Sirolimus and Non-melanoma Skin Cancer Prevention after Kidney Transplantation: A Meta-analysis

  • Gu, Yu-Hong (Department of Pharmaceutics, the Third Affiliated Hospital of Harbin Medical University) ;
  • Du, Jia-Xin (Department of Pharmaceutics, the Third Affiliated Hospital of Harbin Medical University) ;
  • Ma, Man-Ling (Department of Pharmaceutics, the Third Affiliated Hospital of Harbin Medical University)
  • 발행 : 2012.09.30


Background: Whether sirolimus is useful in the prevention of non-melanoma skin cancer (NMSC) remains unclear and we therefore performed this meta-analysis of randomized controlled trials to test the hypothesis that Sirolimus-based immunosuppression is associated with a decrease in NMSC. Methods: The main outcomes were NMSC, squamous-cell carcinoma and basal-cell carcinoma. The pooled risk ratio (RR) with its 95% confidence interval (95%CI) were used to assess the effects. Results: 5 randomized trials involving a total of 1499 patients receiving kidney transplantation were included. Patients undergoing Sirolimus-based immunosuppression had much lower risk of NMSC (RR = 0.49, 95%CI 0.32-0.76, P = 0.001). Subgroup analyses by tumor type showed that Sirolimus-based immunosuppression significantly decreased risk of both squamous-cell carcinoma (RR = 0.58, 95%CI 0.43-0.78, P < 0.001) and basal-cell carcinoma (RR = 0.56, 95%CI 0.37-0.85, P = 0.006). The quality of evidence was high for NMSC, and moderate for squamous-cell carcinoma and basal-cell carcinoma. No evidence of publication bias was observed. Conclusion: High quality evidence suggests that Sirolimus-based immunosuppression decreases risk of non-melanoma skin cancer, and Sirolimus has an antitumoral effect among kidney-transplant recipients.


  1. Alberu J, Pascoe MD, Campistol JM, et al (2011). Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation, 92, 303-10.
  2. Campbell SB, Walker R, Tai SS, et al (2012). Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant, 12, 1146-56.
  3. Campistol JM, Eris J, Oberbauer R, et al (2006). Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol, 17, 581-9.
  4. Cochran WG (1954). The combination of estimates from different experiments. Biometrics, 10, 101-29.
  5. Dantal J, Soulillou JP (2005). Immunosuppressive drugs and the risk of cancer after organ transplantation. N Engl J Med, 352, 1371-3.
  6. de Gruijl FR, Koehl GE, Voskamp P, et al (2010). Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis. Int J Cancer, 127, 796-804.
  7. De Luca A, Maiello MR, D'Alessio A, et al (2012). The RAS/ RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets, 16, S17-27.
  8. De Masson A, Fouchard N, Mery-Bossard L, et al (2011). Cutaneous and mucosal aphthosis during temsirolimus therapy for advanced renal cell carcinoma: review of cutaneous and mucosal side effects of mTOR inhibitors. Dermatology, 223, 4-8.
  9. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  10. Euvrard S, Kanitakis J, Claudy A (2003). Skin cancers after organ transplantation. N Engl J Med, 348, 1681-91.
  11. Euvrard S, Morelon E, Rostaing L, et al (2012). Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med, 367, 329-39.
  12. Flechner SM, Glyda M, Cockfield S, et al (2011). The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant, 11, 1633-44.
  13. Guba M, Graeb C, Jauch KW, et al (2004). Pro- and anticancer effects of immunosuppressive agents used in organ transplantation. Transplantation, 77, 1777-82.
  14. Guyatt GH, Oxman AD, Vist GE, et al (2008). GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 336, 924-6.
  15. Halloran PF (2004). Immunosuppressive drugs for kidney transplantation. N Engl J Med, 351, 2715-29.
  16. Higgins JP, Thompson SG, Deeks JJ, et al (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60.
  17. Higgins JP, Altman DG, Gotzsche PC, et al (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 343, d5928.
  18. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  19. Meguid El Nahas A, Bello AK (2005). Chronic kidney disease: the global challenge. Lancet, 365, 331-40.
  20. Nankivell BJ, Alexander SI (2010). Rejection of the kidney allograft. N Engl J Med, 363, 1451-62.
  21. Nankivell BJ, Kuypers DR (2011). Diagnosis and prevention of chronic kidney allograft loss. Lancet, 378, 1428-37.
  22. Petitti DB, 2000. Meta-analysis, decision analysis, and cost effectiveness analysis: methods for quantitative synthesis in medicine(2nded). Vol., New York, NY: Oxford University Press.
  23. Russell LB, Gold MR, Siegel JE, et al (1996). The role of costeffectiveness analysis in health and medicine. JAMA, 276, 1172-7.
  24. Salgo R, Gossmann J, Schofer H, et al (2010). Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Am J Transplant, 10, 1385-93.
  25. Schena FP, Pascoe MD, Alberu J, et al (2009). Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation, 87, 233-42.
  26. Serra AL, Poster D, Kistler AD, et al (2010). Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med, 363, 820-9.
  27. Simmonds MC, Higgins JP, Stewart LA, et al (2005). Metaanalysis of individual patient data from randomized trials: a review of methods used in practice. Clin Trials, 2, 209-17.
  28. Sun Q, Li X, Cheng D, et al (2011). Special malignancy pattern in Chinese renal transplantation recipients: a single center experience and literature review. Asian Pac J Cancer Prev, 12, 3347-51.
  29. Traywick C, O'Reilly FM (2005). Management of skin cancer in solid organ transplant recipients. Dermatol Ther, 18, 12-8.
  30. Wisgerhof HC, Edelbroek JR, de Fijter JW, et al (2010). Subsequent squamous- and basal-cell carcinomas in kidneytransplant recipients after the first skin cancer: cumulative incidence and risk factors. Transplantation, 89, 1231-8.
  31. Wu C, Shapiro R (2011). Post-transplant malignancy: reducing the risk in kidney transplant recipients. Expert Opin Pharmacother, 12, 1719-29.
  32. Yunus M, Aziz T, Mubarak M (2012). Posttransplant malignancies in renal transplant recipients: 22-years experience from a single center in Pakistan. Asian Pac J Cancer Prev, 13, 575-8.

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