Open Access

Andreas Schnitzbauer, Carl Zuelke, Christian Graeb, Justine Rochon, Itxarone Bilbao, Patrizia Burra, Koert P. de Jong, Christophe Duvoux, Norman M. Kneteman, Rene Adam, Wolf Otto Bechstein, Thomas Becker, Susanne Beckebaum, Olivier Chazouilleres, Umberto Cillo, Michele Colledan, Fred Fandrich, Jean Gugenheim, Johann P. Hauss, Michael Heise, Ernest Hidalgo, Neville Jamieson, Alfred Königsrainer, Philipp E. Lamby, Jan P. Lerut, Heikki Makisalo, Raimund Margreiter, Vincenzo Mazzaferro, Ingrid Mutzbauer, Gerd Otto, Georges-Philippe Pageaux, Antonio D. Pinna, Jacques Pirenne, Magnus Rizell, Giorgio Rossi, Lionel Rostaing, Andre Roy, Victor Sanchez Turrion, Jan Schmidt, Roberto I. Troisi, Bart van Hoek, Umberto Valente, Philippe Wolf, Heiner Wolters, Darius F. Mirza, Tim Scholz, Rudolf Steininger, Gunnar Soderdahl, Simone I. Strasser, Karl-Walter Jauch, Peter Neuhaus, Hans J. Schlitt, Edward K. Geissler

• 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: 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 3-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 registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)