Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.
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.).
Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Darcy A
DA
Krueger
Marguerite M
MM
Care
Katherine
K
Holland
Karen
K
Agricola
Cynthia
C
Tudor
Prajakta
P
Mangeshkar
Kimberly A
KA
Wilson
Anna
A
Byars
Tarek
T
Sahmoud
David Neal
DN
Franz
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018322:Angiofibroma / Q000188:drug therapy; D000927:Anticonvulsants / Q000627:therapeutic use; D001254:Astrocytoma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003071:Cognition / Q000187:drug effects; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005153:Facial Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011788:Quality of Life; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
D000927:Anticonvulsants; D047908:Intracellular Signaling Peptides and Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus