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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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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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Chicago
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.
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.
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.
MLA
Geissler, Edward K, Andreas A Schnitzbauer, Carl Zülke, 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.
@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 Z{\"u}lke, 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, Ren{\'e} 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, Andr{\'e} and Mutzbauer, Ingrid and Schlitt, Angela and Beckebaum, Susanne and Graeb, Christian and Nadalin, Silvio and Valente, Umberto and S{\'a}nchez Turri{\'o}n, Victor and Jamieson, Neville and Scholz, Tim and Colledan, Michele and F{\"a}ndrich, Fred and Becker, Thomas and S{\"o}derdahl, Gunnar and Chazouill{\`e}res, Olivier and M{\"a}kisalo, 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, J{\"u}rgen and Troisi, Roberto and Bhoori, Sherrie and Lerut, Jan and Bilbao, Itxarone and Klein, Christian G and K{\"o}nigsrainer, Alfred and Mirza, Darius F and Otto, Gerd and Mazzaferro, Vincenzo and Neuhaus, Peter and Schlitt, Hans J},
  issn         = {0041-1337},
  journal      = {TRANSPLANTATION},
  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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