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

Abstract

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transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST).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.

Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients

“…Most prior studies, including randomized clinical trials, have centered around prevention and treatment of nonmelanoma skin cancers, as these are a common malignant complication following a kidney transplant (12)(13)(14). While some studies have indicated possible reductions in nonskin cancers with sirolimus use, few have been large enough to provide precise incidence rate comparisons (15,16,28,29).…”

Therapeutic targets: MTOR and related pathways

“…62 In addition, sirolimus appears to be associated with a lower risk of developing and successful treatment of post-transplant malignancies including PTLD, skin carcinomas and Karposi's sarcoma. [63][64][65][66][67][68] These results suggest that sirolimus may minimize the risk of developing post-transplant malignancies while maintaining organ transplant viability and may be used to continue immunosuppression and inhibit malignancies recurrence in successfully treated patients.…”

The role of mTOR inhibition in renal transplant immune suppression

“…47,48 Several studies have reported successful regression of Kaposi's sarcoma and post-transplant lymphoproliferative disease while preserving renal function after replacement of CNI with mTORIs. 49,50 The CONVERT trial revealed a signifi cantly lower incidence of new cancers in patients converted to SRL compared with those continuing on CNI at 12 and 24 months.…”

“…Due to potential toxicities, knowledge of the adverse effects and pharmacokinetic profi les of mTOR-Is is necessary for proper management of patients receiving these agents. malignancies seen in studies [11][12][13] and their potential role in cardiovascular risk reduction following transplantation.…”