Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation

Abstract

BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamouscell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients

“…Most prior studies, including randomized clinical trials, have centered around prevention and treatment of nonmelanoma skin cancers, as these are a common malignant complication following a kidney transplant (12)(13)(14). While some studies have indicated possible reductions in nonskin cancers with sirolimus use, few have been large enough to provide precise incidence rate comparisons (15,16,28,29).…”

“…A number of clinical trials and epidemiologic studies have found the use of sirolimusbased immunosuppressant regimens to be associated with reduced incidence of nonmelanoma skin cancers, which are the most common malignancies following kidney transplantation (11)(12)(13)(14). However, the effects of sirolimus on risk of other cancers are less well defined (15,16).…”

Cancer in the Transplant Recipient

“…(47.6% vs. 70.5%, p ¼ 0.048). However, poor tolerability of mTORI remains a major concern (Euvrard et al 2012). More than 35% of transplant recipients discontinued mTORI treatment owing to significant side effects such as ankle swelling, acne, pneumonitis, and proteinuria, and infective complications have prevented the longer-term use of mTORI in these high-risk groups.…”

Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial

“…In contrast, early (ie, within 6 months of transplantation) conversion to mTORi has been shown in some (but not all) trials to improve transplant function compared with remaining on cyclosporine‐based immunosuppression 8, 9, 10, 11, 12. Another potential benefit of conversion to mTORi is a reduction in the risk of malignancy posttransplantation (especially skin cancer) 13, 14, 15. However, a recent meta‐analysis suggested that sirolimus may be associated with an increased risk of all‐cause mortality 15…”