MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive Glioblastoma: The DIRECTOR Trial

Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 21

Pages Range: 2057-2064

Journal Issue: 9

DOI: 10.1158/1078-0432.CCR-14-2737

Abstract

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/m2 per day)/one week off] or Arm B [3 weeks on (80 mg/m2 per day)/one week off]. The primary endpoint was median timeto-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylationspecific 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.

Authors with CRIS profile

Involved external institutions

Universitätsspital Zürich (USZ) Switzerland (CH) Heinrich-Heine-Universität Düsseldorf Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Universitätsklinikum Knappschaftskrankenhaus Bochum Germany (DE) Medizinische Universität Wien Austria (AT) Universitätsklinikum Köln Germany (DE) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Kepler Universitätsklinikum (KUK) Austria (AT) Universitätsklinikum Freiburg Germany (DE) Universitätsklinikum Leipzig Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Regensburg Germany (DE) Universitätsklinikum Bonn Germany (DE)

How to cite

APA:

Weller, M., Tabatabai, G., Kästner, B., Felsberg, J., Steinbach, J.P., Wick, A.,... Reifenberger, G. (2015). MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive Glioblastoma: The DIRECTOR Trial. Clinical Cancer Research, 21(9), 2057-2064. https://doi.org/10.1158/1078-0432.CCR-14-2737

MLA:

Weller, Michael, et al. "MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive Glioblastoma: The DIRECTOR Trial." Clinical Cancer Research 21.9 (2015): 2057-2064.

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