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Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial

(2016) TRANSPLANTATION. 100(1). p.116-125
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Organization
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.
Keywords
CANCER, METAANALYSIS, TARGET, SURVIVAL, RECURRENCE, IMMUNOSUPPRESSION, RENAL-CELL CARCINOMA, RAPAMYCIN INHIBITORS, PROGRESSION, EVEROLIMUS

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MLA
Geissler, Edward K et al. “Sirolimus Use in Liver Transplant Recipients with Hepatocellular Carcinoma: a Randomized, Multicenter, Open-label Phase 3 Trial.” TRANSPLANTATION 100.1 (2016): 116–125. Print.
APA
Geissler, E. K., Schnitzbauer, A. A., Zülke, C., Lamby, P. E., Proneth, A., Duvoux, C., Burra, P., et al. (2016). Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. TRANSPLANTATION, 100(1), 116–125.
Chicago author-date
Geissler, Edward K, Andreas A Schnitzbauer, Carl Zülke, Philipp E Lamby, Andrea Proneth, Christophe Duvoux, Patrizia Burra, et al. 2016. “Sirolimus Use in Liver Transplant Recipients with Hepatocellular Carcinoma: a Randomized, Multicenter, Open-label Phase 3 Trial.” Transplantation 100 (1): 116–125.
Chicago author-date (all authors)
Geissler, Edward K, 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 Troisi, Sherrie Bhoori, Jan Lerut, Itxarone Bilbao, Christian G Klein, Alfred Königsrainer, Darius F Mirza, Gerd Otto, Vincenzo Mazzaferro, Peter Neuhaus, and Hans J Schlitt. 2016. “Sirolimus Use in Liver Transplant Recipients with Hepatocellular Carcinoma: a Randomized, Multicenter, Open-label Phase 3 Trial.” Transplantation 100 (1): 116–125.
Vancouver
1.
Geissler EK, Schnitzbauer AA, Zülke C, Lamby PE, Proneth A, Duvoux C, et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. TRANSPLANTATION. 2016;100(1):116–25.
IEEE
[1]
E. K. Geissler et al., “Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial,” TRANSPLANTATION, vol. 100, no. 1, pp. 116–125, 2016.
@article{7074027,
  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 Zülke, Carl and Lamby, Philipp E and Proneth, Andrea and Duvoux, Christophe and Burra, Patrizia and Jauch, Karl-Walter and Rentsch, Markus and Ganten, Tom M and Schmidt, Jan and Settmacher, Utz and Heise, Michael and Rossi, Giorgio and Cillo, Umberto and Kneteman, Norman and Adam, René and van Hoek, Bart and Bachellier, Philippe and Wolf, Philippe and Rostaing, Lionel and Bechstein, Wolf O and Rizell, Magnus and Powell, James and Hidalgo, Ernest and Gugenheim, Jean and Wolters, Heiner and Brockmann, Jens and Roy, André and Mutzbauer, Ingrid and Schlitt, Angela and Beckebaum, Susanne and Graeb, Christian and Nadalin, Silvio and Valente, Umberto and Sánchez Turrión, Victor and Jamieson, Neville and Scholz, Tim and Colledan, Michele and Fändrich, Fred and Becker, Thomas and Söderdahl, Gunnar and Chazouillères, Olivier and Mäkisalo, Heikki and Pageaux, Georges-Philippe and Steininger, Rudolf and Soliman, Thomas and de Jong, Koert P and Pirenne, Jacques and Margreiter, Raimund and Pratschke, Johann and Pinna, Antonio D and Hauss, Johann and Schreiber, Stefan and Strasser, Simone and Klempnauer, Jürgen and Troisi, Roberto and Bhoori, Sherrie and Lerut, Jan and Bilbao, Itxarone and Klein, Christian G and Königsrainer, Alfred and Mirza, Darius F and Otto, Gerd and Mazzaferro, Vincenzo and Neuhaus, Peter and Schlitt, Hans J},
  issn         = {0041-1337},
  journal      = {TRANSPLANTATION},
  keywords     = {CANCER,METAANALYSIS,TARGET,SURVIVAL,RECURRENCE,IMMUNOSUPPRESSION,RENAL-CELL CARCINOMA,RAPAMYCIN INHIBITORS,PROGRESSION,EVEROLIMUS},
  language     = {eng},
  number       = {1},
  pages        = {116--125},
  title        = {Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial},
  url          = {http://dx.doi.org/10.1097/TP.0000000000000965},
  volume       = {100},
  year         = {2016},
}

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