Document Detail

Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.
MedLine Citation:
PMID:  21047224     Owner:  NLM     Status:  MEDLINE    
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; number, NCT00411619.).
Darcy A Krueger; Marguerite M Care; Katherine Holland; Karen Agricola; Cynthia Tudor; Prajakta Mangeshkar; Kimberly A Wilson; Anna Byars; Tarek Sahmoud; David Neal Franz
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The New England journal of medicine     Volume:  363     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-04     Completed Date:  2010-11-12     Revised Date:  2013-08-22    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1801-11     Citation Subset:  AIM; IM    
Department of Pediatrics, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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MeSH Terms
Administration, Oral
Angiofibroma / drug therapy
Anticonvulsants / therapeutic use
Astrocytoma / drug therapy*,  etiology,  pathology
Brain Neoplasms / drug therapy*,  etiology,  pathology
Child, Preschool
Cognition / drug effects
Drug Therapy, Combination
Facial Neoplasms / drug therapy
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Prospective Studies
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Quality of Life
Seizures / drug therapy*,  etiology
Sirolimus / administration & dosage,  adverse effects,  analogs & derivatives*,  pharmacokinetics
TOR Serine-Threonine Kinases
Tuberous Sclerosis / complications,  drug therapy*
Young Adult
Grant Support
Reg. No./Substance:
0/Anticonvulsants; 0/Intracellular Signaling Peptides and Proteins; 159351-69-6/everolimus; 53123-88-9/Sirolimus; EC protein, human; EC Serine-Threonine Kinases; EC Kinases
Comment In:
N Engl J Med. 2011 Feb 10;364(6):577   [PMID:  21306252 ]
N Engl J Med. 2011 Feb 10;364(6):576-7; author reply 577   [PMID:  21306253 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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