title: The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine.
abstract: Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.
authors.affiliation: Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia; University of Western Australia, Perth, Australia.
authors.forename: Wai H
authors.initials: WH
authors.lastname: Lim
authors.affiliation: Central and Northern Adelaide Renal and Transplantation Services, South Australia, Australia.
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Russ
authors.affiliation: Centre for Transplant and Renal Research, Westmead Hospital, New South Wales, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, New South Wales, Australia.
authors.forename: Germaine
authors.initials: G
authors.lastname: Wong
authors.affiliation: Renal Unit, Auckland Hospital, Auckland, New Zealand; Department of Medicine, Auckland University, Auckland, New Zealand.
authors.forename: Helen
authors.initials: H
authors.lastname: Pilmore
authors.affiliation: Department of Nephrology and Transplant Services, Monash Medical Centre, Melbourne, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Kanellis
authors.affiliation: Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia; Kidney Node, Charles Perkins Centre, University of Sydney, Australia. Electronic address: steve.chadban@sswahs.nsw.gov.au.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
mesh_terms: D000328:Adult; D001315:Australia / Q000453:epidemiology; D065095:Calcineurin Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015994:Incidence; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage; D009369:Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D009520:New Zealand / Q000453:epidemiology; D016016:Proportional Hazards Models; D065840:Protective Factors; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid
keywords: A2309 trial; ANZDATA; cancer; cyclosporine; epidemiology; everolimus