A Randomized Phase Ⅱ, Trial With Sirolimus-containing Versus mTOR-inhibitor Free Immunosuppression in Patients Undergoing Living Donor Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria
The Milan criteria were adopted in most of western countries for deceased donor allocation
because they identify a subgroup of candidates with hepatocellular carcinoma (HCC) for whom
transplant results are similar to those in patients transplanted for end- stage liver
disease without HCC. There is a debate involving expanding the indications beyond the Milan
criteria in living donor liver transplantation (LDLT). Some transplant surgeons argue that
despite the poorer results, LDLT for advanced HCC may be justified, since donors voluntarily
accept the risks of donor hepatectomy to dedicate a graft for HCC patients, who may
otherwise have no effective treatment. Especially, in Korea where living donor liver
transplantation (LDLT) is commonly performed, the expansion of Milan criteria is inevitable.
Sirolimus is a macrolide antibiotic produced by Streptomyces hygroscopic that has
demonstrated potent immunosuppressive activity in a number of studies. The efficacy of
sirolimus as immunosuppressives has been demonstrated in randomized clinical trials in
kidney transplantation. The use of sirolimus in liver transplantation is rapidly increasing
from the standpoint of reducing the conventional calcineurin inhibitor toxicity. Sirolimus
emerged as an effective alternative for patients with renal insufficiency related to
calcineurin inhibitor toxicity. In recent studies, no differences have been observed with
respect to rejection or major complications.The use of sirolimus in transplant patients is
associated with a dose-dependent increase in serum cholesterol and triglycerides that may
require treatment. In recent studies in liver transplant recipients using sirolimus as part
of a primary immunosuppressive regimen, the occurrence of acute cellular rejection is
relatively low. There is data suggesting that sirolimus is associated with hepatic artery
thrombosis. Numerous current studies have shown that sirolimus may have inhibitory effects
on the development of cancer. Immunosuppressive agent with antineoplastic activity is
inherently attractive in the setting of liver transplantation for HCC. If sirolimus shows
some degree of anti-tumor effect in transplant recipients with advanced HCC, the indication
of LDLT for advanced HCC can be expanded.Our hypothesis is that sirolimus based-regimen will
improve the HCC recurrence free survival. If sirolimus-based protocol shows better
recurrence free survival, the indication of LDLT for HCC can be expanded. LDLT can be one of
the best treatment modalities for advanced HCC. The patients with advanced HCC can have
benefit by liver transplantation.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate recurrence-free survival
To evaluate the anti-tumor effect of sirolimus-based immunosuppressive regimen in patients following living donor liver transplantation for hepatocellular carcinoma exceeding Milan criteria with respect to recurrence-free survival
3 years
Yes
Kwang-woong Lee
Principal Investigator
Seoul National University Hospital
South Korea: Institutional Review Board
KWLee1004-052-316
NCT01374750
May 2010
May 2015
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