Risk assessment in liver transplantation for hepatocellular carcinoma: long-term follow-up of a two-centre experience

Abstract

Background: Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC), but there are ongoing debates regarding outcomes and selection. This study examines the experience of LT for HCC at a high-volume centre.

Methods: A prospectively maintained database was used to identify HCC patients undergoing LT from 2000 to 2020 with more than or equal to 3-years follow-up. Data were obtained from the centre database and electronic medical records. The Metroticket 2.0 HCC-specific 5-year survival scale was calculated for each patient. Kaplan-Meier and Cox-regression analyses were employed assessing survival between groups based on Metroticket score and individual donor and recipient risk factors.

Results: Five hundred sixty-nine patients met criteria. Median follow-up was 96.2 months (8.12 years; interquartile range 59.9-147.8). Three-year recurrence-free (RFS) and overall survival (OS) were 88.6% ( n =504) and 86.6% ( n =493). Five-year RFS and OS were 78.9% ( n =449) and 79.1% ( n =450). Median Metroticket 2.0 score was 0.9 (interquartile range 0.9-0.95). Tumour size greater than 3 cm ( P =0.012), increasing tumour number on imaging ( P =0.001) and explant pathology ( P <0.001) was associated with recurrence. Transplant within Milan ( P <0.001) or UCSF criteria ( P <0.001) had lower recurrence rates. Increasing alpha-fetoprotein (AFP)-values were associated with more HCC recurrence ( P <0.001) and reduced OS ( P =0.008). Chemoembolization was predictive of recurrence in the overall population ( P =0.043) and in those outside-Milan criteria ( P =0.038). A receiver-operator curve using Metroticket 2.0 identified an optimal cut-off of projected survival greater than or equal to 87.5% for predicting recurrence. This cut-off was able to predict RFS ( P <0.001) in the total cohort and predict both, RFS ( P =0.007) and OS ( P =0.016) outside Milan. Receipt of donation after brain death (DBD) grafts (55/478, 13%) or living-donor grafts (3/22, 13.6%) experienced better survival rates compared to donation after cardiac death (DCD) grafts ( n =15/58, 25.6%, P =0.009). Donor age was associated with a higher HCC recurrence ( P =0.006). Both total ischaemia time (TIT) greater than 6hours ( P =0.016) and increasing TIT correlated with higher HCC recurrence ( P =0.027). The use of DCD grafts for outside-Milan candidates was associated with increased recurrence ( P =0.039) and reduced survival ( P =0.033).

Conclusion: This large two-centre analysis confirms favourable outcomes after LT for HCC. Tumour size and number, pre-transplant AFP, and Milan criteria remain important recipient HCC-risk factors. A higher donor risk (i.e. donor age, DCD grafts, ischaemia time) was associated with poorer outcomes.

Trial registration: ClinicalTrials.gov NCT06018857.

Figure 1

Metroticket 2.0 model performance for predicting recurrence in hepatocellular carcinoma (HCC) after liver transplantation (LT). (A) Receiver-operator curve examining the sensitivity and 1-specificity of the Metroticket 2.0 HCC-specific Five-year mortality calculator at predicting recurrence-free survival after LT for HCC. (B) Receiver-operator curve examining the sensitivity and 1-specificity of the Metroticket 2.0 HCC-specific 5-year mortality calculator at predicting recurrence-free survival after LT for HCC stratified by patient hepatitis C status, demonstrating that the model is applicable to patients with (green) and without (blue) HCV.

Figure 2

Survival analysis based on Metroticket 2.0 predicted survival after liver transplantation for hepatocellular carcinoma. Kaplan–Meier survival curves for patients split based on Metroticket 2.0 predicted survival greater than or equal to 87.5% (Green) or less than 87.5% (Red), using the cut-off established using the ROC analysis described and demonstrated in Fig. 1. (A) Recurrence-free survival (RFS) based on Metroticket 2.0. Metroticket 2.0 predicted survival greater than or equal to 87.5% is associated with improved recurrence free (RFS) (P<0.001). (B) Overall survival (OS) based on Metroticket 2.0. Metroticket 2.0 predicted survival greater than or equal to 87.5% approached ability to predict OS but was not significant (P=0.094). (C) RFS for patients outside of Milan Criteria. Metroticket 2.0 predicted survival greater than or equal to 87.5% is associated with improved recurrence free (RFS) (P=0.007). (D) OS for patients outside of Milan Criteria. Metroticket 2.0 predicted survival greater than or equal to 87.5% is associated with improved recurrence free (OS) (P=0.016).

Figure 3

Survival analysis based on graft type after LT for HCC. Kaplan–Meier curves demonstrating the association between graft type and recurrence free (RFS) or overall survival (OS) after liver transplant for hepatocellular carcinoma. Graft types included brain dead (DBD, Blue), cardiac death (DCD, Green) or living donor (LDLT, Red). (A) RFS for all included patients by graft type. Graft type was not associated with reduction in recurrence in the complete cohort (P=0.765) (B) OS for all included patients by graft type. DCD was associated with a reduced survival (0.009). (C) RFS for LT outside of Milan criteria. LT outside of Milan had improved RFS with DBD vs. DCD grafts (P=0.039). (D) OS for LT outside of Milan criteria. LT outside of Milan had improved OS with DBD vs. DCD grafts (P=0.033).

Figure 4

Survival analysis excluding early liver transplantation (LT)-associated mortality. Kaplan–Meier analysis for the subset of patients (n=525) that excludes patients who died of non-hepatocellular carcinoma causes directly attributable to early complications of their LT. (A) RFS for all included patients by graft type. Graft types included brain dead (DBD, Blue), cardiac death (DCD, Green) or living donor (LDLT, Red). Graft type was not associated with reduction in recurrence in this cohort (P=0.603). (B) OS for all included patients by graft type. DCD was associated with a reduced survival (0.046). (C) RFS for LT split based on Metroticket 2.0 predicted survival greater than or equal to 87.5% (Green) or less than 87.5% (Red). After excluding early LT-related complications, Metroticket predicted survival was able to predict RFS (P<0.001). (D) OS for LT split based on Metroticket 2.0 predicted survival. Again, Metroticket was predictive of survival (P=0.004).

Figure 5

Risk profile and outcomes of liver transplantation (LT) for HCC by era. (A) Proportion of patients inside (green) and outside (blue) Milan criteria by each era of our program divided into half-decade blocks, from 2000 to 2005, 2005 to 2010, 2011 to 2015, 2016 to 2020. (B) Proportion of patients inside (green) and outside (blue) Metroticket greater than or equal to 0.875 criteria by each era of our program divided into half-decade blocks. (C) Recurrence-free survival was not different (P=0.162) between eras despite significant differences in risk profile. (D) Overall survival was not different (P=0.149) between eras despite significant differences in risk profile.