Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

Edward K. Geissler*, Andreas A. Schnitzbauer, Carl Zuelke, Philipp E. Lamby, Andrea Proneth, Christophe Duvoux, Patrizia Burra, Karl-Walter Jauch, Markus Rentsch, Tom M. Ganten, Jan Schmidt, Utz Settmacher, Michael Heise, Giorgio Rossi, Umberto Cillo, Norman Kneteman, Rene Adam, Bart van Hoek, Philippe Bachellier, Philippe WolfLionel Rostaing, Wolf O. Bechstein, Magnus Rizell, James Powell, Ernest Hidalgo, Jean Gugenheim, Heiner Wolters, Jens Brockmann, Andre Roy, Ingrid Mutzbauer, Angela Schlitt, Susanne Beckebaum, Christian Graeb, Silvio Nadalin, Umberto Valente, Victor Sanchez Turrion, Neville Jamieson, Tim Scholz, Michele Colledan, Fred Faendrich, Thomas Becker, Gunnar Soderdahl, Olivier Chazouilleres, Heikki Makisalo, Georges-Philippe Pageaux, Rudolf Steininger, Thomas Soliman, Koert P. de Jong, Jacques Pirenne, Raimund Margreiter, Johann Pratschke, Antonio D. Pinna, Johann Hauss, Stefan Schreiber, Simone Strasser, Juergen Klempnauer, Roberto I. Troisi, Sherrie Bhoori, Jan Lerut, Itxarone Bilbao, Christian G. Klein, Alfred Koenigsrainer, Darius F. Mirza, Gerd Otto, Vincenzo Mazzaferro, Peter Neuhaus, Hans J. Schlitt

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).

Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.

Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).

Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Original languageEnglish
Pages (from-to)116-125
Number of pages10
Issue number1
Publication statusPublished - Jan-2016



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