Clinical insights for cancer outcomes in renal transplant patients

Abstract

The long-term fate of renal transplant recipients has remained relatively unchanged over the last 15 years. The cumulative, chronic effects of immunosuppression contribute, to a great extent, to the higher, premature mortality rates linked to cardiovascular disease and malignancy observed in this patient population. Immunosuppression disrupts both antitumor surveillance and antiviral activities, and oncogenic viruses predispose to specific malignancies. Further, some drugs promote carcinogenesis by mechanisms independent of their immunosuppressive effects. In vitro studies have shown that calcineurin inhibitors (CNIs) promote tumor progression by a transforming growth factor-β-dependent mechanism. In contrast, in vivo mouse models have demonstrated that mammalian target of rapamycin (mTOR) inhibitors inhibit metastatic tumor growth and angiogenesis. The association between mTOR-inhibitor and reduced malignancy has been demonstrated in several studies. United Network for Organ Sharing registry data demonstrate that an mTOR-inhibitor either with or without a CNI, is associated with a reduced incidence of tumors compared to regimens that do not utilize mTOR-inhibitor Five years after renal transplantation, patients in the Rapamune Maintenance Regimen study who received sirolimus (SRL)-based CNI-free therapy after cyclosporine (CsA) withdrawal at 3 months showed a reduced incidence of malignancy compared with those who continued a regimen including (CsA) In the CONVERT study, patients who converted to SRL displayed a significantly lower malignancy rate (3.8%) at 24 months compared with those who continued CNI based therapy (11%; P < .001). A randomized, prospective study to evaluate the effect of conversion to SRL from a CNI, compared with continued CNI, showed that SRL was associated with a lower rate of nonmelanoma skin cancer (NMSC) and a longer time to first biopsy-confirmed new NMSC. An mTOR-inhibitor CNI-free regimen should be considered for transplant recipients at high risk for cancer development and for those who develop malignancies over the posttransplant course.