SIROLIMUS CUTS SKIN CANCER RISK IN TRANSPLANT PATIENTS 

July 27, 2012 — Switching to sirolimus (Rapamune, Pfizer) can decrease the risk for new cutaneous squamous cell carcinomas in kidney recipients. Sirolimus use is also associated with a delayed occurrence of skin lesions, compared with the continued use of calcineurin inhibitors.

According to a study published in the July 26 issue of the New England Journal of Medicine, after transplantation, survival free of cutaneous squamous cell carcinoma was significantly longer in patients who received sirolimus than in those who received a calcineurin inhibitor.

The authors, led by Sylvie Euvrard, MD, from the Edouard Herriot Hospital Group in Lyon, France, assigned 120 kidney recipients who were receiving calcineurin inhibitors and had at least 1 cutaneous squamous cell carcinoma to either continue with their current therapy or transition to sirolimus.

New squamous cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after the withdrawal of sirolimus) and in 22 (39%) in the calcineurin inhibitor group. The median time to onset also favored sirolimus (15 vs 7 months; P = .02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98).

However, for the primary end point of the study — survival free of new cutaneous squamous cell carcinoma at 2 years — sirolimus was signficiantly better than calcineurin inhibitors in only a limited group of patients — those who had only 1 cutaneous squamous cell carcinoma at the time of randomization.

In other words, for the primary outcome, sirolimus was not significantly better than calcineurin inhibitors in patients with more than 1 lesion at randomization. It appears that the drug works best against skin cancer in patients who have a low burden of lesions in the first place.

This study has good news and bad news, explained an expert not involved with the research.

"The take-home messages are that not all immunosuppressive drugs cause cancer and that [this study] provides additional evidence that sirolimus is effective in the secondary prevention of one particular cancer — squamous cell carcinoma of the skin," said Donald E. Hricik, MD, from Case Western Reserve University in Cleveland, Ohio. He is also on staff at University Hospitals Case Medical Center, where he is medical director of transplantation services.

But there is one more take-home message, he said. "All drugs are poisons! While sirolimus may have antineoplastic effects, it is associated with a number of potentially serious side effects. Conversion from a calcineurin inhibitor to sirolimus...must be performed after carefully weighing the risks and benefits. For the community physician, this will almost always require input from the patient's transplant center," he toldMedscape Medical News. Indeed, in the sirolimus group, 23% of patients discontinued the drug because of adverse events, and patients in the sirolimus group were much more likely to have a serious adverse event. Overall, there were 60 serious events in the sirolimus group (average per patient, 0.94) and 14 in the calcineurin inhibitor group (average per patient, 0.25).

Research Supports Sirolimus

A number of studies have examined the posttransplant use of sirolimus to reduce the risk for subsequent malignancies. Five-year data from the 2005 Rapamune Maintenance Regimen (RMR) trial, previously reported byMedscape Medical News, demonstrated that transplant patients receiving sirolimus therapy without cyclosporine have a significantly lower risk of developing malignancies than patients who stay on a combination of cyclosporine plus sirolimus.

"Although renal transplant patients remain at higher risk for cancer than the general population, the findings of [the RMR] trial open the possibility for the use of sirolimus-based therapy in high-risk cancer patients and in patients with a cancer that occurs after renal transplantation," said RMR lead author Josep Campistol, MD, from Hospital Clinic de Barcelona, Spain, at that time.

More recently, a study presented at the 2009 American Transplant Congress found that early conversion from a cyclosporine regimen to a sirolimus regimen results in similar patient and graft survival but better renal function and fewer malignancies 30 months after kidney transplantation. In that study, 1 patient receiving sirolimus developed a malignancy, compared with 6 receiving cyclosporine.

Although the difference between the 2 groups in that study in terms of malignancy was not significant, lead author Yvon Lebranchu, MD, from the University François Rabelais in Tours, France, told Medscape Medical News that the difference tended to worsen progressively out to 30 months.

"These are intermediate results.... I speculate that, at the final results at 4 years, there will probably be a difference in terms of malignancy, with less malignancy in the sirolimus groups," he said when the 30-month results were reported.

Study Details

Skin cancers can affect more than half of all organ recipients over the long term. Previous research has shown that after a first cutaneous squamous cell carcinoma, multiple subsequent skin cancers develop in 60% to 80% of kidney recipients within 3 years.

The specific tumor burden of such patients is linked to the immunosuppressive medications used, note Dr. Euvrard and colleagues, but a reduction in cutaneous carcinogenesis after a decrease in immunosuppression has been reported.

In their phase 3 multicenter study, they assigned patients in a 1:1 ratio to transition to sirolimus from calcineurin inhibitors or to continue receiving calcineurin inhibitors. In the sirolimus group, calcineurin inhibitors were discontinued and sirolimus was added to the usual immunosuppressive agents, according to the routine practice of each center (target trough level for sirolimus, 6 to 12 ng/mL).

The authors considered a conversion to sirolimus to be rapid if calcineurin inhibitors were discontinued within 7 days and to be progressive if the conversion took longer than 7 days.

Of the 120 patients in the final analysis, 290 cutaneous squamous cell carcinomas were diagnosed. In this cohort, 55% had a single lesion, and the remainder had multiple lesions (average number, 4.2; range, 2 to 15). In addition, 68% of the patients had 274 other types of skin lesions (68 had basal cell carcinomas, 27 had keratoacanthomas, 90 had in situ carcinomas [or Bowen's disease], and 89 had premalignant keratoses).

Of the 86 patients who completed the 2-year treatment regimen, 20 patients in the sirolimus group developed skin cancers that included squamous cell carcinomas (with 71 lesions), as did 31 patients (with 191 lesions) in the calcineurin inhibitor group (47.6% vs 70.5%; P = .048).

In addition, during the study period, the ratio of squamous cell carcinoma to basal cell carcinoma declined from 3.9 to 1.4 in the sirolimus group and from 1.8 to 1.0 in the calcineurin inhibitor group.

Serious adverse events were more common in the sirolimus group, and there were twice as many in patients who converted to sirolimus with rapid responses than in patients with progressive responses. In the sirolimus group, 23% of patients discontinued the drug because of adverse events; graft function remained stable in both groups.

The study was funded by Hospices Civils de Lyon and grants from the French Ministry of Health, the French Society of Dermatology, and Pfizer. Several authors have disclosed financial relationships with industry, as noted in the paper.

N Engl J Med. 2012; 367:329-339. Abstract