Open Access Highly Accessed Study protocol

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Andreas A Schnitzbauer1, Carl Zuelke1, Christian Graeb2, Justine Rochon3, Itxarone Bilbao4, Patrizia Burra5, Koert P de Jong6, Christophe Duvoux7, Norman M Kneteman8, Rene Adam9, Wolf O Bechstein10, Thomas Becker11, Susanne Beckebaum12, Olivier Chazouillères13, Umberto Cillo14, Michele Colledan15, Fred Fändrich16, Jean Gugenheim17, Johann P Hauss18, Michael Heise19, Ernest Hidalgo20, Neville Jamieson21, Alfred Königsrainer22, Philipp E Lamby1, Jan P Lerut23, Heikki Mäkisalo24, Raimund Margreiter25, Vincenzo Mazzaferro26, Ingrid Mutzbauer1, Gerd Otto27, Georges-Philippe Pageaux28, Antonio D Pinna29, Jacques Pirenne30, Magnus Rizell31, Giorgio Rossi32, Lionel Rostaing33, Andre Roy34, Victor Sanchez Turrion35, Jan Schmidt36, Roberto I Troisi37, Bart van Hoek38, Umberto Valente39, Philippe Wolf40, Heiner Wolters41, Darius F Mirza42, Tim Scholz43, Rudolf Steininger44, Gunnar Soderdahl45, Simone I Strasser46, Karl-Walter Jauch2, Peter Neuhaus47, Hans J Schlitt1 and Edward K Geissler1*

Author Affiliations

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

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BMC Cancer 2010, 10:190  doi:10.1186/1471-2407-10-190

Published: 11 May 2010

Abstract

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)