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

Michael Weller*, Ghazaleh Tabatabai, Bärbel Kästner, Jörg Felsberg, Joachim P. Steinbach, Antje Wick, Oliver Schnell, Peter Hau, Ulrich Herrlinger, Michael C. Sabel, Hans Georg Wirsching, Ralf Ketter, Oliver Bähr, Michael Platten, Jörg C. Tonn, Uwe Schlegel, Christine Marosi, Roland Goldbrunner, Roger Stupp, Krisztian HomicskoJosef Pichler, Guido Nikkhah, Jürgen Meixensberger, Peter Vajkoczy, Spyros Kollias, Johannes Hüsing, Guido Reifenberger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2057-2064
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number9
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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