MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial.

Détails

ID Serval
serval:BIB_F937117C954C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial.
Périodique
Clinical Cancer Research : An Official Journal of the American Association For Cancer Research
Auteur(s)
Weller M., Tabatabai G., Kästner B., Felsberg J., Steinbach J.P., Wick A., Schnell O., Hau P., Herrlinger U., Sabel M.C., Wirsching H.G., Ketter R., Bähr O., Platten M., Tonn J.C., Schlegel U., Marosi C., Goldbrunner R., Stupp R., Homicsko K., Pichler J., Nikkhah G., Meixensberger J., Vajkoczy P., Kollias S., Hüsing J., Reifenberger G., Wick W.
Collaborateur(s)
DIRECTOR Study Group
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
21
Numéro
9
Pages
2057-2064
Langue
anglais
Notes
Publication types: Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
PURPOSE: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.
EXPERIMENTAL DESIGN: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.
RESULTS: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5] and overall survival [A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.
CONCLUSIONS: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.
Mots-clé
Adult, Antineoplastic Agents, Alkylating/administration & dosage, Biomarkers, Tumor/genetics, Brain Neoplasms/drug therapy, Brain Neoplasms/genetics, DNA Methylation/genetics, DNA Modification Methylases/genetics, DNA Repair Enzymes/genetics, Dacarbazine/administration & dosage, Dacarbazine/analogs & derivatives, Disease-Free Survival, Female, Glioblastoma/drug therapy, Glioblastoma/genetics, Humans, Male, Middle Aged, Neoplasm Recurrence, Local/drug therapy, Neoplasm Recurrence, Local/genetics, Prognosis, Promoter Regions, Genetic/genetics, Proportional Hazards Models, Tumor Suppressor Proteins/genetics, Young Adult
Pubmed
Web of science
Open Access
Oui
Création de la notice
22/05/2015 17:45
Dernière modification de la notice
09/05/2019 3:44
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