Sirolimus After Liver Transplant Improves Survival

By Christin Melton
Published: Thursday, May 13, 2010
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In the April issue of Hepatology, researchers from the University of Alberta in Edmonton, Canada, reported that administering sirolimus (Rapamune) after liver transplantation in patients with nonresectable hepatocellular carcinoma (HCC) significantly increased survival rates. An anti-CD25 antibody induction regimen improved survival in liver transplant patients regardless of whether they had HCC.

Investigators, led by Christian Toso, MD, examined data for patients with HCC (n = 2491) and for those without HCC (n = 12167) who had a liver transplant between 2002 and 2009 and were listed in the US Scientific Registry of Transplant Recipients. All the patients received ≥6 months of maintenance therapy with an immunosuppressant, such as tacrolimus (Prograf ), steroids, mycophenolate mofetil, cyclosporine, or a sirolimus-based regimen. Some patients also received induction therapy with an anti-CD25 monoclonal antibody and some received thymoglobulin. Less than 10% of patients received maintenance therapy with cyclosporine or sirolimus. In the HCC subgroup, 12% of patients received induction therapy with an anti-CD25 antibody compared with 10.8% in the group without HCC. The study’s primary endpoint was patient survival at 5 years, and mortality from all causes was factored into survival outcomes data.

Investigators reported that of all the agents used, only anti-CD25 induction therapy with the drugs daclizumab (Zenapax) or basiliximab (Simulect) were associated with better 5-year survival rates. Of all the maintenance regimens, only sirolimusbased therapy improved 5-year survival after transplant, and this was only for patients with HCC. A multivariate analysis (Table) of HCC patients that adjusted for age, disease severity, year of transplant, neoadjuvant therapy, tumor volume, and the level of serum alpha fetoprotein found that those who received anti-CD25 therapy before transplant for HCC had a survival advantage of 6% compared with those who did not (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.45-0.9; P ≤.01); and sirolimus offered a 14.4% 5-year survival advantage compared with nonsirolimus regimens (HR, 0.53; 95% CI, 0.31-0.92; P ≤.05). Both results were statistically significant. The multivariate analysis showed that use of cyclosporine was associated with a 30% increase in mortality. Toso said sirolimus-based maintenance therapy was associated with worse survival in patients without HCC compared to other immunosuppressive regimens, but the trend was not significant.

In a presentation at the recent annual International Liver Conference in Europe, Toso said the activity of sirolimus in patients with HCC relates more to a cytostatic effect than a cytotoxic effect. “I would expect the rate of growth of an HCC recurrence will be slower in a patient treated with sirolimus,” he said. “I’m not sure that sirolimus will prevent recurrence or kill a preexisting tumor,” he added. Toso urged physicians to use sirolimus as maintenance therapy in patients with HCC but suggested waiting a few weeks after transplant before initiating therapy because sirolimus increases the risk of delayed wound healing and incisional hernia. He was less concerned with its association with an increase in hepatic artery thrombosis, which he said is uncommon. The article in Hepatology is available at http://bit.ly/csjL8x.

Toso C, Merani S, Bigam DL, Shapiro J, Kneteman J. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology. 2009. [Epub ahead of print]

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