Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

Abstract

Malignancy after solid organ transplantation remains a major cause of posttransplant mortality. The mammalian target of rapamycin (mTOR) inhibitor class of immunosuppressants exerts various antioncogenic effects, and the mTOR inhibitor everolimus is licensed for the treatment of several solid cancers. In kidney transplantation, evidence from registry studies indicates a lower rate of de novo malignancy under mTOR inhibition, with some potentially supportive data from randomized trials of everolimus. Case reports and small single-center series have suggested that switch to everolimus may be beneficial following diagnosis of posttransplant malignancy, particularly for Kaposi's sarcoma and nonmelanoma skin cancer, but prospective studies are lacking. A systematic review has shown mTOR inhibition to be associated with a significantly lower rate of hepatocellular carcinoma (HCC) recurrence versus standard calcineurin inhibitor therapy. One meta-analysis has concluded that patients with nontransplant HCC experience a low but significant survival benefit under everolimus monotherapy, so far unconfirmed in a transplant population. Data are limited in heart transplantation, although observational data and case reports have indicated that introduction of everolimus is helpful in reducing the recurrence of skin cancers. Overall, it can be concluded that, in certain settings, everolimus appears a promising option to lessen the toll of posttransplant malignancy.

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

“…A specific azathioprine signature mutation has recently been identified in cSCC (47); procarcinogenic mechanisms for the calcineurin inhibitor, cyclosporine, include reduced UV DNA damage repair (48), reduced apoptotic response to UV (49), and ATF3 induction and suppression of p53-dependent senescence (48,50). In contrast, mTOR inhibitors are associated with reduced cSCC risk, possibly through both antiproliferative and antiangiogenic properties (34,(51)(52)(53) and the risk associated with newer immunosuppressive drugs, including tacrolimus and mycophenolate, may also be reduced, but supportive epidemiologic data are not yet established (54,55). Voriconazole, an antifungal agent commonly used in transplantation, has direct photocarcinogenic effects (56) and is associated with significantly increased risk of aggressive cSCC (57).…”

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

“…(9) The mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) offers an alternative immunosuppressant to CNIs, with the potential to reduce CNI-related nephrotoxicity without loss of efficacy (10) and possibly to lower the risk of posttransplant malignancies. (11) The randomized H2304 study demonstrated that EVR with reduced TAC was associated with significantly better renal function and comparable efficacy over the first 3 years after liver transplantation compared with standard TAC therapy. (12)(13)(14) The recent SIMCER trial examined the use of EVR in combination with mycophenolic acid (MPA) to support a CNI-free regimen early after liver transplantation.…”

Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

“…Besides, the effect of other immunosuppressive agents provided a neutral effect on the occurrence of postrenal transplantation malignancy. Although clinical trials provided the safety and efficacy of monotherapy with mTOR inhibitor after transplantation, most patients in Taiwan received combination therapy as maintenance therapy. Further studies on the effect of combination therapy may be considered to find out the optimal regimen in transplantation recipients.…”