Causes of mortality among patients with early-stage hepatocellular carcinoma

Background and Aims: Early detection of hepatocellular carcinoma (HCC) can reduce cancer-related mortality; however, there are often competing risks from comorbid conditions, including cirrhosis. Understanding causes of death among patients with early-stage HCC can inform strategies to improve surveillance effectiveness. Approach and Results: We conducted a retrospective cohort study of patients with early-stage HCC [Barcelona Clinic Liver Cancer (BCLC) stages 0/A] at 4 U.S. health systems between 2008 and 2022. We defined the primary cause of death as HCC-related, liver-related (non-HCC), and death from other causes. We used multivariable and Fine–Gray analysis, with liver transplant as a competing outcome, to identify factors associated with mortality. Among 1336 patients with early-stage HCC, 598 (44.8%) died during a median follow-up of 32.4 months—220 (37%) HCC-related, 114 (19%) liver-related, and 179 (30%) from other causes. Median time to death was similar between the groups: 24 (95% CI 22–31), 19 (95% CI 15–23), and 23 (95% CI 19–27) months for HCC-related, liver-related, and other causes of mortality, respectively. Curative treatment was associated with reduced HCC-related (HR 0.34; 95% CI 0.23–0.48) and liver-related mortality (HR 0.23; 95% CI 0.14–0.38). Predictors of HCC-related mortality included alpha-fetoprotein (AFP) >20 ng/mL (HR 2.19; 95% CI 1.59–3.03) and tumor diameter >3 cm (HR 1.69; 95% CI 1.20–2.37). Liver-related mortality was associated with MASLD (metabolic dysfunction–associated steatotic liver disease) etiology (HR 1.99; 95% CI 1.09–3.65), Child–Pugh B cirrhosis (HR 2.64; 95% CI 1.58–4.42), and Albumin–Bilirubin (ALBI) grade 2 (vs. grade 1: HR 2.47; 95% CI 1.21–5.06). Conclusions: Cause of death varies among patients with early-stage HCC, although HCC-related death remains the most common cause. Efforts are needed to optimize curative treatment effectiveness among patients with early-stage HCC to reduce cancer-related mortality.