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Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation

Josep M. Campistol^*, Josette Eris, Rainer Oberbauer, Peter Friend, Brian Hutchison^||, José M. Morales^¶, Kerstin Claesson^#, Giovanni Stallone^**, Graeme Russ, Lionel Rostaing, Henri Kreis, James T. Burke^||||, Yves Brault^||||, Joseph A. Scarola^¶¶, John F. Neylan^¶¶ for the Rapamune Maintenance Regimen Study Group

^* Hospital Clinic i Provincial, Barcelona, Spain; Royal Prince Alfred Hospital, Camperdown, Australia; Allgemeines Krankenhaus, Vienna, Austria; Oxford Transplant Centre, Oxford, United Kingdom; ^|| Sir Charles Gairdner Hospital, Perth, Australia; ^¶ Hospital 12 de Octubre, Madrid, Spain; ^# Akademiska sjukhuset, Uppsala, Sweden; ^** Universita’ degli Studi di Bari, Bari, Italy; The Queen Elizabeth Hospital, Woodville, South Australia, Australia; CHU Rangueil, Toulouse, France; Hôpital Necker, Paris, France; ^|||| Wyeth Research, Paris, France; and ^¶¶ Wyeth Research, Collegeville, Pennsylvania

Address correspondence to: Dr. Josep M. Campistol, Unidad de Transplante Renal, Hospital Clinic i Provincial, C/ Villarroel 170, Barcelona 08036, Spain. Phone: +34-93-227-54-23; Fax: +34-93-227-54-98; E-mail: jmcampis{at}clinic.ub.es

Received for publication September 23, 2005. Accepted for publication November 22, 2005.

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo ± 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi’s sarcoma. Patients who received SRL-based, calcineurin inhibitor–free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673