Abstract
BackgroundThe treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to evaluate the efficacy and safety of mTOR inhibitors for improving the clinical symptoms of TSC.MethodsWe performed a systematic search of major electronic databases (PubMed, EMBASE, Cochrane Library and WanFang, CNKI, and VIP databases) to identify randomized controlled trials (RCTs) and quasi-randomized studies from the date of database inception to November 2017; the Chinese Food and Drug Administration and clinicaltrials.gov were also searched for unpublished studies. The endpoints of the study were the tumor response rate and seizure frequency response rate (the proportion of patients achieving a ≥ 50% reduction relative to the baseline). Two researchers screened articles, assessed the risk of bias and extracted data independently. The included RCTs were analyzed using RevMan 5.3, which was provided by the Cochrane Collaboration.ResultsCompared with the placebo, mTOR inhibitors significantly reduced tumor volume in both angiomyolipoma (AML) (RR = 24.69, 95% CI = 3.51,173.41, P = 0.001) and subependymal giant cell astrocytoma (SEGA) (RR = 27.85, 95% CI = 1.74,444.82, P = 0.02). Compared with the placebo, mTOR inhibitors significantly reduced seizure frequency (RR = 2.12, 95% CI = 1.41,3.19, P = 0.0003). Regarding safety, compared with patients who did not receive mTOR inhibitors, those who did had a higher risk of suffering stomatitis (RR = 3.20, 95% CI = 1.49,6.86, P = 0.003). In contrast, patients who did and did not receive mTOR inhibitors experienced similar adverse events, such as upper respiratory tract infections (RR = 1.08, 95% CI = 0.81,1.45, P = 0.59) and nasopharyngitis (RR = 0.86, 95% CI = 0.60,1.21, P = 0.38).ConclusionIn view of the efficacy and safety associated with tumor and seizure frequency in the TSC patients, mTOR inhibitors is a good therapeutic choice. Unlike the risks of upper respiratory tract infections and nasopharyngitis, mTOR inhibitors seem to increase the risk of stomatitis, mostly grade 1 and 2.
Highlights
Tuberous sclerosis complex (TSC) is an orphan disease that affects many organ systems to varying degrees and is typically characterized by benign tumors of the skin, brain, kidneys, heart, lungs and retina
The underlying molecular etiology of tuberous sclerosis complex (TSC) is explained as the abnormal activation of mTOR complexes 1 (mTORC1) caused by the genetic mutation of TSC1 [2] or TSC2 [3], which leads to uncontrolled cellular proliferation via the promotion of protein synthesis and stimulates benign tumor growth in many systems [4]
We found that patients who received mammalian target of rapamycin (mTOR) inhibitors had a higher risk of suffering stomatitis than those who did not (RR = 3.20, 95% confidence intervals (CIs) = 1.49,6.86, P = 0.003)
Summary
Tuberous sclerosis complex (TSC) is an orphan disease that affects many organ systems to varying degrees and is typically characterized by benign tumors of the skin (facial angiofibroma), brain (subependymal giant cell astrocytoma), kidneys (angiomyolipoma), heart (rhabdomyoma), lungs (lymphangioleiomyomatosis) and retina (optic nerve tumor). Genetic testing for TSC1 and TSC2 was included in the diagnostic criteria developed at the 2012 International TSC Consensus Conference [5]. Based on this pathogenic mechanism, rapamycin and its derivatives have been considerd as a new therapy for TSC, and they have recently received extensive attention at home and abroad. The treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising.
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