Sirolimus for Renal Transplant Recipients
Sirolimus for Renal Transplant Recipients
Sirolimus has antineoplastic effects and may reduce skin cancer rates in kidney transplant patients. This prospective, multicenter, randomized, open-label, controlled trial randomized 86 kidney transplant recipients (≥1 year posttransplant) with history of nonmelanoma skin cancer (NMSC) to continue calcineurin inhibitor (CNI) or convert to sirolimus. Patients were stratified by number of NMSC lesions (0–5, 6–20) in previous year. Primary end point was number of biopsy-confirmed new NMSC lesions per patient-year. Yearly NMSC rate was significantly lower with sirolimus (1.31 vs. 2.48 lesions/patient-year; p = 0.022). Squamous cell carcinoma occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate was similar in both. A lower proportion of patients receiving sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma (41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Incidence of treatment-emergent adverse events was similar between groups; however, discontinuation rates related to adverse events were significantly higher with sirolimus (46.2% vs. 0%; p < 0.001). In kidney transplant recipients with history of NMSC, conversion from CNI to sirolimus reduced rates of NMSC, without increasing acute rejection risk.
Advances in immunosuppression have considerably enhanced transplantation outcomes, with reduced acute rejection episodes and improved short-term graft and patient survival. However, improvement in long-term outcomes, including the risk for posttransplant malignancies with long-term immunosuppression, is still needed.
Compared with the age-matched general population, kidney transplant recipients experience greater rates of de novo and recurrent neoplasms, most commonly involving the skin. Nonmelanoma skin cancer (NMSC) accounts for more than 90% of posttransplant skin cancers. The course of squamous cell carcinoma (SCC) is more aggressive in immunosuppressed transplant recipients and may occur from 65 to 250 times more frequently in transplant patients versus the general population, while basal cell carcinoma (BCC) occurs 10–20 times more often. Prevalence of cutaneous neoplasms increases with duration of immunosuppressive therapy.
The etiology of immunosuppression-related, posttransplant malignancy may be a combination of reduced immunosurveillance and the direct oncogenic potential of specific immunosuppressants. Reports associating reduction or discontinuation of immunosuppression, along with use of sirolimus, with decreased carcinogenesis led to recommendations for immunosuppression reduction and switching to therapy with mammalian target of rapamycin (mTOR) inhibitors, when appropriate.
Sirolimus, an mTOR inhibitor, is an immunosuppressive drug with antitumor effects via inhibition of cancer cell proliferation, suppression of tumor angiogenesis and promotion of tumor cell apoptosis. Sirolimus exhibits its immunosuppressant effects via inhibition of T- and B-cell proliferation. The mechanism by which this inhibition occurs is also responsible for the inhibitory effects of sirolimus on cancer cell proliferation, prompting research of sirolimus-based therapy and posttransplant malignancy. Lower malignancy rates have been observed in transplant patients receiving sirolimus-based immunosuppression versus patients receiving calcineurin inhibitor (CNI) therapy. Most of these reports were based on retrospective or post hoc analyses.
This open-label, randomized, controlled trial is the first multicenter study prospectively designed to better characterize the above observations through comparing the rates of new NMSC lesions with conversion to sirolimus versus continued CNI therapy in stable kidney transplant recipients at high risk for developing further skin cancer.
Abstract and Introduction
Abstract
Sirolimus has antineoplastic effects and may reduce skin cancer rates in kidney transplant patients. This prospective, multicenter, randomized, open-label, controlled trial randomized 86 kidney transplant recipients (≥1 year posttransplant) with history of nonmelanoma skin cancer (NMSC) to continue calcineurin inhibitor (CNI) or convert to sirolimus. Patients were stratified by number of NMSC lesions (0–5, 6–20) in previous year. Primary end point was number of biopsy-confirmed new NMSC lesions per patient-year. Yearly NMSC rate was significantly lower with sirolimus (1.31 vs. 2.48 lesions/patient-year; p = 0.022). Squamous cell carcinoma occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate was similar in both. A lower proportion of patients receiving sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma (41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Incidence of treatment-emergent adverse events was similar between groups; however, discontinuation rates related to adverse events were significantly higher with sirolimus (46.2% vs. 0%; p < 0.001). In kidney transplant recipients with history of NMSC, conversion from CNI to sirolimus reduced rates of NMSC, without increasing acute rejection risk.
Introduction
Advances in immunosuppression have considerably enhanced transplantation outcomes, with reduced acute rejection episodes and improved short-term graft and patient survival. However, improvement in long-term outcomes, including the risk for posttransplant malignancies with long-term immunosuppression, is still needed.
Compared with the age-matched general population, kidney transplant recipients experience greater rates of de novo and recurrent neoplasms, most commonly involving the skin. Nonmelanoma skin cancer (NMSC) accounts for more than 90% of posttransplant skin cancers. The course of squamous cell carcinoma (SCC) is more aggressive in immunosuppressed transplant recipients and may occur from 65 to 250 times more frequently in transplant patients versus the general population, while basal cell carcinoma (BCC) occurs 10–20 times more often. Prevalence of cutaneous neoplasms increases with duration of immunosuppressive therapy.
The etiology of immunosuppression-related, posttransplant malignancy may be a combination of reduced immunosurveillance and the direct oncogenic potential of specific immunosuppressants. Reports associating reduction or discontinuation of immunosuppression, along with use of sirolimus, with decreased carcinogenesis led to recommendations for immunosuppression reduction and switching to therapy with mammalian target of rapamycin (mTOR) inhibitors, when appropriate.
Sirolimus, an mTOR inhibitor, is an immunosuppressive drug with antitumor effects via inhibition of cancer cell proliferation, suppression of tumor angiogenesis and promotion of tumor cell apoptosis. Sirolimus exhibits its immunosuppressant effects via inhibition of T- and B-cell proliferation. The mechanism by which this inhibition occurs is also responsible for the inhibitory effects of sirolimus on cancer cell proliferation, prompting research of sirolimus-based therapy and posttransplant malignancy. Lower malignancy rates have been observed in transplant patients receiving sirolimus-based immunosuppression versus patients receiving calcineurin inhibitor (CNI) therapy. Most of these reports were based on retrospective or post hoc analyses.
This open-label, randomized, controlled trial is the first multicenter study prospectively designed to better characterize the above observations through comparing the rates of new NMSC lesions with conversion to sirolimus versus continued CNI therapy in stable kidney transplant recipients at high risk for developing further skin cancer.
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