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

Edward K Geissler; Andreas A Schnitzbauer; Carl Zülke; 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; René Adam; Bart van Hoek; Philippe Bachellier; Philippe Wolf; Lionel Rostaing; Wolf O Bechstein; Magnus Rizell; James Powell; Ernest Hidalgo; Jean Gugenheim; Heiner Wolters; Jens Brockmann; André Roy; Ingrid Mutzbauer; Angela Schlitt; Susanne Beckebaum; Christian Graeb; Silvio Nadalin; Umberto Valente; Victor Sánchez Turrión; Neville Jamieson; Tim Scholz; Michele Colledan; Fred Fändrich; Thomas Becker; Gunnar Söderdahl; Olivier Chazouillères; Heikki Mäkisalo; 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; Jürgen Klempnauer; Roberto I Troisi; Sherrie Bhoori; Jan Lerut; Itxarone Bilbao; Christian G Klein; Alfred Königsrainer; Darius F Mirza; Gerd Otto; Vincenzo Mazzaferro; Peter Neuhaus; Hans J Schlitt

doi:10.1097/TP.0000000000000965

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

Edward K Geissler, Andreas A Schnitzbauer, Carl Zülke, 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, René Adam, Bart van Hoek, Philippe Bachellier, Philippe WolfLionel Rostaing, Wolf O Bechstein, Magnus Rizell, James Powell, Ernest Hidalgo, Jean Gugenheim, Heiner Wolters, Jens Brockmann, André Roy, Ingrid Mutzbauer, Angela Schlitt, Susanne Beckebaum, Christian Graeb, Silvio Nadalin, Umberto Valente, Victor Sánchez Turrión, Neville Jamieson, Tim Scholz, Michele Colledan, Fred Fändrich, Thomas Becker, Gunnar Söderdahl, Olivier Chazouillères, Heikki Mäkisalo, 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, Jürgen Klempnauer, Roberto I Troisi, Sherrie Bhoori, Jan Lerut, Itxarone Bilbao, Christian G Klein, Alfred Königsrainer, Darius F Mirza, Gerd Otto, Vincenzo Mazzaferro, Peter Neuhaus, Hans J Schlitt

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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.

Original language	English
Pages (from-to)	116-25
Number of pages	10
Journal	Transplantation
Volume	100
Issue number	1
DOIs	https://doi.org/10.1097/TP.0000000000000965
Publication status	Published - Jan 2016

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Geissler, E. K., Schnitzbauer, A. A., Zülke, 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., ... Schlitt, H. J. (2016). Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Transplantation, 100(1), 116-25. https://doi.org/10.1097/TP.0000000000000965

@article{392529ebaf1c4d09b9011f9b781bed3b,

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

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.",

author = "Geissler, {Edward K} and Schnitzbauer, {Andreas A} and Carl Z{\"u}lke and Lamby, {Philipp E} and Andrea Proneth and Christophe Duvoux and Patrizia Burra and Karl-Walter Jauch and Markus Rentsch and Ganten, {Tom M} and Jan Schmidt and Utz Settmacher and Michael Heise and Giorgio Rossi and Umberto Cillo and Norman Kneteman and Ren{\'e} Adam and {van Hoek}, Bart and Philippe Bachellier and Philippe Wolf and Lionel Rostaing and Bechstein, {Wolf O} and Magnus Rizell and James Powell and Ernest Hidalgo and Jean Gugenheim and Heiner Wolters and Jens Brockmann and Andr{\'e} Roy and Ingrid Mutzbauer and Angela Schlitt and Susanne Beckebaum and Christian Graeb and Silvio Nadalin and Umberto Valente and Turri{\'o}n, {Victor S{\'a}nchez} and Neville Jamieson and Tim Scholz and Michele Colledan and Fred F{\"a}ndrich and Thomas Becker and Gunnar S{\"o}derdahl and Olivier Chazouill{\`e}res and Heikki M{\"a}kisalo and Georges-Philippe Pageaux and Rudolf Steininger and Thomas Soliman and {de Jong}, {Koert P} and Jacques Pirenne and Raimund Margreiter and Johann Pratschke and Pinna, {Antonio D} and Johann Hauss and Stefan Schreiber and Simone Strasser and J{\"u}rgen Klempnauer and Troisi, {Roberto I} and Sherrie Bhoori and Jan Lerut and Itxarone Bilbao and Klein, {Christian G} and Alfred K{\"o}nigsrainer and Mirza, {Darius F} and Gerd Otto and Vincenzo Mazzaferro and Peter Neuhaus and Schlitt, {Hans J}",

year = "2016",

month = jan,

doi = "10.1097/TP.0000000000000965",

language = "English",

volume = "100",

pages = "116--25",

journal = "Transplantation",

issn = "0041-1337",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

Geissler, EK, Schnitzbauer, AA, Zülke, C, Lamby, PE, Proneth, A, Duvoux, C, Burra, P, Jauch, K-W, Rentsch, M, Ganten, TM, Schmidt, J, Settmacher, U, Heise, M, Rossi, G, Cillo, U, Kneteman, N, Adam, R, van Hoek, B, Bachellier, P, Wolf, P, Rostaing, L, Bechstein, WO, 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, Turrión, VS, Jamieson, N, Scholz, T, Colledan, M, Fändrich, F, Becker, T, Söderdahl, G, Chazouillères, O, Mäkisalo, H, Pageaux, G-P, Steininger, R, Soliman, T, de Jong, KP, Pirenne, J, Margreiter, R, Pratschke, J, Pinna, AD, Hauss, J, Schreiber, S, Strasser, S, Klempnauer, J, Troisi, RI, Bhoori, S, Lerut, J, Bilbao, I, Klein, CG, Königsrainer, A, Mirza, DF, Otto, G, Mazzaferro, V, Neuhaus, P & Schlitt, HJ 2016, 'Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial', Transplantation, vol. 100, no. 1, pp. 116-25. https://doi.org/10.1097/TP.0000000000000965

TY - JOUR

T1 - Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma

T2 - A Randomized, Multicenter, Open-Label Phase 3 Trial

AU - Geissler, Edward K

AU - Schnitzbauer, Andreas A

AU - Zülke, Carl

AU - Lamby, Philipp E

AU - Proneth, Andrea

AU - Duvoux, Christophe

AU - Burra, Patrizia

AU - Jauch, Karl-Walter

AU - Rentsch, Markus

AU - Ganten, Tom M

AU - Schmidt, Jan

AU - Settmacher, Utz

AU - Heise, Michael

AU - Rossi, Giorgio

AU - Cillo, Umberto

AU - Kneteman, Norman

AU - Adam, René

AU - van Hoek, Bart

AU - Bachellier, Philippe

AU - Wolf, Philippe

AU - Rostaing, Lionel

AU - Bechstein, Wolf O

AU - Rizell, Magnus

AU - Powell, James

AU - Hidalgo, Ernest

AU - Gugenheim, Jean

AU - Wolters, Heiner

AU - Brockmann, Jens

AU - Roy, André

AU - Mutzbauer, Ingrid

AU - Schlitt, Angela

AU - Beckebaum, Susanne

AU - Graeb, Christian

AU - Nadalin, Silvio

AU - Valente, Umberto

AU - Turrión, Victor Sánchez

AU - Jamieson, Neville

AU - Scholz, Tim

AU - Colledan, Michele

AU - Fändrich, Fred

AU - Becker, Thomas

AU - Söderdahl, Gunnar

AU - Chazouillères, Olivier

AU - Mäkisalo, Heikki

AU - Pageaux, Georges-Philippe

AU - Steininger, Rudolf

AU - Soliman, Thomas

AU - de Jong, Koert P

AU - Pirenne, Jacques

AU - Margreiter, Raimund

AU - Pratschke, Johann

AU - Pinna, Antonio D

AU - Hauss, Johann

AU - Schreiber, Stefan

AU - Strasser, Simone

AU - Klempnauer, Jürgen

AU - Troisi, Roberto I

AU - Bhoori, Sherrie

AU - Lerut, Jan

AU - Bilbao, Itxarone

AU - Klein, Christian G

AU - Königsrainer, Alfred

AU - Mirza, Darius F

AU - Otto, Gerd

AU - Mazzaferro, Vincenzo

AU - Neuhaus, Peter

AU - Schlitt, Hans J

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

U2 - 10.1097/TP.0000000000000965

DO - 10.1097/TP.0000000000000965

M3 - Article

C2 - 26555945

SN - 0041-1337

VL - 100

SP - 116

EP - 125

JO - Transplantation

JF - Transplantation

IS - 1

ER -

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

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