mTOR Inhibitors in the Treatment of Subependymal Giant-Cell Astrocytomas Associated With Tuberous Sclerosis

Komotar, Ricardo J; Starke, Robert M; Connolly, E Sander; Sisti, Michael B

doi: 10.1227/01.neu.0000395796.64099.76
Science Times

Subependymal giant-cell astrocytomas (SEGA) arise in 5 to 20% of patients with tuberous sclerosis complex.1,2 Patients with tuberous sclerosis are at a significantly increased risk of death, including sudden death from acute hydrocephalus as a result from obstruction of the foramen of Monro from these intraventricular lesions.1,3 Although these glioneuronal tumors are typically slow growing, they do not regress spontaneously. In fact, serial scans often demonstrate the natural history of these lesions to involve progressive size and volume increase over time.3-5 The current standard of care involves surgical resection for symptomatic and/or documented progression, although complete resection is not always possible and variable rates of recurrence, morbidity, and mortality have been reported.6,7 With this in mind, studies have focused on the genetic pathophysiology of this condition with emphasis on alternate medical therapies.

Tuberous sclerosis complex is an autosomal dominant disorder in which mutations in 2 tuberous sclerosis genes—TSC1 (hamartin) or TSC2 (tuberin)—are found in more than 85% of patients.8 Proteins encoded by these genes help act as a tumor-suppression complex to limit activation of the mammalian target rapamycin (mTOR) complex 1. When these genes are deficient, mTOR complex 1 is constitutively up-regulated, leading to uncontrolled cell growth and protein synthesis.9,10 A number of promising studies have suggested that inhibitors of mTOR (Sirolimus and Rapamycin) may lead to regression or stabilization of renal angiomyolipomas,11,12 lymphangioleiomyomatosis,11,13 and facial angiofibromas.14 These findings have provided the impetus for investigations regarding mTOR inhibitors in the treatment of subependymal giant cell astrocytomas.

A recent study enrolled 28 patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas to assess the outcomes of treatment with Everolimus (an mTOR inhibitor) dosed orally at 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter.15 Four patients (14%) had prior surgery or gamma-knife therapy, but were enrolled following tumor progression on serial scans. The results were remarkable, with 21 of the 28 patients (75%) experiencing a volume reduction of 30% and 9 patients (32%) experiencing a reduction in volume of at least 50%. Moreover, overall seizure frequency decreased during the study period and patients reported a better quality of life according to the Childhood Epilepsy questionnaire. Median duration of treatment was 21.5 months (range, 4.7 to 34.4). Of note, larger subependymal giant-cell astrocytoma lesions showed the greatest percent reductions and several patients had documented improvement in their hydrocephalus and ventriculomegaly.

Most importantly, mTOR inhibitor therapy appears to be relatively safe. The investigators found no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma treated with Everolimus. All reported adverse events were consistent with the known safety profile of Everolimus. Upper respiratory illness and stomatitis were the most common adverse events, along with hyperlipidemia and increased triglycerides.

The optimal duration of mTOR inhibitor treatment for SEGA associated with tuberous sclerosis remains unknown. Three patients discontinued treatment and another patient stopped therapy after having a ≥75% in the volume of the subependymal giant-cell astrocytoma, but resumed therapy 4.5 months later when tumor progression began. One patient had initial shrinkage of the tumor (an 18% reduction in volume at 6 months relative to baseline) that was followed by progression (resulting in, at 18 months, a 16% increase relative to baseline). In an associated study involving the role of mTOR inhibitors in 25 adult patients with pulmonary angiomyolipoma and associated tuberous sclerosis, volume reduction was achieved in 47% of patients and forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and residual volume were also improved.11 Sustained reduction in angiomyolipoma volume was seen in only 5 of 18 patients (28%), and improvements in FEV1, FVC, and residual lung volume subsided after discontinuation of treatment. Thus, it appears that mTOR inhibitor treatment may necessitate chronic administration of Everolimus in order to maintain tumor suppression.

This study has important ramifications for the treatment of patients with Tuberous Sclerosis and associated subependymal giant cell astrocytomas. The promising findings that revealed a high rate of tumor volume reduction and concomitant seizure frequency after administration with Everolimus15 suggest mTOR inhibitors may represent a potential medical alternative to neurosurgical intervention in carefully selected cases. Enthusiasm should be cautioned, however, as it appears continuous treatment with TOR inhibitors may be necessary to achieve and sustain efficacy. In this setting, the risk of long-term Everolimus administration remains unknown, and given the side-effect profile of mTOR inhibitors, the rate of nearly inevitable adverse events may outweigh the benefits of chronic treatment. Moreover, the majority of patients receiving this treatment would be within the pediatric population, thereby increasing the possibility of drug related complications over time. Given these limitations, a more realistic utilization of Everolimus may involve preoperative administration in select cases to reduce tumor size, facilitate resection, and minimize operative morbidity. Clearly, further long-term follow up of these patients and additional studies are warranted regarding this novel and promising agent.

Ricardo J. Komotar

Robert M. Starke

E. Sander Connolly

Michael B. Sisti

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