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mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors

: Schnitzbauer, A.A.; Filmann, N.; Adam, R.; Bachellier, P.; Bechstein, W.O.; Becker, T.; Bhoori, S.; Bilbao, I.; Brockmann, J.; Burra, P.; Chazoullières, O.; Cillo, U.; Colledan, M.; Duvoux, C.; Ganten, T.M.; Gugenheim, J.; Heise, M.; Hoek, B. van; Jamieson, N.; Jong, K.P. de; Klein, C.G.; Klempnauer, J.; Kneteman, N.; Lerut, J.; Mäkisalo, H.; Mazzaferro, V.; Mirza, D.F.; Nadalin, S.; Neuhaus, P.; Pageaux, G.-P.; Pinna, A.D.; Pirenne, J.; Pratschke, J.; Powel, J.; Rentsch, M.; Rizell, M.; Rossi, G.; Rostaing, L.; Roy, A.; Scholz, T.; Settmacher, U.; Soliman, T.; Strasser, S.; Söderdahl, G.; Troisi, R.I.; Turrión, V.S.; Schlitt, H.J.; Geissler, E.K.


Annals of surgery 272 (2020), Nr.5, S.855-862
ISSN: 0003-4932
ISSN: 1528-1140
Fraunhofer ITEM ()

Objective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). Summary and Background Data: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial ( NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. Patients and Methods: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. Results: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52–0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49–0.59, P = 0.0079–0.0245). Conclusions: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients.