Tumor burden and frailty: No association in liver transplant candidates with hepatocellular carcinoma

Background: Frailty studies in liver transplant (LT) candidates have largely focused on patients with cirrhosis without hepatocellular carcinoma (HCC). However, HCC patients represent a distinct subgroup - typically older, with better compensated liver disease and more non-hepatic comorbidities. These factors, along with tumor burden, may influence frailty. We aimed to characterize and compare frailty in HCC versus non-HCC LT candidates. Methods: We included adults with cirrhosis listed for LT at a single U.S. center (2012-2024) who underwent ambulatory frailty assessment using the Liver Frailty Index (LFI; “frail”= LFI≥4.4). HCC tumor characteristics at diagnosis—including number of lesions, tumor size, AFP levels, and initial treatment—were captured using automated extraction. Logistic regression evaluated associations between tumor burden and frailty. Results: Of 2,420 LT patients, 801 (33%) had HCC. Frailty was observed in only 9% of HCC patients, compared to 21% of non-HCC patients. Among frail patients, those with HCC were older, had lower MELD scores, and lower rates of ascites, hepatic encephalopathy and dialysis. Rates of hypertension and diabetes were similar, though HCC patients trended toward more coronary artery disease. Tumor burden, total tumor diameter, and AFP did not differ between frail and non-frail HCC patients ( p >0.21), and were not associated with frailty in regression analyses. Conclusion: In this large cohort of HCC LT candidates, frailty was associated with hepatic (e.g., MELD, ascites, HE) and non-hepatic (e.g., gender, obesity) factors, but not with tumor characteristics. This differs from patients with non-HCC malignancy, in whom cancer-related frailty is common. Patients with HCC awaiting liver transplantation, who generally have well-compensated liver disease, may therefore exhibit a distinct frailty profile—driven by non-hepatic comorbidities rather than by liver failure or tumor burden. These findings support the need for HCC-specific frailty research to guide evaluation and management.