mTOR inhibition is most beneficial after liver transplantation for hepatocellular carcinoma in patients with active tumors

Schnitzbauer, A.A.; Filmann, N.; Adam, R.P.; Bachellier, P.; Bechstein, W.O.; Becker, T.; Bhoori, S.; Bilbao, I.; Brockmann, J.; Burra, P.; Chazoullieres, 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.; Makisalo, 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.P.; Scholz, T.; Settmacher, U.; Soliman, T.; Strasser, S.; Soderdahl, G.; Troisi, R.I.; Turrion, V.S.; Schlitt, H.J.; Geissler, E.K.

doi:doi:10.1097/SLA.0000000000004280

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 LTwas 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...Show moreObjective: 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 LTwas 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.Show less

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mTOR inhibition is most beneficial after liver transplantation for hepatocellular carcinoma in patients with active tumors