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

Geissler, E. K., Schnitzbauer, A. A., Zulke, C., Lamby, P. E., Proneth, A., Duvoux, C., Burra, P., Jauch, K. W., Rentsch, M., Ganten, T. M., Schmidt, J., Settmacher, U., Heise, M., Rossi, G., Cillo, U., Kneteman, N., Adam, R., van Hoek, B., Bachellier, P., Wolf, P., Rostaing, L., Bechstein, W. O., Rizell, M., Powell, J., Hidalgo, E., Gugenheim, J., Wolters, H., Brockmann, J., Roy, A., Mutzbauer, I., Schlitt, A., Beckebaum, S., Graeb, C., Nadalin, S., Valente, U., Turrion, V. S., Jamieson, N., Scholz, T., Colledan, M., Fandrich, F., Becker, T., Soderdahl, G., Chazouilleres, O., Makisalo, H., Pageaux, G. P., Steininger, R., Soliman, T., de Jong, K. P., Pirenne, J., Margreiter, R., Pratschke, J., Pinna, A. D., Hauss, J., Schreiber, Stefan, Strasser, S., Klempnauer, J., Troisi, R. I., Bhoori, S., Lerut, J., Bilbao, I., Klein, C. G., Konigsrainer, A., Mirza, D. F., Otto, G., Mazzaferro, V., Neuhaus, P. and Schlitt, H. J. (2016) Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial Transplantation, 100 (1). pp. 116-125. DOI 10.1097/TP.0000000000000965.

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Abstract

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.

Document Type: Article
Additional Information: Times Cited: 22 Geissler, Edward K. Schnitzbauer, Andreas A. Zuelke, Carl Lamby, Philipp E. Proneth, Andrea Duvoux, Christophe Burra, Patrizia Jauch, Karl-Walter Rentsch, Markus Ganten, Tom M. Schmidt, Jan Settmacher, Utz Heise, Michael Rossi, Giorgio Cillo, Umberto Kneteman, Norman Adam, Rene van Hoek, Bart Bachellier, Philippe Wolf, Philippe Rostaing, Lionel Bechstein, Wolf O. Rizell, Magnus Powell, James Hidalgo, Ernest Gugenheim, Jean Wolters, Heiner Brockmann, Jens Roy, Andre Mutzbauer, Ingrid Schlitt, Angela Beckebaum, Susanne Graeb, Christian Nadalin, Silvio Valente, Umberto Sanchez Turrion, Victor Jamieson, Neville Scholz, Tim Colledan, Michele Faendrich, Fred Becker, Thomas Soderdahl, Gunnar Chazouilleres, Olivier Makisalo, Heikki Pageaux, Georges-Philippe Steininger, Rudolf Soliman, Thomas de Jong, Koert P. Pirenne, Jacques Margreiter, Raimund Pratschke, Johann Pinna, Antonio D. Hauss, Johann Schreiber, Stefan Strasser, Simone Klempnauer, Juergen Troisi, Roberto I. Bhoori, Sherrie Lerut, Jan Bilbao, Itxarone Klein, Christian G. Koenigsrainer, Alfred Mirza, Darius F. Otto, Gerd Mazzaferro, Vincenzo Neuhaus, Peter Schlitt, Hans J.
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
DOI etc.: 10.1097/TP.0000000000000965
ISSN: 0041-1337
Projects: Future Ocean
Date Deposited: 17 Mar 2017 07:07
Last Modified: 22 May 2017 11:28
URI: http://eprints.uni-kiel.de/id/eprint/36103

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