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Clinical Trial
. 2016 Jan;100(1):116-25.
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  1 , 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
Affiliations
Clinical Trial

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

Edward K Geissler et al. Transplantation. 2016 Jan.

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.

Trial registration: ClinicalTrials.gov NCT00355862.

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Figures

FIGURE 1
FIGURE 1
Patient disposition. * Reported for one patient who did not withdraw prematurely. ** Patients excluded from the ITT analysis due to violations of major eligibility criteria, as predefined in the statistical analysis plan.
FIGURE 2
FIGURE 2
Efficacy data on ITT population.
FIGURE 3
FIGURE 3
Efficacy data on low-versus high risk subgroups (ITT population).
See this image and copyright information in PMC

Comment in

References

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