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Reuters Health Information (2012-12-28): Sirolimus advantageous after liver transplantation for cancer


Sirolimus advantageous after liver transplantation for cancer

Last Updated: 2012-12-28 12:30:20 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Recurrent hepatoma after liver transplantation is less likely with immunosuppression protocols that include sirolimus, a meta-analysis suggests.

The improved outcomes - including lower recurrence-related mortality even with significant poor prognostic factors - "support the potential antiproliferative tumor effect" of sirolimus, say the authors of the report online December 20 in Alimentary Pharmacology and Therapeutics.

Dr. Nigel Heaton at King's College Hospital, London, and colleagues explain that calcineurin inhibitors (like the commonly used immunosuppressants cyclosporine and tacrolimus) have been implicated in tumor formation.

But sirolimus, in contrast to the similarly named tacrolimus, is not a calcineurin inhibitor. Instead, it achieves its immunosuppressant effects by inhibiting mammalian target of rapamycin (mTOR) receptors, and it has antitumor effects as well.

"The antitumor activity of sirolimus occurs at the same concentrations as the maintenance target levels in posttransplant patients," the authors note.

To assess cancer outcomes with sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma (HCC), the team conducted a systematic review of the literature and identified five relevant studies involving a total of 474 patients.

All the studies used sirolimus in combination with a calcineurin inhibitor (CNI), either cyclosporine or tacrolimus. "Sirolimus can be used for CNI renal sparing, but is not effective enough to be used as a single agent -- particularly early post transplant," Dr. Heaton explained in an email to Reuters Health. Three of the studies compared sirolimus-treated patients to those treated with only a calcineurin inhibitor.

Median follow-up ranged from 18 to 49 months. The tumor recurrence rate was lower with sirolimus use (4.9%-12.9%) than with calcineurin inhibitors (17.3%-38.7%), the researchers found. Recurrence-free survival was also much better with sirolimus. For example, at five years, recurrence-free survival in the two groups was 79%-80% versus 54%-60%, respectively.

The odds ratio for recurrence with sirolimus vs calcineurin inhibitors was 0.30 (p<0.001); for recurrence-related mortality the OR was 0.29 (p=0.005), and for overall mortality it was 0.35 (p<0.001), according to the report.

Dr. Heaton and colleagues acknowledge that the quality of all the included studies was low, and there are limitations to their analysis. Nonetheless, they conclude, "The review showed lower recurrence rate, longer recurrence-free survival and overall survival and lower recurrence-related mortality in sirolimus-treated patients in comparison with the calcineurin inhibitor-treated patients following liver transplantation for hepatocellular carcinoma."

Dr. Heaton added this perspective: "Although there is some evidence for benefit of using sirolimus post transplant for HCC, it is not really strong. Outcomes from properly randomized trials are awaited." In their paper, he and his co-authors specifically mention the SiLVER trial, which should help in proving the oncological benefit of sirolimus post liver transplantation for HCC.

As Dr. Heaton noted, a question remains. "Is the effect currently observed due to the action of sirolimus, or is part of it due to lower levels of CNI-based immunosuppression?"


Aliment Pharmacol Ther 2012.

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