• Andreas A Schnitzbauer, Natalie Filmann, René Adam, Philippe Bachellier, Wolf O Bechstein, Thomas Becker, Sherrie Bhoori, Itxarone Bilbao, Jens Brockmann, Patrizia Burra, Olivier Chazoullières, Umberto Cillo, Michele Colledan, Christoph Duvoux, Tom M Ganten, Jean Gugenheim, Michael Heise, Bart van Hoek, Neville Jamieson, Koert P de Jong, Christian G Klein, Jürgen Klempnauer, Norman Kneteman, Jan Lerut, Heikki Mäkisalo, Vincenzo Mazzaferro, Darius F Mirza, Silvio Nadalin, Peter Neuhaus, George-Philippe Pageaux, Antonio D Pinna, Jaques Pirenne, Johann Pratschke, James Powel, Markus Rentsch, Magnus Rizell, Giorgio Rossi, Lionel Rostaing, André Roy, Tim Scholz, Utz Settmacher, Thomas Soliman, Simone Strasser, Gunnar Söderdahl, Roberto I Troisi, Victor Sánchez Turrión, Hans J Schlitt, and Edward K Geissler.
• Universitätsklinikum Frankfurt, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Frankfurt am Main, Germany.
• Ann. Surg. 2020 Nov 1; 272 (5): 855-862.

ObjectiveThe 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 DataPatients 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 (Clinicaltrials.gov: 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 MethodsData 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.ResultsSirolimus 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).ConclusionsmTOR-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.Clinical Trial RegistrationEudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

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