Trial Information

A Prospective Randomised, Open-Labeled Study Comparing Sirolimus Versus FK506 In OLT for Patients With HCC Exceeding Milan Criteria

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in Asia and Africa.
Although the first-line therapy for HCC is liver resection, the concomitant cirrhosis often
leaves orthotopic liver transplantation (OLT) rather than liver resection as the only
potentially curative option. The risk of recurrence is the major concern in patients
transplanted for HCC. It has been demonstrated that utilizing more restrictive selection
criteria before submitting cirrhotic patients with HCC to liver transplantation is
associated with a better outcome. The Milan criteria (one nodule ≤5 cm or 2-3 nodules all ＜3
cm, without macroscopic vascular invasion and extrahepatic spreading)provide a simple means
of selecting patients with HCC for transplantation with a low risk (≈10%) for recurrence.
However, the benefit of OLT for patients with HCC within the Milan criteria is opposed by a
critical organ shortage, which lengthens the waiting time and thus allows tumor progression
during the waiting period. Nearly one third of patients who have a transplant for HCC fall
outside the Milan criteria on the basis of pathological findings in the explanted liver, and
had a higher risk of tumor recurrence.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.

Although it can be hypothesized that the pharmacologic immunosuppression required after
liver transplantation for HCC may be accelerated tumor recurrence and metastasis, recent
reports have suggest that not all immunosuppressive drugs necessarily promote HCC recurrence
in transplant recipients. Sirolimus has emerged as a new, potent immunosuppressive agent
which unlike other immunosuppressants [cyclosporine (CsA), tacrolimus (FK506), and
azathioprine (AZA)] has potent antitumor activity in vitro and in vivo. The
immunosuppressive and antitumor effects of sirolimus share a common mechanism of action.
Sirolimus inhibits the mammalian target of sirolimus (mTOR), which prevents acute graft
rejection mediated by interleukin-2 and could block other cytokine signal transduction, thus
directly inhibits tumor cell proliferation and angiogenesis. And the most important is that
the antitumor activity of SRL has been shown at the same concentrations as maintenance
target levels in posttransplant patients.

Thus, it seems reasonable to speculate that sirolimus could simultaneously contribute to
inhibition of tumor recurrence and preventing of rejection in OLT for patients with HCC.