MADRID — Switching renal transplant recipients to sirolimus-based long-term immunosuppression markedly reduced their rate of nonmelanoma skin cancer in the first-ever randomized controlled trial of this cancer-prevention strategy.
This study is a landmark event because it shows that renal transplant teams are finally taking seriously the extraordinarily high risk of skin cancer in their patients, Dr. Julio Pascual observed at the 13th World Congress on Cancers of the Skin, which was sponsored by the Skin Cancer Foundation.
The blinded randomized trial, conducted at J.W. Goethe University in Frankfurt, Germany, follows a handful of prior uncontrolled studies by multiple transplant groups showing that converting renal transplant recipients from long-term immunosuppression with the calcineurin inhibitors cyclosporine and tacrolimus to the proliferation stimulation inhibitors sirolimus or everolimus often brings rapid improvement and prevents recurrence of multiple squamous cell carcinomas, basal cell carcinomas, melanoma, and Kaposi's sarcoma, said Dr. Pascual, a nephrologist and transplant physician at Hospital del Mar, Barcelona.
The Frankfurt study involved 44 renal transplant recipients with premalignant skin lesions who had been on calcineurin inhibitor-based immunosuppressive therapy for a mean of 3.8 years before they were randomized to a switch to sirolimus or continuation of their original immunosuppression.
Of 33 patients evaluable after 6 months of follow-up, only 1 of 16 on sirolimus developed nonmelanoma skin cancer, compared with 8 of 17 controls. Moreover, no one in the sirolimus group experienced worsening of preexisting premalignant lesions and five showed improvement. In contrast, five patients in the control group had progression of their preexisting premalignancies (Am. J. Transplant. 2010;10:1385-93).
Cancer accounts for 30% of all deaths in kidney transplant recipients, and squamous cell carcinoma is the cancer they develop most frequently. Indeed, registry studies show that the risk of nonmelanoma skin cancer is more than 20-fold greater in renal transplant recipients than the general population.
The duration, intensity, and type of immunosuppressive therapy play a crucial role in the development of these skin cancers. Use of azathioprine and the calcineurin inhibitors is a risk factor for skin cancer--they interfere with DNA repair and immunosurveillance. In addition, the calcineurin inhibitors are nephrotoxic. Sirolimus and everolimus are not only nonnephrotoxic, they inhibit angiogenesis and tumor growth, Dr. Pascual explained.
Nevertheless, he continued, most of his colleagues in renal transplant medicine have been slow to take their patients' elevated skin cancer risk as seriously as it deserves.
Dr. Pascual recalled last year's report on the 24-month results from the CONVERT trial, in which 830 renal transplant recipients were randomized 2:1 to convert from cyclosporine or tacrolimus to sirolimus or stay on their calcineurin inhibitor. This is a major study in the renal transplant field whose chief endpoints involved mortality, graft survival, urinary protein excretion, and glomerular filtration rate. Buried within the findings was the fact that the sirolimus group had a 3% incidence of neoplasia during follow-up, significantly less than the 9% rate in controls (Transplantation 2009;87:233-42).
"To me this is the most important finding in this trial, and it only gets about three lines in the results section," he said.
Dr. Pascual reported having no financial conflicts.