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Correlation Between O⁶-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

Olivier L. Chinot, Maryline Barrié, Stephane Fuentes, Nathalie Eudes, Sophie Lancelot, Philippe Metellus, Xavier Muracciole, Diane Braguer, L'Houcine Ouafik, Pierre-Marie Martin, Henry Dufour, Dominique Figarella-Branger

From the Unité de Neuro-Oncologie, Service de Neurochirurgie, Service de Pharmacie, Service de Radiothérapie, Laboratoire de Transfert d'Oncologie Biologique, Service d'Anatomie Pathologique et de Neuropathologie, Centre Hospitalier Universitaire Timone, Assistance Publique–Hôpitaux de Marseille, and Université de la Méditérranée, Faculté de Médecine de Marseille, and Laboratoire de Cancérologie Expérimentale, Institut National de la Santé et de la Recherche, Equipe Mixte 0359, Centre National de la Recherche Scientifique 2737, Laboratoire de Biopathologie de l'Adhésion et de la Signalisation, Faculté de Médecine de Marseille, and Université de la Méditérranée, Marseille, France

Address reprint requests to Olivier Chinot, MD, Université de la Méditérranée, Faculté de Médecine de Marseille, Assistance Publique-Hôpitaux de Marseille, Unité de Neuro-Oncologie, Centre Hospitalier Universitaire Timone, 264 rue Saint Pierre, 13385 Marseille Cedex 05, France; e-mail: olivier.chinot{at}mail.ap-hm.fr

Purpose 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.

Patients and 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%).

Conclusion 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.

Supported by the Foundation Lionel Perrier, the Fondation Nelia and Amadeo Barletta, and the Institut National du Cancer Project No. RS019 (coordinated by D.F.-B.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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