THE ROLE OF EVEROLIMUS IN PATIENTS WITH TUBEROUS SCLEROSIS COMPLEX-ASSOCIATED MANIFESTATIONS: A SYSTEMATIC REVIEW

Andrew F. Lukwaro, Akanganyira Kasenene and Prof. Xujun Ye

ABSTRACT

Background: Tuberous sclerosis or tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in tuberous sclerosis complex 1(TSC1) or tuberous sclerosis complex 2 (TSC2) genes that affects multiple organs such as the kidneys, brain, lungs, heart, and skin. Objective: This systematic review aims to assess the clinical value of everolimus for various manifestations in TSC patients. Methods: We searched PubMed, Cochrane Library, Clinical Trials (http://www.clinicaltrials.gov) and Google Scholar from January 2009 to December 2018. We included RCTs published in English, enrolled patients aged 0-65 years, with a definitive diagnosis of TSC on everolimus therapy for at least 18 weeks, medically stable and unlikely to require surgery during the trial. Two reviewers singly extracted data, assessed study quality, and applicability, and the strength of evidence for each study graded by consensus. Results: Four RCTs that met inclusion criteria assessed the effects of everolimus in TSC patients, and two RCTs reported the impact of everolimus on rate of tumor response (angiomyolipoma, skin lesion, and subependymal giant cell astrocytomas), tumor volume, tumor progression rate. These two RCTs revealed a higher percentage of tumor response, a significant reduction in tumor size and low tumor progression rate when compared to placebo. And two studies described the impacts of everolimus on neurological manifestations of TSC wherein one showed reduced frequency of TSC-associated seizures and no improvement in neurocognitive functioning or behavior in the other. The most common everolimus-related adverse reactions were stomatitis and mouth ulceration. Conclusions: Everolimus produced a significant impact on the reduction of tumor size, angiomyolipoma progression rate, improved tumor response rate, reduced frequency of seizures, but no effects in neurocognitive functioning or behavior changes and, also everolimus increased the incidence of stomatitis and mouth ulcerations.

Keywords: Everolimus, Tuberous sclerosis, Tuberous sclerosis-associated manifestations, Randomized controlled trials.