mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors
Andreas A. Schnitzbauer, Natalie Filmann, René Adam, Philippe Bachellier, Wolf O. Bechstein, Thomas Becker, Sherrie Bhoori, Itxarone Bilbao, Jens Brockmann, Patrizia Burra, O. Chazoullières, Umberto Cillo, M. Colledan, C. Duvoux, Tom M. Ganten, Jean Gugenheim, Michael Heise, Bart van Hoek, Neville V. Jamieson, Koert P. de Jong, Christian Klein, Jürgen Klempnauer, Norman M. Kneteman, Jan Lerut, Heikki Mäkisalo, Vincenzo Mazzaferro, Darius F. Mirza, Silvio Nadalin, P. Neuhaus, G.-P. Pageaux, Antonio Daniele Pinna, Jaques Pirenne, Johann Pratschke, James Powel, Markus Rentsch, Magnus Rizell, G. Rossi, Lionel Rostaing, André Roy, Tim Scholz, Utz Settmacher, Thomas Soliman, Simone I. Strasser, Gunnar Söderdahl, Roberto Troisi, Víctor Sánchez Turrión, Hans J. Schlitt, Edward K. Geissler
Abstract
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 (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 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. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.