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

Edward K. Geissler , Andrea Schnitzbauer , Carl Zülke , Philipp Lamby , Andrea Proneth , Christophe Duvoux (1) , Patrizia Burra , Karl-Walter Jauch , Markus Rentsch , Tom Ganten , Jan Schmidt , Utz Settmacher , Michael Heise , Giorgio Rossi , Umberto Cillo , Norman Kneteman , René Adam (2) , Bart van Hoek , Philippe Bachellier (3) , Philippe Wolf , Lionel Rostaing (4) , Wolf Bechstein , Magnus Rizell , James Powell , Ernest Hidalgo , Jean Gugenheim (5) , 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 (6) , Heikki Mäkisalo , Georges-Philippe Pageaux (7, 8) , Rudolf Steininger , Thomas Soliman , Koert de Jong , Jacques Pirenne , Raimund Margreiter , Johann Pratschke , Antonio Pinna , Johann Hauss , Stefan Schreiber , Simone Strasser , Jürgen Klempnauer , Roberto Troisi , Sherrie Bhoori , Jan Lerut , Itxarone Bilbao , Christian Klein , Alfred Königsrainer , Darius Mirza , Gerd Otto , Vincenzo Mazzaferro , Peter Neuhaus , Hans Schlitt

1 Service d'hépato-gastro-entérologie [APHP Henri Mondor]
2 CHB - Centre hépato-biliaire
3 Hôpital de Hautepierre [Strasbourg]
4 Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation
5 CHU Nice - Centre Hospitalier Universitaire de Nice
6 CHU Saint-Antoine [AP-HP]
7 Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi]
8 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)

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.

Domaines: Immunologie; Chirurgie

Edward K. Geissler, Andrea Schnitzbauer, Carl Zülke, Philipp Lamby, Andrea Proneth, et al.. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.. Transplantation, 2016, 100 (1), pp.116 - 125. ⟨10.1097/TP.0000000000000965⟩. ⟨hal-01886891⟩