Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis

N Engl J Med. 2010 Nov 4;363(19):1801-11. doi: 10.1056/NEJMoa1001671.


Background: Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.

Methods: Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter.

Results: We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported.

Conclusions: Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Angiofibroma / drug therapy
  • Anticonvulsants / therapeutic use
  • Astrocytoma / drug therapy*
  • Astrocytoma / etiology
  • Astrocytoma / pathology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / etiology
  • Brain Neoplasms / pathology
  • Child
  • Child, Preschool
  • Cognition / drug effects
  • Drug Therapy, Combination
  • Everolimus
  • Facial Neoplasms / drug therapy
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Male
  • Prospective Studies
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Quality of Life
  • Seizures / drug therapy*
  • Seizures / etiology
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacokinetics
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis / complications
  • Tuberous Sclerosis / drug therapy*
  • Young Adult


  • Anticonvulsants
  • Intracellular Signaling Peptides and Proteins
  • Everolimus
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00411619