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Widely-used immunosuppressive regimens for kidney transplant appear to carry similar long-term cancer risks, Australian researchers found.

Skin cancer and other cancers did not occur any sooner whether patients got azathioprine (Azasan, Imuran) and prednisolone or cyclosporine (Gengraf, Neoral, Sandimmune) monotherapy or switched from cyclosporine to the other regimen.

The lack of difference between treatments persisted in multivariate analysis of the randomized trial with more than 20 years of follow-up, Martin P. Gallagher, MD, of the George Institute for International Health in Camperdown, Australia, and colleagues.

"The risk may be mediated by the total burden of immunosuppression more than the agent," they wrote online in the Journal of the American Society of Nephrology.

Much debate has centered on effects of the various agents and dose regimens, with concerns raised about azathioprine and cyclosporine, among others, Gallagher's group noted.

Even if there were small differences that the study wasn't powered to detect, despite a median of 20.6 years of follow-up, the clinical implications would be questionable "because most modern transplant regimens use combinations of antiproliferative agents and calcineurin antagonists," they added.

The regimens used in the study reflected common practice over the past decades, which differs from modern practice with new antiproliferative agents and mandated cyclosporine drug monitoring, they cautioned.

But factors other than the specific immunosuppressive therapy contributed much more to cancer risk after transplantation, the researchers showed.

In multivariate analyses, significant predictors of skin cancer were older age, non-brown eye color, fairer skin, and a functioning transplant, which together predicted 10- to 28-fold higher incidence over time.

Independent predictors of other cancer types in the kidney transplant patients were older age and history of smoking, which combined to elevate risk approximately six-fold over time.

The researchers analyzed long-term follow-up on 481 patients in the Australian Multicenter Trial of Cyclosporine Withdrawal, which had randomized patients to the following:

• Standard therapy of azathioprine and prednisolone.
• Long-term cyclosporine.
• Cyclosporine followed by withdrawal at three months followed by maintenance azathioprine and prednisolone.

During follow-up, 46% of patients developed at least one cancer. For 19% it was a non-skin cancer, while 35% had at least one skin cancer, excluding melanoma.

Overall cumulative incidence of non-skin cancer at 20 years after transplant was similar among the treatment regimens: 27% for both the azathioprine and prednisolone and cyclosporine monotherapy groups and 28% for the switch group (P=0.96).

Time-to-development of the first non-skin cancer likewise didn't differ significantly, with a mean of 16.0 years, 15.3 years, and 15.7 years, respectively.

For skin cancer, the cumulative incidence of skin cancer at 20 years again did not differ among the three randomized treatment groups (50%, 48%, and 46%, respectively, P=0.69).

The mean time to the first non-melanoma skin cancer was similar at 13.6 years with azathioprine and prednisolone, 14.3 years with cyclosporine alone, and 15.2 years with cyclosporine followed by azathioprine and prednisolone.

Indeed, there is no compelling clinical evidence for one regimen over another in the literature on post-transplant malignancy, Gallagher's group concluded.

"Despite the existing knowledge regarding cancer risk, no immunosuppressive treatment strategies have been proved to reduce this risk," they wrote in the paper.

One recent study suggested a lower risk with sirolimus (Rapamune), but this has not yet been validated by other studies or meta-analyses, they said.

The Australian Multicenter Trial of Cyclosporine Withdrawal included a largely white population in Australia, which has among the world's highest skin cancer rates.

"The absolute estimates of risk may differ for transplant recipients in different settings, but it is likely that the relative differences will hold true," the investigators suggested in the paper.

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