Trial Information

A Prospective Randomised, Open-labeled, Trial Comparing Sirolimus-Containing Versus mTOR-Inhibitor-Free Immunosuppression in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma

There are two major issues to face in patients who underwent liver transplantation for
hepatocellular carcinoma (HCC). First, the patient requires adequate immunosuppressive
medication to avoid rejection of its allograft. Second, the risk for HCC recurrence has to
be reduced to a minimum.

To date, it is a wide spread argument that immunosuppressive agents for the reduction of
allograft rejection are generally tumorogenic, or at least are permissive of cancer
development although little is known about their tumorogenic effect. In clinical studies
substantiated by experimental data, cyclosporin (CsA) enhances cancer cell growth
characteristics and angiogenesis in tumors and inhibits DNA repair mechanisms, promoting
their growth. In an experimental rat-model CsA promoted liver tumor recurrence and growth.
In other experimental studies a higher proliferation rate of human hepatoma cells in the
presence of tacrolimus was demonstrated.

Nevertheless not all immunosuppressive agents do necessarily promote tumor growth, and in
fact, can have antineoplastic activities. Sirolimus, in immunosuppressive doses, has potent
antiangiogenic properties that inhibit tumor growth. The antiangiogenetic mechanism is due
to inhibition of vascular endothelial growth factor (VEGF) production and signaling to
endothelial cells. Besides that, sirolimus directly blocks critical intracellular pathways
(mTOR) and inhibits cell-cycle. Through increased E-cadherin expression on tumor cells,
tumor metastasis can be reduced by increased tumor cell binding.

In this context it has to be mentioned that in mouse models where a transplant recipient
also has a tumor, the pro-tumor effects of CsA are completely negated by sirolimus.

Especially HCC seems to be particularly sensitive to VEGF/angiogenesis, indicating a
potential susceptibility to the action of sirolimus which could be shown by the group of
E.K. Geissler and colleagues in Regensburg.

From a clinical perspective there is a recent pilot study from Kneteman et al. indicating
that early conversion of immunosuppression from CNI to mTOR-inhibitors after OLT in HCC
patients (n=21) with a "high risk" for tumor recurrence results in a tumor recurrence rate
of only 19% and a 4-year over all survival of 83% in this group. Moreover, in the "low-risk"
group (n=19) the 4-year tumor recurrence rate was only 1/19. Post-HCC recurrence survival
was 15.5 months, which is marked improvement compared to currently published data. Although
this study only reports on a small number of patients and is not controlled, it suggests the
potential role for sirolimus to ameliorate tumor recurrence, leading to a more benign course
of renewed tumor disease.

Among the most serious complications of immunosuppressive therapy in organ transplantation
is the high risk of previous neoplasia recurrence, or the development of de novo cancer. HCC
comprises 80-90 % of malignancies indicating OLT. Before the introduction of strict criteria
for the enrollment of primary liver tumors, tumor recurrence led to poor mid- and long-term
results. HCC thus has an unacceptable recurrence rate following OLT when the tumor exceeds 5
cm in size. ELTR data from 2003 showed a 5 year patient overall survival for hepatic
malignancy (including more than 80% HCC in this group since 1997) of merely 53%, comparing
poorly with data from non-cholestatic liver cirrhosis of 74% and even acute liver failure of
62%. Based on previous work, and a landmark publication in 1996 by Mazzaferro et al. many
centers have restricted their indication for liver transplantation due to clinical criteria
based on tumor size and number to the so-called ´Milan Criteria´.

Implementing these criteria, recent single center data show an improvement in both
disease-free and overall survival following OLT for HCC. Nevertheless approximately 30% of
patients in these studies who were thought to be within Milan Criteria before
transplantation, proved by histopathological examination to have extended disease. This led
to a dramatic decline in overall and disease-free survival, from 71-85% to 40-50%, and from
65-78% to 27-30%, respectively.

In total all preclinical and clinical observations have led us to the purpose that the use
of sirolimus in HCC patients could improve survival after liver transplantation by
decreasing tumor recurrence rate. Thus patients should experience less posttransplant
problems with HCC recurrence, and therefore could expect a longer, and better quality of
life.