Andreas A Schnitzbauer1, Natalie Filmann2, René Adam3, Philippe Bachellier4, Wolf O Bechstein1, Thomas Becker5, Sherrie Bhoori6, Itxarone Bilbao7, Jens Brockmann8, Patrizia Burra9, Olivier Chazoullières10, Umberto Cillo11, Michele Colledan12, Christoph Duvoux13, Tom M Ganten14, Jean Gugenheim15, Michael Heise1, Bart van Hoek16, Neville Jamieson17, Koert P de Jong18, Christian G Klein19, Jürgen Klempnauer20, Norman Kneteman21, Jan Lerut22, Heikki Mäkisalo23, Vincenzo Mazzaferro6, Darius F Mirza24, Silvio Nadalin25, Peter Neuhaus26, George-Philippe Pageaux27, Antonio D Pinna28, Jaques Pirenne29, Johann Pratschke30, James Powel31, Markus Rentsch32, Magnus Rizell33, Giorgio Rossi34, Lionel Rostaing35, André Roy36, Tim Scholz37, Utz Settmacher38, Thomas Soliman39, Simone Strasser40, Gunnar Söderdahl41, Roberto I Troisi42, Victor Sánchez Turrión43, Hans J Schlitt44, Edward K Geissler45,46. 1. Universitätsklinikum Frankfurt, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Frankfurt am Main, Germany. 2. Universitätsklinikum Frankfurt, Institut für Biostatistik und Mathematisches Modellierung, Frankfurt am Main, Germany. 3. Hôpital Paul Brousse, Centre Hépato Biliaire, Paris, France. 4. Les Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Service de Chirurgie Générale, Hépatique, Endocrinienne, et Transplantation, Strasbourg, France. 5. Universitätsklinikum Schleswig-Holstein - Campus Kiel, Klinik für Allgemeine Chirurgie, Viszeral-, Thorax, Transplantations- und Kinderchirurgie, Kiel, Germany. 6. Fondazione IRCCS Istituto Nazionale dei Tumori, National Cancer Institute Milan, Department of Surgery, Transplantation and Hepatobiliary Cancer Unit, Milano, Italy. 7. Hospital Universitari Vall d'Hebron, Servicio de Cirugía General, Unidad de Trasplante Hepatico, Barcelona, Spain. 8. Universitätsklinikum Münster, Klinik für Allgemein- und ViszeralchirurgieMünster, Germany. 9. Università degli Studi di Padova, Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche (DiSCOG), Padova, Italy. 10. Hôpital Saint Antoine, Federation d'Hepato-Gastro-Enterologie, Service d'Hepatologie, Paris, France. 11. Università di Padova, Azienda Ospedaliera di Padova, Chirurgia Epatobiliare e Trapianto Epatico, Padova, Italy. 12. Azienda Ospedaliera Papa Giovanni XXIII, Chirurgia terza e Chirurgia Toracica, Bergamo (BG), Italy. 13. Université Paris-Est Créteil Val-de-Marne, Centre Hospitalier Universitaire Henri-Mondor, Service d'Hepatologie et de Gastroenterologie, Unite d'Hepatologie et de Transplantation Hepatique, Paris, France. 14. Universitätsklinikum Heidelberg, Fürst Stirum Klinik Bruchsal, Bruchsal, Germany. 15. Centre Hospitalier Universitaire de Nice, Hôpital ARCHET 2, Service de Chirurgie Digestive, Centre de Transplantation Hépatique, Nice Cedex, France. 16. Leiden University Medical Center (LUMC), Dept. of Gastroenterology and Hepatology, Leiden, Netherlands. 17. Cambridge University Hospitals, NHS Foundation Trust, Addenbrooke's Hospital, Department of Surgery, Hills Road, Cambridge, United Kingdom. 18. University Medical Center Groningen, University of Groningen, Department of Surgery, Div. of Hepato-Pancreatico-Biliary Surgery & Liver Transplantation, Groningen, Netherlands. 19. Universitätsklinikum Essen, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Essen, Germany. 20. Medizinische Hochschule Hannover, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Hannover, Germany. 21. University of Alberta, Alberta Health Services Liver Transplant Program, Alberta, Canada. 22. Institute for Experimental and Clinical Research (IREC), Université catholique Louvain(UCL), Brussels, Belgium. 23. Helsinki University Central Hospital, Division of Transplantation and Liver Surgery, Helsinki, Finland. 24. University Hospitals Birmingham, NHS Foundation Trust, The Queen Elizabeth Hospital, Liver and Hepato-Pancreato-Biliary (HPB) Unit, Edgbaston, Birmingham, United Kingdom. 25. Klinikum der Universität Tübingen, Klinik für Allgemeine, Viszeral- und Transplantationschirurgie, Tübingen, Germany. 26. Charité Campus Virchow Klinikum, Universitätsmedizin Berlin, Klinik für Allgemein-, Visceral- und Transplantationschirurgie, Berlin, Germany. 27. CHRU de Montpellier, APEMAD, Hôpital Saint-Eloi, Service d'Hepato-Gastroentérologie et Transplantation Hepatique, Cedex 5, France. 28. Universita di Bologna, Policlinico S. Orsola-Malpighi, Chirurgia Generale e dei Trapianti, Bologna, Italy. 29. UZ Leuven, Campus Gasthuisberg, Abdominale Transplantatiechirurgie, Leuven, Belgium. 30. Charité - Universitätsmedizin Berlin Augustenburger Platz 1, 13353 Berlin. 31. Royal Infirmary of Edinburgh, NHS Lothian, Hepatic-Pancreatico-Biliary Surgical Services and Edinburgh Transplant Unit, 51 Little France Crescent, Edinburgh, Scotland, United Kingdom. 32. Klinikum der Ludwig-Maximillians-Universität München-Großhadern, current affiliation: Klinikum Ingolstadt, Klinik für Allgemein-, Viszeral- und Thoraxchirurgie, Ingolstadt, Germany. 33. Sahlgrenska University Hospital, Department of Surgery and Transplantation, Göteborg, Sweden. 34. Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico IRCCS di Milano, Centro Trapianti Fegato, Pad Zonda I piano, Milano, Italy. 35. Department of Nephrology, Hemodialysis, Apheresis and Transplantation, Grenoble-Alpes University Hospital Center, Avenue du Maquis du Grésivaudan, La Tronche, France. 36. Hopital St Luc, Centre Hospitalier de l'Université Montréal (CHUM), Hepatobiliary and Pancreatic Surgery Unit, Principal Pavillion, 1058 Rue St Denis Montreal, Quebec, Canada. 37. Uppsala University Hospital, Deptartment for Transplant Surgery, Uppsala, Sweden. 38. Universitätsklinikum Jena, Klinik für Allgemein-, Viszeral- und Gefässchirurgie, Jena, Germany. 39. Medizinische Universität Wien, AKH- Wien, Universitätsklinik für Chirurgie, Abteilung für Transplantation, Vienna, Austria. 40. Royal Prince Alfred Hospital, AW Morrow Gastroenterology, and Liver Centre and Liver Transplant Unit, Camperdown, Sydney, Australia. 41. Karolinska University Hospital, Department of Transplantation Surgery, Stockholm, Sweden. 42. Ghent University Hospital and Medical School, Hepato- Biliary and Pancreatic Surgery, Ghent, Belgium. 43. Hospital Universitario Puerta de Hierro-Majadahonda, Departamento de Cirugía, Unidad de Trasplante Hepático, Calle Manuel de Falla 1, Madrid, Spain. 44. University Hospital Regensburg, Department of Surgery, Franz-Josef-Strauss-Allee 11, Regensburg, Germany. 45. University Hospital Regensburg, Department of Surgery and Section of Experimental Surgery, Franz-Josef-Strauss-Allee 11, Regensburg, Germany. 46. Division of Tumor Therapy, Fraunhofer Institute of Experimental Medicine and Toxicology, Regensburg, Germany.
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.
RCT Entities:
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.
Authors: Wojciech Andrzej Straś; Dariusz Wasiak; Beata Łągiewska; Olga Tronina; Marta Hreńczuk; Joanna Gotlib; Wojciech Lisik; Piotr Małkowski Journal: Ann Transplant Date: 2022-01-26 Impact factor: 1.530
Authors: Ramin Raul Ossami Saidy; Maximilian Paul Postel; Michael Johannes Pflüger; Wenzel Schoening; Robert Öllinger; Safak Gül-Klein; Moritz Schmelzle; Frank Tacke; Johann Pratschke; Dennis Eurich Journal: Cancers (Basel) Date: 2021-03-31 Impact factor: 6.639
Authors: Safak Gül-Klein; Henriette Hegermann; Robert Röhle; Moritz Schmelzle; Frank Tacke; Wenzel Schöning; Robert Öllinger; Tomasz Dziodzio; Patrick Maier; Julius M Plewe; David Horst; Igor Maximilian Sauer; Johann Pratschke; Nils Lachmann; Dennis Eurich Journal: J Inflamm Res Date: 2021-06-23