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 fromsirolimus; 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.
Sirolimus use in liver transplant recipients with Hepatocellular carcinoma : a randomized, Multicenter, open-label phase 3 Trial / E.K. Geissler, A.A. Schnitzbauer, C. Zölke, P.E. Lamby, A. Proneth, C. Duvoux, P. Burra, K. Jauch, M. Rentsch, T.M. Ganten, J. Schmidt, U. Settmacher, M. Heise, G. Rossi, U. Cillo, N. Kneteman, R. Adam, B. Van Hoek, P. Bachellier, P. Wolf, L. Rostaing, W.O. Bechstein, M. Rizell, J. Powell, E. Hidalgo, J. Gugenheim, H. Wolters, J. Brockmann, A. Roy, I. Mutzbauer, A. Schlitt, S. Beckebaum, C. Graeb, S. Nadalin, U. Valente, V.S. Turrión, N. Jamieson, T. Scholz, M. Colledan, F. Fändrich, T. Becker, G. Söderdahl, O. Chazouillères, H. Mäkisalo, G. Pageaux, R. Steininger, T. Soliman, K.P. De Jong, J. Pirenne, R. Margreiter, J. Pratschke, A.D. Pinna, J. Hauss, S. Schreiber, S. Strasser, J. Klempnauer, R.I. Troisi, S. Bhoori, J. Lerut, I. Bilbao, C.G. Klein, A. Königsrainer, D.F. Mirza, G. Otto, V. Mazzaferro, P. Neuhaus, H.J. Schlitt. - In: TRANSPLANTATION. - ISSN 0041-1337. - 100:1(2016), pp. 116-125. [10.1097/TP.0000000000000965]
Sirolimus use in liver transplant recipients with Hepatocellular carcinoma : a randomized, Multicenter, open-label phase 3 Trial
G. Rossi;V. Mazzaferro;
2016
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 fromsirolimus; 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.
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