• 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 Homicsko, Josef Pichler, Guido Nikkhah, Jürgen Meixensberger, Peter Vajkoczy, Spyros Kollias, Johannes Hüsing, Guido Reifenberger, Wolfgang Wick, and DIRECTOR Study Group.
• Department of Neurology, University Hospital Zurich, Zurich, Switzerland. michael.weller@usz.ch.
• Clin Cancer Res. 2015 May 1; 21 (9): 2057-64.

PurposeRechallenge 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 DesignPatients 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.ResultsBecause 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.ConclusionsTemozolomide 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.©2015 American Association for Cancer Research.

42 keywords...

hide…