1. mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors
- Author
-
Antonio Daniele Pinna, Natalie Filmann, Lionel Rostaing, Jens Brockmann, Michael Heise, Andreas A. Schnitzbauer, Simone I. Strasser, Giorgio Rossi, Silvio Nadalin, Jean Gugenheim, Tom M. Ganten, Umberto Cillo, Norman M. Kneteman, Koert P. de Jong, André Roy, Víctor Sánchez Turrión, Thomas Becker, Christoph Duvoux, Markus Rentsch, Jürgen Klempnauer, Utz Settmacher, George Philippe Pageaux, Christian Klein, Roberto Troisi, Edward K. Geissler, Darius F. Mirza, Gunnar Söderdahl, Peter Neuhaus, Jan Lerut, Hans J. Schlitt, Patrizia Burra, Vincenzo Mazzaferro, Johann Pratschke, T. Scholz, Neville V. Jamieson, Wolf O. Bechstein, James Powel, Thomas Soliman, Heikki Mäkisalo, Magnus Rizell, René Adam, Bart van Hoek, Michele Colledan, Itxarone Bilbao, Philippe Bachellier, Olivier Chazoullières, Sherrie Bhoori, Jaques Pirenne, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Schnitzbauer, A, Filmann, N, Adam, R, Bachellier, P, Bechstein, W, Becker, T, Bhoori, S, Bilbao, I, Brockmann, J, Burra, P, Chazoullieres, O, Cillo, U, Colledan, M, Duvoux, C, Ganten, T, Gugenheim, J, Heise, M, van Hoek, B, Jamieson, N, de Jong, K, Klein, C, Klempnauer, J, Kneteman, N, Lerut, J, Makisalo, H, Mazzaferro, V, Mirza, D, Nadalin, S, Neuhaus, P, Pageaux, G, Pinna, A, Pirenne, J, Pratschke, J, Powel, J, Rentsch, M, Rizell, M, Rossi, G, Rostaing, L, Roy, A, Scholz, T, Settmacher, U, Soliman, T, Strasser, S, Soderdahl, G, Troisi, R, Turrion, V, Schlitt, H, Geissler, E, Universitätsklinikum Frankfurt, Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Les Hôpitaux Universitaires de Strasbourg (HUS), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, IRCCS Istituto Nazionale dei Tumori [Milano], Vall d'Hebron University Hospital [Barcelona], Universitätsklinikum Münster, Universita degli Studi di Padova, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Azienda Ospedaliera di Padova, Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UniversitätsKlinikum Heidelberg, Centre Hospitalier Universitaire de Nice (CHU Nice), Leiden University Medical Center (LUMC), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Addenbrooke's Hospital, Cambridge University NHS Trust, University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Medizinische Hochschule Hannover (MHH), University of Alberta, Université Catholique de Louvain = Catholic University of Louvain (UCL), Helsinki University Hospital, University Hospitals Birmingham [Birmingham, Royaume-Uni], Queens Elizabeth Hospital [Birmingham], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, UZLeuven, Royal Infirmary of Edinburgh, Ludwig-Maximilians-Universität München (LMU), Sahlgrenska University Hospital [Gothenburg], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, CHU Grenoble, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Uppsala University Hospital, Universitätsklinikum Jena [Jena], Medizinische Universität Wien = Medical University of Vienna, Royal Prince Alfred Hospital, Karolinska University Hospital [Stockholm], Ghent University Hospital, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], University Hospital Regensburg, Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Publica, Schnitzbauer, A. A., Filmann, N., Adam, R., Bachellier, P., Bechstein, W. O., Becker, T., Bhoori, S., Bilbao, I., Brockmann, J., Burra, P., Chazoullieres, O., Cillo, U., Colledan, M., Duvoux, C., Ganten, T. M., Gugenheim, J., Heise, M., van Hoek, B., Jamieson, N., de Jong, K. P., Klein, C. G., Klempnauer, J., Kneteman, N., Lerut, J., Makisalo, H., Mazzaferro, V., Mirza, D. F., Nadalin, S., Neuhaus, P., Pageaux, G. -P., Pinna, A. D., Pirenne, J., Pratschke, J., Powel, J., Rentsch, M., Rizell, M., Rossi, G., Rostaing, L., Roy, A., Scholz, T., Settmacher, U., Soliman, T., Strasser, S., Soderdahl, G., Troisi, R., Turrion, V. S., Schlitt, H. J., Geissler, E. K., Università degli Studi di Padova = University of Padua (Unipd), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Herrada, Anthony, Groningen Institute for Organ Transplantation (GIOT), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Male ,Oncology ,[SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery ,medicine.medical_treatment ,Medizin ,Liver transplantation ,MESH: Intention to Treat Analysis ,mTOR-inhibition ,0302 clinical medicine ,MESH: Liver Neoplasms ,Clinical endpoint ,MESH: Carcinoma, Hepatocellular ,Milan criteria ,MESH: Aged ,MESH: Middle Aged ,Liver Neoplasms ,Hazard ratio ,Middle Aged ,Intention to Treat Analysis ,3. Good health ,Survival Rate ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,multivariate COX regression ,Female ,030211 gastroenterology & hepatology ,MESH: Immunosuppressive Agents ,MESH: Neoplasm Recurrence, Local ,Immunosuppressive Agents ,medicine.drug ,medicine.medical_specialty ,MESH: Liver Transplantation ,Carcinoma, Hepatocellular ,MESH: Survival Rate ,AFP ,[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery ,03 medical and health sciences ,Internal medicine ,medicine ,Carcinoma ,Humans ,Survival rate ,Aged ,Sirolimus ,MESH: Humans ,business.industry ,medicine.disease ,digestive system diseases ,MESH: Male ,Liver Transplantation ,Surgery ,MESH: Sirolimus ,Neoplasm Recurrence, Local ,business ,MESH: Female - Abstract
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. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862. ispartof: ANNALS OF SURGERY vol:272 issue:5 pages:855-862 ispartof: location:United States status: published
- Published
- 2020