Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance

Abstract

Increasing success in renal transplantation and longer patient survival has meant that post-transplant malignancies are having an increasing impact on long-term graft and patient survival. Choice of the immunosuppressive agents provides one of the controllable risk factors for the development of malignancies in this population. Calcineurin inhibitors (CNIs) are associated with an increased incidence of cancers, whereas the proliferation signal inhibitors (PSIs), everolimus and sirolimus have demonstrated anti-oncogenic effects in pre-clinical models and are currently being investigated as anti-cancer agents in clinical trials. There is increasing evidence demonstrating a lower incidence of post-transplant malignancies in renal transplant recipients receiving PSI-based immunosuppression compared with those receiving CNIs. Conversion from CNIs to PSIs has been shown to lead to the regression of Kaposi's sarcoma in renal transplant recipients and is now part of accepted standard care for this tumour in this setting. The anti-cancer properties of PSI-based regimens have the potential to combine the dual benefits of immunosuppression without the use of CNIs and the direct anti-oncogenic effects through their inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. In the absence of formal clinical trial evidence on the best way to use PSIs in this setting, a workshop was held to provide practical guidance on immunosuppressive strategies in the context of malignancy, given the current state of knowledge.

Untitled

“…23 Mammalian target of rapamycin inhibitor use causes regression of solidtumor metastasis and should be introduced rapidly in these patients. 26,27 Potential wound healing issues, especially in obese patients with diabetes mellitus, should be given serious consideration when starting these medications. Rapid taper of calcineurin inhibitors also is recommended.…”

“…The dosage of azathioprine/mycophenolate may be tapered slowly if clinically warranted, and it is recommended that steroid therapy be maintained. 27 Dosage regimens for mTOR in renal recipients have been well described before patients develop a posttransplant malignancy and these dosages may be used while other immunosuppressive drugs are reduced or stopped. 28 Mammalian target of rapamycin inhibitors should not be expected to yield complete remissions in all cases.…”

“…They prolong survival in some patients, and clinicians should keep a careful watch for adverse events. 27 It recently has been shown that sirolimus does not significantly affect survival among subjects who had de novo malignancies. 29 Long-term evaluation of treatment regimens that minimize malignancy is important.…”

The role of mTOR inhibition in renal transplant immune suppression

“…51 Given the current data in the setting of malignancy, consideration should be given to the use of mTOR-Is in patients with malignancy based on their direct antioncogenic effects and their ability to minimize concomitant immunosuppression. 52 …”

Acquired Cystic Kidney Disease and Renal Cell Cancer after Transplantation

“…In 2004, the expected remaining lifetime of a US transplant recipient 50 to 54 yr of age, which was the average age of the patients with renal cell cancer in the report by Schwarz et al, was 17 yr. Cancer may soon be the leading cause of death late after transplantation (16). Despite the low prevalence of renal cell cancer in ESRD, the relatively benign course of the affected patients in the report by Schwarz et al, and the possibility of lesser cancer risk with newer immunosuppressive regimens (17), it is time to rethink the published guidelines and consider screening all kidney transplant candidates and recipients for ACKD and renal cell cancer.…”