Clinical trial NCT00554125: Sirolimus-Based Immunosuppression Therapy in OLT for Patients With HCC Exceeding Milan Criteria
Official title: A Prospective Randomised, Open-Labeled Study Comparing Sirolimus Versus FK506 In OLT for Patients With HCC Exceeding Milan Criteria
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: Sirolimus; Orthotopic liver transplantation; HCC
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2007-11-06
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate the influence of sirolimus on outcome after OLT for HCC exceeding Milan criteria.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* The major organ (liver,heart, lung and kidney) function after OLT was normal.
* Pathologically proved HCC before randomisation .
* Tumor exceeding the Milan criteria (one nodule ≤5 cm or 2-3 nodules all \<3 cm, without macroscopic vascular invasion and extrahepatic spreading).
* Signed, written informed consent.

Exclusion Criteria:

* Extrahepatic metastasis, nodal involvement, perioperative deaths (within 30 days after operation), and tumor thrombi in the proximal main trunk of the portal vein and / or vena cava
* History of cardiac disease.
* Active clinically serious infection (\>grade 2 Nation Cancer Institute NCI-CTCAE version 3.0).
* Known history of human immunodeficiency virus (HIV) infection.
* Any condition that is unstable or which could jeopardize the safety of the patient and his / her compliance in the study.
* Pregnant or breast-feeding patients.

Primary outcomes:
measure: Disease-free survival
timeFrame: 3-,5-year
Secondary outcomes:
measure: overall survival
timeFrame: 3-,5-year
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Liver Cancer Institute and Zhongshan Hospital, Fudan University
Study officials:
affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
name: Jia Fan, MD
role: STUDY_DIRECTOR
References:
citation: Treiber G. mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther. 2009 Feb;9(2):247-61. doi: 10.1586/14737140.9.2.247.