A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma
Authors: Schnitzbauer Andreas A , Zuelke Carl , Graeb Christian , Rochon Justine , Bilbao Itxarone , Burra Patrizia , de Jong Koert P , Duvoux Christophe , Kneteman Norman M , Adam Rene , Bechstein Wolf O , Becker Thomas , Beckebaum Susanne , Chazouillères Olivier , Cillo Umberto , Colledan Michele , Fändrich Fred , Gugenheim Jean , Hauss Johann P , Heise Michael , Hidalgo Ernest , Jamieson Neville , Königsrainer Alfred , Lamby Philipp E , Lerut Jan P , Mäkisalo Heikki , Margreiter Raimund , Mazzaferro Vincenzo , Mutzbauer Ingrid , Otto Gerd , Pageaux Georges-Philippe , Pinna Antonio D , Pirenne Jacques , Rizell Magnus , Rossi Giorgio , Rostaing Lionel , Roy Andre , Turrion Victor Sanchez , Schmidt Jan , Troisi Roberto I , van Hoek Bart , Valente Umberto , Wolf Philippe , Wolters Heiner , Mirza Darius F , Scholz Tim , Steininger Rudolf , Soderdahl Gunnar , Strasser Simone I , Jauch Karl-Walter , Neuhaus Peter , Schlitt Hans J , Geissler Edward K 
Published: 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: NCT00355862
(EudraCT Number: 2005-005362-36)