Sirolimus-Based Immunosuppression Therapy in OLT for Patients With HCC Exceeding Milan Criteria

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00554125
Recruitment Status : Unknown
Verified October 2007 by Fudan University.
Recruitment status was:  Recruiting
First Posted : November 6, 2007
Last Update Posted : November 6, 2007
Information provided by:
Fudan University

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

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: sirolimus Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Prevention
Official Title: A Prospective Randomised, Open-Labeled Study Comparing Sirolimus Versus FK506 In OLT for Patients With HCC Exceeding Milan Criteria
Study Start Date : August 2007
Estimated Study Completion Date : August 2013

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: 2, III ,intervention Drug: sirolimus
given at an initial dose of 3 mg/m2, and adjusted over time to achieve steady-state whole-blood trough levels of approximately 5-8 ng/mL

Primary Outcome Measures :
  1. Disease-free survival [ Time Frame: 3-,5-year ]

Secondary Outcome Measures :
  1. overall survival [ Time Frame: 3-,5-year ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00554125

Contact: Jian Zhou, MD +86-21-64037181

Liver Cancer Institute and Zhongshan Hospital, Fudan University Recruiting
Shanghai, China, 200032
Contact: Jian Zhou, MD    +86-21-64037181   
Sponsors and Collaborators
Fudan University
Study Director: Jia Fan, MD Liver Cancer Institute and Zhongshan Hospital, Fudan University, 200032, Shanghai, China.

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number): Identifier: NCT00554125     History of Changes
Other Study ID Numbers: ZSH-LCI-FJ-0002
First Posted: November 6, 2007    Key Record Dates
Last Update Posted: November 6, 2007
Last Verified: October 2007

Keywords provided by Fudan University:
Sirolimus; Orthotopic liver transplantation; HCC

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs