Number 8
Skin cancer in kidney transplant patients has been strongly associated with exposure to calcineurin inhibitor drugs (CNIs) such as tacrolimus. The use of sirolimus - a powerful immunosuppressant and ostensibly anti-neoplastic - was examined in this paper that I rank the 8th best in 2012.
Skin cancer in kidney transplant patients has been strongly associated with exposure to calcineurin inhibitor drugs (CNIs) such as tacrolimus. The use of sirolimus - a powerful immunosuppressant and ostensibly anti-neoplastic - was examined in this paper that I rank the 8th best in 2012.
Euvrard et al on behalf og the TUMORAPA study group published this important RCT in July 2012 in NEJM titled: "Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation"
(pubmed link).
(pubmed link).
Some background...
- Skin cancers affect 50% of organ-transplant recipients during their long-term course
- Several studies have shown that after a first cutaneous squamous-cell carcinoma, multiple subsequent skin cancers develop in 60 to 80% of kidney-transplant recipients within 3 years
- Cutaneous squamous-cell carcinoma appears to be one of the most appropriate markers for initiating a change in immunosuppressive medication for organ-transplant recipients
- Skin cancers result from both a decrease in immunosurveillance and drug-specific properties.
- Inhibitors of the mammalian target of rapamycin (mTOR), including sirolimus (Rapamune, Pfizer) and everolimus, are newer immunosuppressants that have antineoplastic properties
Research question: the efficacy of sirolimus for the secondary prevention of skin cancers in kidney-transplant recipients receiving calcineurin inhibitors.
The investigators randomly assigned in a phase 3 open label study, transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell 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.
- 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.
The main limitations were limited follow-up of 2 years and small sample size. An important consideration in this study would be whether the graft rejection rate is higher with sirolimus - no difference was observed but this could be a reflection of the small sample and short follow-up.
Bottom-line: think about switching from CNIs to sirolimus in patients following the diagnosis of the first skin cancer. As well, the earlier the conversion occurs after an initial diagnosis of cutaneous squamous-cell carcinoma, the greater the efficacy (i.e, at the first occurrence of a cutaneous squamous-cell carcinoma, as compared with introduction after the occurrence of multiple cutaneous squamous-cell carcinomas.) What we don't know for sure is whether sirolimus would be associated with a higher graft rejection rate in a larger sample with longer follow-up.
