improve adherence and compliance to surveillance and in enhanced screening methods, such as more advanced imaging techniques (e.g., abbreviated magnetic resonance imaging)18 or the use of non-invasive biomarkers (e.g., alpha-fetoprotein [AFP]-L3, des-gamma-carboxy prothrombin [DCP]), which will identify HCC at earlier stages when curative treatments are feasible.19
The shift of systemic therapies from the dominance of sorafenib to the emergence of atezolizumab-bevacizumab or lenvatinib presented in this study reflects the significant progress in systemic treatment of HCC management, offering promising survival benefits for patients with advanced-stage disease, although data is limited for non-reimbursed treatments in South Korea. An additional limitation is that it lacks data on the long-term prognostic impact of the change in etiology and treatment pattern on a national basis. While we expect to see improvement in survival outcomes with improvement in therapeutic modalities, it is essential to validate the efficacy of these newly emerging systemic therapies through a large-scale cohort and guide treatment directions in the future.
This study highlighted a shift in patient demographics with an increase in the older patient population, changes in etiology with ALD and MASLD emerging as major etiologies, increased utilization of minimally invasive surgeries, and the emergence and development of systemic treatments increasing adoption of immune checkpoint inhibitor treatment for advanced HCC that align with the global trends of HCC epidemiology. Future studies should investigate how the shifting landscape of HCC etiology and treatment strategies influence patient outcomes and prognosis.
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