- Volume 13 Issue 9
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.
Sirolimus;non-melanoma skin cancer;kidney transplantation;meta-analysis
- 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. https://doi.org/10.1097/TP.0b013e3182247ae2
- 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. https://doi.org/10.1111/j.1600-6143.2012.04004.x
- 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. https://doi.org/10.1681/ASN.2005090993
- Cochran WG (1954). The combination of estimates from different experiments. Biometrics, 10, 101-29. https://doi.org/10.2307/3001666
- Dantal J, Soulillou JP (2005). Immunosuppressive drugs and the risk of cancer after organ transplantation. N Engl J Med, 352, 1371-3. https://doi.org/10.1056/NEJMe058018
- 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.
- 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.
- 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. https://doi.org/10.1159/000329902
- DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88. https://doi.org/10.1016/0197-2456(86)90046-2
- Euvrard S, Kanitakis J, Claudy A (2003). Skin cancers after organ transplantation. N Engl J Med, 348, 1681-91. https://doi.org/10.1056/NEJMra022137
- 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. https://doi.org/10.1056/NEJMoa1204166
- 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. https://doi.org/10.1111/j.1600-6143.2011.03573.x
- Guba M, Graeb C, Jauch KW, et al (2004). Pro- and anticancer effects of immunosuppressive agents used in organ transplantation. Transplantation, 77, 1777-82. https://doi.org/10.1097/01.TP.0000120181.89206.54
- 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. https://doi.org/10.1136/bmj.39489.470347.AD
- Halloran PF (2004). Immunosuppressive drugs for kidney transplantation. N Engl J Med, 351, 2715-29. https://doi.org/10.1056/NEJMra033540
- Higgins JP, Thompson SG, Deeks JJ, et al (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60. https://doi.org/10.1136/bmj.327.7414.557
- 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. https://doi.org/10.1136/bmj.d5928
- Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
- Meguid El Nahas A, Bello AK (2005). Chronic kidney disease: the global challenge. Lancet, 365, 331-40. https://doi.org/10.1016/S0140-6736(05)17789-7
- Nankivell BJ, Alexander SI (2010). Rejection of the kidney allograft. N Engl J Med, 363, 1451-62. https://doi.org/10.1056/NEJMra0902927
- Nankivell BJ, Kuypers DR (2011). Diagnosis and prevention of chronic kidney allograft loss. Lancet, 378, 1428-37. https://doi.org/10.1016/S0140-6736(11)60699-5
- 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.
- Russell LB, Gold MR, Siegel JE, et al (1996). The role of costeffectiveness analysis in health and medicine. JAMA, 276, 1172-7. https://doi.org/10.1001/jama.1996.03540140060028
- 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. https://doi.org/10.1111/j.1600-6143.2009.02997.x
- 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. https://doi.org/10.1097/TP.0b013e3181927a41
- 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. https://doi.org/10.1056/NEJMoa0907419
- 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. https://doi.org/10.1191/1740774505cn087oa
- 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.
- Traywick C, O'Reilly FM (2005). Management of skin cancer in solid organ transplant recipients. Dermatol Ther, 18, 12-8. https://doi.org/10.1111/j.1529-8019.2005.05002.x
- 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. https://doi.org/10.1097/TP.0b013e3181d84cdc
- Wu C, Shapiro R (2011). Post-transplant malignancy: reducing the risk in kidney transplant recipients. Expert Opin Pharmacother, 12, 1719-29.
- 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. https://doi.org/10.7314/APJCP.2012.13.2.575
- Lymphoma-associated skin cancer: incidence, natural history, and clinical management vol.53, pp.3, 2013, https://doi.org/10.1111/ijd.12208
- Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients vol.15, pp.1, 2014, https://doi.org/10.1111/ajt.12969
- Clinical Practice of Blood Transfusion in Orthotopic Organ Transplantation: A Single Institution Experience vol.16, pp.17, 2015, https://doi.org/10.7314/APJCP.2015.16.17.8009
- Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis vol.4, pp.9, 2015, https://doi.org/10.1002/cam4.487
- Post kidney transplantation Kaposi's sarcoma: the experience of a Mediterranean North African center vol.30, pp.4, 2016, https://doi.org/10.1111/ctr.12694
- Checking whether there is an increased risk of post-transplant lymphoproliferative disorder and other cancers with specific modern immunosuppression regimens in renal transplantation: Protocol for a network meta-analysis of randomized and observational studies vol.3, pp.1, 2014, https://doi.org/10.1186/2046-4053-3-16