Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data

Abstract

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.Design Systematic review and meta-analysis of individual patient data.Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

A molecular signature for delayed graft function

“…While use of sirolimus is associated with reduced risk of malignancy in transplant recipients, it also correlates with an increased risk of death when the allograft has originated from a cadaveric donor. No such correlation, however, has been observed from living donor allografts, supporting the central role of mTOR signalling and associated pathways for the regulation of cellular metabolism and health span (Knoll et al, 2014). …”

Sirolimus e Prevenção Primária de Cancro Cutâneo Não-melanoma em Transplantados Renais – Um Estudo Retrospetivo

“…A par da redução da incidência de CCNM, houve um aumento na mortalidade nos casos tratados com sirolimus, sobretudo à custa de doença cardiovascular e de infeções. 16 Os nossos resultados têm, ainda assim, de ser interpretados à luz das limitações inerentes a um estudo retrospetivo. Apenas foram incluídos os doentes com referenciação à Dermatologia e não toda a população transplantada renal.…”

“…16 Num extremo, tendo em conta a metanálise previamente referida, Sharif et al consideram pouco útil o switch para sirolimus com o objetivo de reduzir CCNM, por dois motivos: i) embora o cancro cutâneo seja aquele que é mais frequentemente diagnosticado em transplantados renais, a mortalidade atribuível a este é de apenas 3,2% e a maioria das mortes deve-se a melanoma (que corresponde a menos de 3% dos cancros cutâneos); ii) as taxas de descontinuação após switch para sirolimus (21,6%) são superiores às verificadas com a manutenção dos inibidores da calcineurina (9,6%). 10 Esta é uma perspetiva de um nefrologista e com a qual não podemos concordar plenamente.…”

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…”