title: A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).
authors.affiliation: University Hospital Regensburg, Department of Surgery, Regensburg, Germany.
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authors.initials: AD
authors.lastname: Pinna
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
authors.forename: Magnus
authors.initials: M
authors.lastname: Rizell
authors.forename: Giorgio
authors.initials: G
authors.lastname: Rossi
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Andre
authors.initials: A
authors.lastname: Roy
authors.forename: Victor Sanchez
authors.initials: VS
authors.lastname: Turrion
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Troisi
authors.forename: Bart
authors.initials: B
authors.lastname: van Hoek
authors.forename: Umberto
authors.initials: U
authors.lastname: Valente
authors.forename: Philippe
authors.initials: P
authors.lastname: Wolf
authors.forename: Heiner
authors.initials: H
authors.lastname: Wolters
authors.forename: Darius F
authors.initials: DF
authors.lastname: Mirza
authors.forename: Tim
authors.initials: T
authors.lastname: Scholz
authors.forename: Rudolf
authors.initials: R
authors.lastname: Steininger
authors.forename: Gunnar
authors.initials: G
authors.lastname: Soderdahl
authors.forename: Simone I
authors.initials: SI
authors.lastname: Strasser
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
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authors.lastname: Schlitt
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mesh_terms: D001315:Australia; D002170:Canada; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000601:surgery*; D018572:Disease-Free Survival; D005060:Europe; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects / Q000401:mortality; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012008:Recurrence; D012307:Risk Factors; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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