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Meta-Analysis
. 2014 Nov 24:349:g6679.
doi: 10.1136/bmj.g6679.

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

Greg A Knoll  1 , Madzouka B Kokolo  2 , Ranjeeta Mallick  2 , Andrew Beck  2 , Chieny D Buenaventura  2 , Robin Ducharme  3 , Rashad Barsoum  4 , Corrado Bernasconi  5 , Tom D Blydt-Hansen  6 , Henrik Ekberg  7 , Claudia R Felipe  8 , John Firth  9 , Lorenzo Gallon  10 , Marielle Gelens  11 , Denis Glotz  12 , Jan Gossmann  13 , Markus Guba  14 , Ahmed Ali Morsy  4 , Rebekka Salgo  15 , Earnst H Scheuermann  13 , Helio Tedesco-Silva  8 , Stefan Vitko  16 , Christopher Watson  17 , Dean A Fergusson  3
Affiliations
Meta-Analysis

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

Greg A Knoll et al. BMJ. .

Erratum in

  • BMJ. 2014;349:g7543

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare the following: GAK has received honorariums and/or research support from Astellas Canada, Pfizer Canada, Roche Canada, and Novartis Canada. AB, CDB, and MBK had partial salary support from Roche Canada. CB has received personal fees from Hoffmann-La Roche unrelated to this submitted work; TDBH received a grant from Wyeth for an investigator initiated trial that was included as part of this submitted work; TDBH has received personal fees from Astellas Canada for advisory board activities unrelated to this submitted work; HTS has received personal fees and research grant support from Pfizer unrelated to this submitted work; CW received a grant from Wyeth for a trial that was included as part of this submitted work; CW has received personal fees from Wyeth for advisory board activities and lectures.

Figures

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Fig 1 PRISMA flow chart of included trials on effect of sirolimus on malignancy and survival after kidney transplantation
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Fig 2 Time to first malignancy in patients with kidney transplant according to immunosuppressive treatment group
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Fig 3 Time to first non-melanoma skin cancer in patients with kidney transplant according to immunosuppressive treatment group
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Fig 4 Overall survival in patients with kidney transplant according to immunosuppressive treatment group
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Fig 5 Risk of cancer and death in patients with kidney transplant treated with sirolimus versus control
See this image and copyright information in PMC

Comment in

References

    1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LYC, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725-30. - PubMed
    1. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N. A study of the quality of life and cost-utility of renal transplantation. Kidney Int 1996;50:235-42. - PubMed
    1. US Renal Data System. USRDS 2013 Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013.
    1. WHO-ONT collaboration. Global observatory on donation and transplantation. www.transplant-observatory.org/Pages/home.aspx
    1. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M, et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823-31. - PubMed

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