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.