Abstract

Background: Hepatocellular carcinoma (HCC) recurrence risk after liver transplantation (LT) has been evaluated with different prediction models following pathology explant analysis. The inclusion of alpha-feto protein (AFP) in these models, such as the novel R3-AFP score (1), have significantly improved risk stratification of HCC recurrence post-LT. The SiLVER trial (NCT00355862) evaluated the efficacy of mTOR inhibitors (Sirolimus-Group B) compared to mTOR-free based immunosuppression (Group A) to reduce post-LT HCC recurrence (2). Here, we aimed to validate the prognostic and predictive discrimination power of R3-AFP scoring on the intention-to-treat population (ITT) included in the SiLVER trial (NCT00355862).

Methods: We included the intention-to-treat (ITT) patient population from the SiLVER Study. Cox proportional hazard survival analysis was performed, estimating hazard ratios (HR) and 95% confidence intervals (95% CI). Discriminant function was evaluated using the Harrell’s c-index. A competing risk regression analysis was also conducted estimating sub-HR. Calibration was conducted through expected versus observed events estimating the baseline hazard.

Results: Overall, 528 patients signed written informed consent of which 20 were excluded for the intention-to-treat analysis (Group A, n=256 ; Group B, n=252). The 5-year recurrence rate in the ITT population was 18.7% (95% CI 15.3-22.6; n=88 recurrences). The frequency distribution of the R3-AFP score was 42.6% low risk group (n=216), 35.7% (n=181) intermediate risk, 19.5% high risk group (n=99), and 2.2% very high risk group (n=11). The R3-AFP score correctly stratified HCC recurrence risk (Figure 1) (reference: low risk group): intermediate risk group SHR 1.80 (95% CI 1.02;3.18), high risk group SHR 4.20 (2.41;7.31), and very high risk group SHR 9.55 (3.66;24.92). Discrimination power for the R3_AFP model was 0.75 (95% CI 0.69;0.81) in the ITT population; lower in the mTOR group [Group A 0.75 (CI 0.69-0.81) when compared to Group B 0.67 (0.59-0.75); P=0.048]. No significant differences were observed between expected and observed events across R3-AFP strata.

Conclusion: The R3-AFP score has been validated in the ITT population of the SiLVER trial, a high-quality evidenced-based data, showing good performance. The model had lower discrimination of the risk of recurrence in exposed subjects with mTOR immunosuppression. This should lead to further hypothesis testing.

• 1. Costentin C, et al. JHEP Rep. 2022 Feb 2;4(5):100445. doi: 10.1016/j.jhepr.2022.100445.
• 2. Geissler, EK; et al. Transplantation 100(1):p 116-125, January 2016. | DOI: 10.1097/TP.0000000000000965