Dose-level response rates of mtor inhibition in tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA)

BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease usually diagnosed in childhood. Subependymal giant cell astrocytomas (SEGA) are benign brain lesions occurring in up to 20% of patients with TSC. Treatment with mTOR inhibitors has been proven effective in inducing SEGA shrinkage, but discontinuation results in re-growth. Evidence suggests that mTOR inhibition seems a disease-modifying treatment for TSC beyond inducing SEGA shrinkage; however concerns remain regarding negative long-term effects. MethodsThrough this retrospective case series, an attempt was made to determine the minimal mTOR inhibitor dose needed to maintain radiological response of SEGA in six pediatric patients treated at The Hospital for Sick Children since 2007. This study reviews medication doses and blood levels as related to SEGA size on MRIs at 3-month intervals. Blood levels were monitored every 3 months and 2 weeks after dose adjustment. Total dose reduction by 25% was considered after SEGA shrinkage was maintained on two consecutive MRIs. ResultsAll patients demonstrated SEGA shrinkage greater than 50% when treated with mTOR inhibition at therapeutic doses (4-5mg/m(2)). When sirolimus doses were weaned in two patients by 50%, SEGAs regrew by 84% and 32%. In two patients, responses have been maintained with 30% decrease in sirolimus dose. One patient underwent SEGA resection and one remains on therapeutic dose. ConclusionsTherapeutic dose of mTOR inhibitor is effective in shrinking TSC-related SEGAs. Doses less than 2.5mg/m(2) were insufficient to maintain response in this limited series. Pediatr Blood Cancer 2015;62:1754-1760. (c) 2015 Wiley Periodicals, Inc.