Abstract
BackgroundTwo novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.MethodsWe searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.ResultsA total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3–2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21–8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.ConclusionWith the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.
Highlights
The mammalian target of rapamycin kinase is a key element of intracellular signal transduction, and responsible for the regulation of cell growth, survival, proliferation, and angiogenesis [1,2,3,4]
The dosage of mammalian targets of rapamycin (mTOR) inhibitors significantly varies among included trials: temsirolimus was used ranging from 20 mg to 250 mg iv weekly, and the dose of everolimus was 10 mg or 5 mg po. daily, respectively
The pooled relative risk (RR) for fatal adverse events (FAEs) showed that the use of mTOR inhibitors significantly increased risk of developing FAEs in cancer patients with RR of 3.244 (95%confidence intervals (CIs): 1.214–8.667, p = 0.008, figure 3) using a fixed-effects model (I2 = 0%, p = 0.912)
Summary
The mammalian target of rapamycin (mTOR) kinase is a key element of intracellular signal transduction, and responsible for the regulation of cell growth, survival, proliferation, and angiogenesis [1,2,3,4]. Several clinical trials testing the rapalogues in monotherapy or in combinations with other cytotoxic agents have been conducted in patients with many malignancies, and survival benefits have been observed in advanced renal cell cancer when compared to the controls [11,12]. Based on these results, the United States Food and Drug Administration (FDA) have approved everolimus and temsirolimus as the treatment for advanced renal cell cancer [13]. Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined
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