A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.
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).
Schnitzbauer
Andreas A
AA
University Hospital Regensburg, Department of Surgery, Regensburg, Germany.
Zuelke
Carl
C
Graeb
Christian
C
Rochon
Justine
J
Bilbao
Itxarone
I
Burra
Patrizia
P
de Jong
Koert P
KP
Duvoux
Christophe
C
Kneteman
Norman M
NM
Adam
Rene
R
Bechstein
Wolf O
WO
Becker
Thomas
T
Beckebaum
Susanne
S
Chazouillères
Olivier
O
Cillo
Umberto
U
Colledan
Michele
M
Fändrich
Fred
F
Gugenheim
Jean
J
Hauss
Johann P
JP
Heise
Michael
M
Hidalgo
Ernest
E
Jamieson
Neville
N
Königsrainer
Alfred
A
Lamby
Philipp E
PE
Lerut
Jan P
JP
Mäkisalo
Heikki
H
Margreiter
Raimund
R
Mazzaferro
Vincenzo
V
Mutzbauer
Ingrid
I
Otto
Gerd
G
Pageaux
Georges-Philippe
GP
Pinna
Antonio D
AD
Pirenne
Jacques
J
Rizell
Magnus
M
Rossi
Giorgio
G
Rostaing
Lionel
L
Roy
Andre
A
Turrion
Victor Sanchez
VS
Schmidt
Jan
J
Troisi
Roberto I
RI
van Hoek
Bart
B
Valente
Umberto
U
Wolf
Philippe
P
Wolters
Heiner
H
Mirza
Darius F
DF
Scholz
Tim
T
Steininger
Rudolf
R
Soderdahl
Gunnar
G
Strasser
Simone I
SI
Jauch
Karl-Walter
KW
Neuhaus
Peter
P
Schlitt
Hans J
HJ
Geissler
Edward K
EK
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
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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