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

Research output: Contribution to journalArticlepeer-review


  • Andreas A Schnitzbauer
  • Carl Zuelke
  • Christian Graeb
  • Justine Rochon
  • Itxarone Bilbao
  • Patrizia Burra
  • Koert P de Jong
  • Christophe Duvoux
  • Norman M Kneteman
  • Rene Adam
  • Wolf O Bechstein
  • Thomas Becker
  • Susanne Beckebaum
  • Olivier Chazouillères
  • Umberto Cillo
  • Michele Colledan
  • Fred Fändrich
  • Jean Gugenheim
  • Johann P Hauss
  • Michael Heise
  • Ernest Hidalgo
  • Neville Jamieson
  • Alfred Königsrainer
  • Philipp E Lamby
  • Jan P Lerut
  • Heikki Mäkisalo
  • Raimund Margreiter
  • Vincenzo Mazzaferro
  • Ingrid Mutzbauer
  • Gerd Otto
  • Georges-Philippe Pageaux
  • Antonio D Pinna
  • 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/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).


Original languageEnglish
Pages (from-to)190
JournalBMC Cancer
Publication statusPublished - 2010


  • Australia, Canada, Carcinoma, Hepatocellular, Disease-Free Survival, Europe, Humans, Immunosuppressive Agents, Intracellular Signaling Peptides and Proteins, Kaplan-Meier Estimate, Liver Neoplasms, Liver Transplantation, Prospective Studies, Protein-Serine-Threonine Kinases, Recurrence, Risk Factors, Sirolimus, TOR Serine-Threonine Kinases, Time Factors, Transplantation, Homologous, Treatment Outcome