A new study suggesting rapamycin is likely helpful in skin cancers…
Discussion
In this prospective study, the conversion to sirolimus monotherapy in kidney transplant recipients with high-risk cSCC was associated with a significant reduction in the incidence of moderately differentiated lesions, a tendency toward a lower incidence of lesions with other features of poor prognosis, and an adequate safety and tolerability profile.
The de novo use or conversion to mTOR inhibitors have been associated with reduction in the incidence of de novocSCC lesions1–4. Yet, long-term benefit has been limited by poor tolerability5,6,12 and increased risk of acute rejection when administered as monotherapy5,12,15. To overcome these constrains, this trial purposefully chose non-sensitized and stable kidney transplant recipients who had been diagnosed with squamous cell skin carcinoma with poor prognosis characteristics, and used conversion to monotherapy with mTOR inhibitors as adjuvant to the dermatological therapy. In this population, the potential anti-tumor benefits would outweigh the transplant-related risks.
The most noteworthy finding was a substantial decrease in the incidence density of moderately differentiated lesions (present in 83% of the patients in the sirolimus group) from the second year of sirolimus administration, compared to a significant increase in this parameter in the control group over time. This is in agreement with previous research indicating that the advantage of converting to sirolimus on the dermatologic course of SCC lesions in kidney transplant recipients requires long-term treatment. For example, in the five-year follow-up of the TUMORAPA study,7 survival free of new skin lesions was longer in the sirolimus-converted group over time.
The possible mechanisms by which mTOR inhibitors act on keratinocyte carcinogenesis may explain these results, as they include sustained processes of inhibition of cell phosphorylation and proliferation, regulation of angiogenesis, reduction of cytokine release, and suppression of oncogenes such as AFT3 (activating transcription factor 3) and GRO-α (growth regulatory oncogene alpha)8–12.
In this study, conversion to sirolimus was well tolerated, with no discontinuation due to adverse events in the first year after conversion. The absence of a high loading dose, unlike in previous investigations1–3 and in agreement with most recent reports14–16, and the maintenance of blood sirolimus concentrations close to 10 ng/mL were critical to achieving this outcome. Renal function was maintained, no episodes of acute allograft rejection occurred, and there was no de novo DSA within the 3-years follow-up, suggesting the effectiveness of sirolimus monotherapy in selected non-sensitized patients.
The small number of patients included, the absence of a randomized control group, and the fact that this comparator group was composed of patients with exclusion criteria or who refused conversion are some limitations of the study.
In conclusion, the stepwise conversion from CNI-based to sirolimus monotherapy may act as adjuvant to the dermatological therapy for kidney transplant recipients with high-risk cSCC, potentially improving the quality of patients’ life. The absence of an attack dose resulted in a good profile of tolerability. Finally, there was no negative impact on the mid-term results of the transplant.
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