Abstract
BACKGROUND: Systemic therapy for hepatocellular carcinoma (HCC) can prolong survival, but outcomes vary, and predictors of response are not fully defined. Frailty is associated with worse outcomes in cirrhosis and liver transplantation, but its impact on patients with advanced HCC is unknown. PATIENTS AND METHODS: An international, multicentre, prospective, observational cohort of adults commencing systemic therapy for HCC from 2019 to 2022 was analysed. Frailty was assessed by the Liver Frailty Index (LFI). The primary outcome was overall survival; secondary outcomes were disease progression, adverse events, and treatment discontinuation. RESULTS: Among 102 patients, 80% were male and the median age was 67 years [interquartile range (IQR) 60-73 years]. Most had viral hepatitis (hepatitis C virus 39%, hepatitis B virus 29%), were Child-Pugh A (75%), Eastern Cooperative Oncology Group (ECOG) 0-1 (89%), and Barcelona Centre Liver Cancer (BCLC) stage C (59%). Similar proportions received tyrosine kinase inhibitors (54%) and immunotherapy (46%). The median LFI was 4.13 (IQR 3.81-4.43): 4% were robust (LFI <3.2), 75% were pre-frail (LFI 3.2-<4.5), and 22% were frail (LFI 4.5+). LFI was independently associated with death (adjusted hazard ratio 1.74, 95% confidence interval 1.17-2.59, P = 0.006), after adjustment for Child-Pugh score and albumin-bilirubin grade. The optimal cut-off for survival at 1 year was LFI 4.2 (area under the curve 0.658), significant on univariable and multivariable analyses at predicting death. Frailty was associated with earlier systemic therapy discontinuation, despite similar rates of disease progression and adverse events; cessation of treatment due to functional decline was more common among frail patients. Sensitivity analysis excluding patients above Child-Pugh B8 or ECOG 2 did not change results. CONCLUSION: The LFI is an independent predictor of death among patients with HCC undergoing systemic therapy.