Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide
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Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide Mark Davies1*, Anurag Saxena2 and John C. Kingswood3
Abstract Tuberous sclerosis complex (TSC) is a genetic disorder characterised by highly variable comorbid dysfunction and subsequent morbidity. The mTOR inhibitor everolimus is indicated for the treatment of adult TSC patients with renal angiomyolipomas (AMLs) and for subependymal giant astrocytoma (SEGA) in both adults and children, based on data from the EXIST-1 and EXIST-2 trials. However, due to the historical predominance of everolimus in the oncology setting, some physicians who treat TSC patients may be unfamiliar with everolimus-associated adverse events (AEs) and appropriate management strategies. This article aims to serve as a resource for specialists including nephrologists, paediatricians, neurologists and geneticists who require practical guidance on the management of events such as non-infectious pneumonitis, rash, stomatitis, infections, and renal AEs. Additional consideration is given to drug interactions, hepatic impairment, fertility, and sexual maturation. Since patients with TSC receive clinical benefit from continued therapy, it is important that everolimus-related events are dealt with appropriately through strategies such as dose modification, interruption, the provision of supportive care, regular monitoring, and patient education. Keywords: Everolimus, Adverse events, Tuberous sclerosis complex, TSC, Subependymal giant astrocytoma, SEGA, Renal angiomyolipoma, AML
Background Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder [1]. Prevalence rates vary, but estimates typically fall in the range of 6.8 to 12.4 per 100,000 people [2]. TSC is caused by mutations in TSC1 on chromosome 9 or TSC2 on chromosome 16; however, two-thirds of cases result from de novo mutations [3]. Mutations in TSC1 or TSC2 result in inappropriate mTORC1 signalling within cells, and this is thought to be responsible for many of the features of TSC [4]. TSC is a highly variable condition in both the type and severity of its manifestations. A history of seizures has been reported in up to 85% of patients, often beginning in the first few years of life (>80% of patients) [5–7],
* Correspondence: [email protected] 1 Department of Oncology, South West Wales Cancer Centre, Singleton Hospital, Swansea SA2 8QA, UK Full list of author information is available at the end of the article
with intellectual disability found in ~45% of cases [8]. The condition is also commonly associated with the development of benign tumours in organs such as the kidneys, brain, heart and skin [9, 10]. Renal angiomyolipomas (AMLs) are among the most common features of TSC [9, 10], affecting around ~70% of patients [11, 12]. They manifest as benign tumours composed of abnormal blood vessels and cells, with either adipocyte-like or smooth muscle-like phenotypes [9], and commonly occur in both kidneys [9
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