TY - JOUR
T1 - A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma
AU - Schnitzbauer, Andreas A
AU - Zuelke, Carl
AU - Graeb, Christian
AU - Rochon, Justine
AU - Bilbao, Itxarone
AU - Burra, Patrizia
AU - de Jong, Koert P
AU - Duvoux, Christophe
AU - Kneteman, Norman M
AU - Adam, Rene
AU - Bechstein, Wolf O
AU - Becker, Thomas
AU - Beckebaum, Susanne
AU - Chazouillères, Olivier
AU - Cillo, Umberto
AU - Colledan, Michele
AU - Fändrich, Fred
AU - Gugenheim, Jean
AU - Hauss, Johann P
AU - Heise, Michael
AU - Hidalgo, Ernest
AU - Jamieson, Neville
AU - Königsrainer, Alfred
AU - Lamby, Philipp E
AU - Lerut, Jan P
AU - Mäkisalo, Heikki
AU - Margreiter, Raimund
AU - Mazzaferro, Vincenzo
AU - Mutzbauer, Ingrid
AU - Otto, Gerd
AU - Pageaux, Georges-Philippe
AU - Pinna, Antonio D
AU - Pirenne, Jacques
AU - Rizell, Magnus
AU - Rossi, Giorgio
AU - Rostaing, Lionel
AU - Roy, Andre
AU - Turrion, Victor Sanchez
AU - Schmidt, Jan
AU - Troisi, Roberto I
AU - van Hoek, Bart
AU - Valente, Umberto
AU - Wolf, Philippe
AU - Wolters, Heiner
AU - Mirza, Darius F
AU - Scholz, Tim
AU - Steininger, Rudolf
AU - Soderdahl, Gunnar
AU - Strasser, Simone I
AU - Jauch, Karl-Walter
AU - Neuhaus, Peter
AU - Schlitt, Hans J
AU - Geissler, Edward K
PY - 2010
Y1 - 2010
N2 - 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).
AB - 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).
KW - Australia
KW - Canada
KW - Carcinoma, Hepatocellular
KW - Disease-Free Survival
KW - Europe
KW - Humans
KW - Immunosuppressive Agents
KW - Intracellular Signaling Peptides and Proteins
KW - Kaplan-Meier Estimate
KW - Liver Neoplasms
KW - Liver Transplantation
KW - Prospective Studies
KW - Protein-Serine-Threonine Kinases
KW - Recurrence
KW - Risk Factors
KW - Sirolimus
KW - TOR Serine-Threonine Kinases
KW - Time Factors
KW - Transplantation, Homologous
KW - Treatment Outcome
U2 - 10.1186/1471-2407-10-190
DO - 10.1186/1471-2407-10-190
M3 - Article
C2 - 20459775
SN - 1471-2407
VL - 10
SP - 190
JO - BMC Cancer
JF - BMC Cancer
ER -