Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide.
OBJECTIVE
This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma.


METHODS
Patients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression.


RESULTS
Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%).


CONCLUSIONS
This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.
Chinot
Olivier L
OL
Unité de Neuro-Oncologie, Service de Neurochirurgie, Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, and Université de la Méditérranée, Faculté de Médecine de Marseille, Marseille, France. olivier.chinot@mail.ap-hm.fr
Barrié
Maryline
M
Fuentes
Stephane
S
Eudes
Nathalie
N
Lancelot
Sophie
S
Metellus
Philippe
P
Muracciole
Xavier
X
Braguer
Diane
D
Ouafik
L'Houcine
L
Martin
Pierre-Marie
PM
Dufour
Henry
H
Figarella-Branger
Dominique
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality* / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D011336:Probability; D011446:Prospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide