Survival benefit associated with liver transplantation for hepatocellular carcinoma based on tumor burden scores at listing

Abstract

Introduction: Liver transplantation (LT) provides significant survival benefits to patients with unresectable HCC. In the United States, organ allocation policies for HCCs within the United Network for Organ Sharing criteria do not prioritize patients based on their differences in oncological characteristics. This study assessed whether transplant-associated survival benefits (TASBs) vary among patients with different tumor burden scores (TBS) measured at the time of listing.

Methods: We analyzed data from adults applying for HCC MELD exception points between 2002 and 2019, with follow-up until December 2023, using the Scientific Registry of Transplant Recipients. TBS was determined based on the largest tumor diameter and number of HCCs. Patients were categorized into low (≤3), intermediate (3.1-5), and high (>5) TBS groups. TASB was measured as the difference in 5-year survival with and without LT.

Results: This study included 36,634 LT candidates. High-TBS patients had higher waitlist dropout rates and marginally lower post-transplant survival, resulting in a significantly greater TASB. The 5-year TASB for the low, intermediate, and high TBS groups were 15.7, 22.1, and 25.0 months, respectively. The adjusted survival benefit expressed in 5-year survival differences was 21.9%, 34.5%, and 39.4% in the low, intermediate, and high TBS groups, respectively (p<0.001).

Conclusions: Higher TBS during listing correlates with greater LT benefits for patients with unresectable HCC within UNOS criteria. We conclude that organ allocation policies in the United States should prioritize patients with high TBS due to their increased risk of dropout and comparable post-transplant survival when compared to patients with less advanced tumors.

Graphical abstract

FIGURE 1

Flow diagram of the study population. After screening 211,230 patients, 174,596 were excluded, and 36,634 were included in the study. After a median follow-up of 31.0 months (IQR:10.4–74.6), a total of 24,457 patients were transplanted (66.7%), 2347 patients were still on the waitlist, 248 were removed from the waitlist because their conditions had improved, 2145 (5.8%) patients had died while waiting for surgery, and 7437 (20.3%) patients dropped out and were no longer suitable for liver transplant.

FIGURE 2

Unadjusted cumulative incidence function (Panel A) and competing risk regression analysis using the Fine-Gray method with multivariable adjustment on waitlist dropout (Panel B). Red line: low tumor burden (TBS≤3), green line: medium tumor burden (TBS=3.1-5), and blue line: high tumor burden (TBS>5). Subdistribution hazard models showed that patients with higher TBS had a greater relative incidence of waitlist dropout (subdistribution HR=1.52 [1.41–1.64], p<0.001). Adjusted for recipient age, MELD score, sex, blood type, body mass index, recipient race, risk factors for HCC (HCV status, HBV status, history of alcohol-associated cirrhosis, diagnosis of MAFLD, others), history of diabetes, need for dialysis, serum AFP level at the time of listing, and number of locoregional therapies received while on the waitinglist.

FIGURE 3

(A) Kaplan-Meier survival functions on the waitlist for liver transplantation for HCC stratified by TBS obtained at the time of listing. (B) Kaplan-Meier post- liver transplant survival functions of patients stratified by TBS at listing. (C) Kaplan-Meier post- liver transplant survival functions of disease-free survival stratified by TBS at listing. Multivariable-adjusted Cox proportional hazard regression showed that patients with highTBS had a 92% higher risk of death  on the waitlist than patients with low TBS (adjusted HR =1.92; 95% CI: 1.78–2.07). After liver transplantation, patients with high TBS had only a 29% and 34% higher likelihood of death or recurrent HCC in comparison to patients with low TBS. Multivariate analyses (*) for pre liver transplant outcomes were adjusted for age, MELD score, gender, blood type, BMI, recipient race, HCV, HBV, EtOH and MAFLD etiology, history of diabetes, need for dialysis, listing AFP, number of locoregional therapy, and multivariate analyses for post liver transplant outcomes  (**) were adjusted for above covariates as well as donor age, gender, race and cold ischemic time.

FIGURE 4

(A) Transplant-related survival benefit measured in months after liver transplantation stratified by the TBS measured at listing. The transplant-related survival benefit was measured as the difference between the AUCs representing the unadjusted survival functions of patients who underwent liver transplant and those who did not (Kaplan-Meier; p<0.001). (B) Multivariable-adjusted 5-year transplant-related survival benefits stratified by TBS (median and IQRs annotated). The adjusted transplant-related survival benefit was measured as the difference in 5-year survival probability between patients who underwent liver transplantation and those patients who did not receive transplantation (p<0.001). ** The multivariable model was adjusted for age, the MELD score, sex, blood type, body mass index (BMI), race, risk factors for HCC (HCV status, HBV status, alcohol-associated cirrhosis, MAFLD, others), history of diabetes, need for dialysis, serum levels of AFP at listing, number of locoregional therapies received while waiting for liver transplant, donor age, donor sex, donor race/ethnicity, and cold ischemic time.