Sirolimus-Based Immunosuppression Therapy 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.