mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors
Andreas Schnitzbauer
(1)
,
Natalie Filmann
(1)
,
René Adam
(2)
,
Philippe Bachellier
(3)
,
Wolf Bechstein
(1)
,
Thomas Becker
(4)
,
Sherrie Bhoori
(5)
,
Itxarone Bilbao
(6)
,
Jens Brockmann
(7)
,
Patrizia Burra
(8)
,
Olivier Chazoullières
(9)
,
Umberto Cillo
(10)
,
Michele Colledan
(11)
,
Christoph Duvoux
(12)
,
Tom Ganten
(13)
,
Jean Gugenheim
(14)
,
Michael Heise
(1)
,
Bart van Hoek
(15)
,
Neville Jamieson
(16, 17)
,
Koert de Jong
(18, 19)
,
Christian Klein
(20)
,
Jürgen Klempnauer
(21)
,
Norman Kneteman
(22)
,
Jan Lerut
(23)
,
Heikki Mäkisalo
(24)
,
Vincenzo Mazzaferro
(5)
,
Darius Mirza
(25, 26)
,
Silvio Nadalin
(27)
,
Peter Neuhaus
(28)
,
George-Philippe Pageaux
(29, 30)
,
Antonio Pinna
(31)
,
Jaques Pirenne
(32)
,
Johann Pratschke
(28)
,
James Powel
(33)
,
Markus Rentsch
(34)
,
Magnus Rizell
(35)
,
Giorgio Rossi
(36)
,
Lionel Rostaing
(37)
,
André Roy
(38)
,
Tim Scholz
(39)
,
Utz Settmacher
(40)
,
Thomas Soliman
(41)
,
Simone Strasser
(42)
,
Gunnar Söderdahl
(43)
,
Roberto Troisi
(44)
,
Victor Sánchez Turrión
(45)
,
Hans Schlitt
(46)
,
Edward Geissler
(46, 47)
1
Universitätsklinikum Frankfurt
2 CHB - Centre Hépato-Biliaire [Hôpital Paul Brousse]
3 HUS - Les Hôpitaux Universitaires de Strasbourg
4 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
5 IRCCS Istituto Nazionale dei Tumori [Milano]
6 Vall d'Hebron University Hospital [Barcelona]
7 Universitätsklinikum Münster
8 Unipd - Università degli Studi di Padova = University of Padua
9 CHU Saint-Antoine [AP-HP]
10 Azienda Ospedaliera di Padova
11 Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy]
12 Hôpital Henri Mondor
13 UniversitätsKlinikum Heidelberg
14 CHU Nice - Centre Hospitalier Universitaire de Nice
15 LUMC - Leiden University Medical Center
16 CUH - Cambridge University Hospitals - NHS
17 Addenbrooke's Hospital
18 UMCG - University Medical Center Groningen [Groningen]
19 University of Groningen [Groningen]
20 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
21 MHH - Medizinische Hochschule Hannover = Hannover Medical School
22 University of Alberta
23 UCL - Université Catholique de Louvain = Catholic University of Louvain
24 HUS - Helsinki University Hospital [Finland]
25 University Hospitals Birmingham [Birmingham, Royaume-Uni]
26 Queens Elizabeth Hospital [Birmingham]
27 Universitätsklinikum Tübingen - University Hospital of Tübingen
28 Charité - UniversitätsMedizin = Berlin University Medicine
29 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
30 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
31 Policlinico S. Orsola-malpighi
32 UZLeuven
33 Royal Infirmary of Edinburgh
34 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
35 Sahlgrenska University Hospital [Gothenburg]
36 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
37 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
38 CHUM - Centre Hospitalier de l'Université de Montréal
39 Uppsala University Hospital
40 Universitätsklinikum Jena [Jena]
41 Medizinische Universität Wien = Medical University of Vienna
42 Royal Prince Alfred Hospital
43 Karolinska University Hospital [Stockholm]
44 Ghent University Hospital
45 Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain]
46 University Hospital Regensburg
47 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
2 CHB - Centre Hépato-Biliaire [Hôpital Paul Brousse]
3 HUS - Les Hôpitaux Universitaires de Strasbourg
4 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
5 IRCCS Istituto Nazionale dei Tumori [Milano]
6 Vall d'Hebron University Hospital [Barcelona]
7 Universitätsklinikum Münster
8 Unipd - Università degli Studi di Padova = University of Padua
9 CHU Saint-Antoine [AP-HP]
10 Azienda Ospedaliera di Padova
11 Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy]
12 Hôpital Henri Mondor
13 UniversitätsKlinikum Heidelberg
14 CHU Nice - Centre Hospitalier Universitaire de Nice
15 LUMC - Leiden University Medical Center
16 CUH - Cambridge University Hospitals - NHS
17 Addenbrooke's Hospital
18 UMCG - University Medical Center Groningen [Groningen]
19 University of Groningen [Groningen]
20 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
21 MHH - Medizinische Hochschule Hannover = Hannover Medical School
22 University of Alberta
23 UCL - Université Catholique de Louvain = Catholic University of Louvain
24 HUS - Helsinki University Hospital [Finland]
25 University Hospitals Birmingham [Birmingham, Royaume-Uni]
26 Queens Elizabeth Hospital [Birmingham]
27 Universitätsklinikum Tübingen - University Hospital of Tübingen
28 Charité - UniversitätsMedizin = Berlin University Medicine
29 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
30 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
31 Policlinico S. Orsola-malpighi
32 UZLeuven
33 Royal Infirmary of Edinburgh
34 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
35 Sahlgrenska University Hospital [Gothenburg]
36 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
37 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
38 CHUM - Centre Hospitalier de l'Université de Montréal
39 Uppsala University Hospital
40 Universitätsklinikum Jena [Jena]
41 Medizinische Universität Wien = Medical University of Vienna
42 Royal Prince Alfred Hospital
43 Karolinska University Hospital [Stockholm]
44 Ghent University Hospital
45 Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain]
46 University Hospital Regensburg
47 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
Thomas Becker
- Fonction : Auteur
- PersonId : 765733
- ORCID : 0000-0001-8458-2738
Christian Klein
- Fonction : Auteur
- PersonId : 758553
- ORCID : 0000-0001-7594-7280
Giorgio Rossi
- Fonction : Auteur
- PersonId : 792786
- ORCID : 0000-0002-9330-7436
Lionel Rostaing
- Fonction : Auteur
- PersonId : 862455
- ORCID : 0000-0002-5130-7286
- IdRef : 058653562
Résumé
Objective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial).
Summary and background data: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data.
Patients and methods: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence.
Results: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245).
Conclusions: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients.