By Abby S. Van Voorhees, MD, January 01, 2013
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Sylvie Euvrard, MD, about her recent New England Journal of Medicine article, “Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation.”
Dr. Van Voorhees: Let’s start by talking about the risk of skin cancers in organ transplant patients. How frequently are these problematic? What is the ratio of squamous cell carcinoma (SCC) to basal cell carcinoma (BCC) in this population? If a person develops one skin cancer, what is the likelihood of him or her developing additional ones?
Dr. Euvrard: Skin cancers are the most frequent malignancies among organ transplant recipients and affect more than half of patients in the long term. The risk increases linearly for basal cell carcinomas and exponentially for squamous cell carcinomas. After a first SCC, several retrospective studies have shown that 70 to 100 percent of patients will develop subsequent multiple skin tumors within the following three to five years. The appearance of the first SCC appears to be one of the most appropriate markers to initiate a change of immunosuppressive treatment and to assess the effect of this change on carcinogenesis according to skin-tumor counts. [pagebreak]
Dr. Van Voorhees: What is known about why patients get skin cancers while on the transplant medications? Is it solely a result of immunosuppression? Is it possible that the drugs themselves play a direct role?
Dr. Euvrard: Organ transplant recipients share common risk factors with the normal population such as age, fair skin type, and sunburns. The special tumor burden of these patients is related to the load, meaning the length of immunosuppression per se, but also to the specific properties of some immunosuppressive drugs, especially calcineurin inhibitors such as cyclosporine and tacrolimus.
Dr. Van Voorhees: Prior to your study, what was known about medications like sirolimus in the prevention of skin cancers? What made you suspect that this medication might be advantageous?
Dr. Euvrard: Initially, studies in mice reported that sirolimus inhibited tumor growth while cyclosporine induced cancer progression. Thereafter, several clinical studies had shown that organ transplant recipients under sirolimus as first-line treatment had less skin cancer than those under calcineurin inhibitors within the two first years after transplantation. These first clinical studies concerned patients who had never developed skin cancer and who were treated with sirolimus just after transplantation. [pagebreak]
Dr. Van Voorhees: Tell us about your study. Did you find a difference in the rate of skin cancer development between the sirolimus group and the calcineurin-inhibitor group? What kind of skin cancers did you find? Was there any alteration in the type?
Dr. Euvrard: Our study assessed the efficacy of sirolimus in secondary skin cancer prevention in patients who had already developed squamous cell carcinoma with a mean delay of 10 years post-graft.
The number of SCCs and of other skin tumors was lower by a factor of three in the sirolimus group as compared to the calcineurin inhibitors group. The ratio of SCC to BCC decreased in both groups as compared to the pre-study period (partially due to close monitoring), but more in the sirolimus than in the calcineurin inhibitors group. Patients in the study who had new premalignant keratoses were treated very quickly so their premalignant keratoses did not have time to become SCCs, even in the calcineurin inhibitors group.
Dr. Van Voorhees: Was there any advantage for either the sirolimus group or the calcineurin-inhibitor group in the prevention of metastatic disease in your patients?
Dr. Euvrard: We observed four metastatic skin cancers, including two SCCs, one Merkel-cell carcinoma, and one melanoma. All occurred under calcineurin inhibitors. Only one metastatic SCC occurred in a patient who had been initially randomized in the sirolimus group, six months after he was switched back to calcineurin inhibitors due to sirolimus intolerance. [pagebreak]
Dr. Van Voorhees: Speaking of intolerance, how well is sirolimus tolerated? What adverse events are seen with its use? Do these seem like potential side effects that may limit the utility of this medication?
Dr. Euvrard: The study began in 2004, when transplant physicians were less expert with the use of sirolimus than they are now. More than half of the patients had a rapid conversion with a loading dose, which led to many adverse events within the first weeks. (We considered the conversion to sirolimus rapid if calcineurin inhibitors were discontinued within seven days. A high dose of sirolimus was given initially, and thereafter the dosage was tapered progressively according to the sirolimus blood levels.) Many of them were improved by drug reduction or complementary treatments. The adverse events included, mainly, edema, proteinuria, pneumonitis, and cutaneous effects, such as aphthous ulcers, acne-like lesions, and rash. There were twice as many serious adverse events and drug discontinuations in patients who had been converted with rapid protocols as in those with progressive protocols. We would probably have significantly fewer serious adverse events and drug discontinuations if the study started again in 2012, as the transplant physicians who administer these therapies have improved their use of progressive protocols. [pagebreak]
Dr. Van Voorhees: What do you feel that dermatologists in the community should understand about your work? If a patient who has had a transplant in the past comes into the office with a new SCC are there recommendations that you’d like to suggest for their management?
Dr. Euvrard: Dermatologists should inform the transplant physician about the occurrence of an SCC and raise the question of a revision of immunosuppression. They should not wait for multiple or aggressive SCCs to ask that this measure be considered; the current data suggests that the earlier the conversion occurs after the first SCC, the greater the efficacy.
Many transplant physicians are reluctant to change immunosuppression in long-term organ transplant recipients and many patients are “overtreated.” Revision of immunosuppression includes switching to sirolimus (or everolimus) along with minimization (decrease of the doses of associated immunosuppressive drugs), which should also be considered.