Study protocol
A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma
- † Equal contributors
1 University Hospital Regensburg, Department of Surgery, Regensburg, Germany
2 Department of Surgery, Munich University - Grosshadern Campus, Munich, Germany
3 Regensburg University Hospital, Center for Clinical Studies, Regensburg, Germany
4 Department of Hepatobiliopancreatic Surgery and Transplants, Hospital Universitari Vall d'Hebron, Barcelona, Spain
5 Gastroenterology Section, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Padua, Italy
6 Department of Surgery, Division of Hepato-Pancreatico-Biliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
7 Unité de Transplantation Hépatique, Service d'Hépato-Gastroentérologie, Hôpital Henri-Mondor, AP-HP, Université Paris-XII Val de Marne, Créteil, France
8 Section of Hepatobiliary, Pancreatic, and Transplant Surgery, University of Alberta, Edmonton, Canada
9 AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France, and Univ Paris-Sud, UMR-S776, Villejuif F-94800, France
10 Department of General and Vascular Surgery, Johann Wolfgang Goethe University, Frankfurt, Germany
11 Clinic for General-, Visceral- and Transplant Surgery, Medizinische Hochschule Hannover, Hannover, Germany
12 Department of Gastroenterology and Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Duisburg and Essen, Germany
13 Service d'Hépatologie et Centre de Référence des Maladies Inflammatoires du Foie et des Voies Biliaires, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, France
14 Unità di Chirurgia Epatobiliare e Trapianto Epatico, Dipartimento di Chirurgia Generale e Trapianti d'Organo, Azienda Ospedaliera di Padova, Padova, Italy
15 Liver and Lung Transplantation Unit, Azienda Ospedaliera "Ospedali Riuniti", Bergamo, Italy
16 Department of General and Cardiothoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany
17 Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet, Nice, France
18 Clinic for Visceral, Transplantation, Thoracic and Vascular Surgery, University Leipzig, Leipzig, Germany
19 Department of General, Visceral and Vascular Surgery, University Hospital of the Friedrich-Schiller-University, Jena, Germany
20 Scottish Liver Transplant Unit, The Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK
21 Department of Surgery, Addenbrooke's Hospital, Cambridge, UK
22 Department of General-, Visceral- and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany
23 Department of Abdominal and Transplantation Surgery, Universite catholique de Louvain, Brussels, Belgium
24 Clinic of Surgery, Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
25 Department of General and Transplant Surgery, Medical University Innsbruck, Innsbruck, Austria
26 National Cancer Institute, Milan, Italy
27 Department of Transplantation and Hepatobiliarypancreatic Surgery, Johannes Gutenberg University Mainz, Germany
28 Liver Transplant Unit, Centre Hospitalier Universitaire (CHU) Saint Eloi, Montpellier, France
29 Transplant, General and Emergency Surgery DPT, St. Orsola-Malpighi University Hospital, Bologna, Italy
30 Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
31 Department of Surgery, Transplantation and Liver Surgery Service, Sahlgrenska University Hospital, Gothenburg, Sweden
32 Unità Operativa Chirurgia Generale e Trapianti di Fegato, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy
33 Nephrology, Dialysis, and Organ Transplant Unit, University Hospital, CHU Rangueil, Toulouse, France
34 Department of Surgery, Saint-Luc Hospital, CHUM, Montreal, Quebec, Canada
35 Liver Transplant Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain
36 Department of General Surgery, Ruprecht-Karls-University, Heidelberg, Germany
37 Department of General & Hepato-biliary Surgery, Liver Transplantation Service, Ghent University Hospital Medical School, Ghent, Belgium
38 Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
39 Department of Transplantation, San Martino University Hospital, Genoa, Italy
40 Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, Strasbourg, France
41 Department of General and Visceral Surgery, Münster University, Münster, Germany
42 Hepatobiliary Pancreatic Surgery Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
43 Surgical Department, Transplant Section, The Rikshospitalet University Hospital, Oslo, Norway
44 Division for Transplantation, Department of Surgery, Medical University Vienna, Vienna, Austria
45 Department of Transplantation Surgery, Karolinska University Hospital Huddinge, Stockholm, Sweden
46 AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney NSW 2050, Australia
47 Department of General, Visceral, and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
BMC Cancer 2010, 10:190 doi:10.1186/1471-2407-10-190
Published: 11 May 2010Abstract
Background
The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
Methods/Design
The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.
Discussion
If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.
Trial Register
Trial registered at http://www.clinicaltrials.gov webcite: NCT00355862
(EudraCT Number: 2005-005362-36)
