title: MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/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.
  
  
  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: Department of Neurology, University Hospital Zurich, Zurich, Switzerland. michael.weller@usz.ch.
authors: Michael
authors: M
authors: Weller
authors: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Ghazaleh
authors: G
authors: Tabatabai
authors: Clinical Trial Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
authors: Bärbel
authors: B
authors: Kästner
authors: Department of Neuropathology, Heinrich Heine University Düsseldorf, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jörg
authors: J
authors: Felsberg
authors: Dr. Senckenberg Institute for Neuro-Oncology, University Hospital Frankfurt, Frankfurt, Germany.
authors: Joachim P
authors: JP
authors: Steinbach
authors: Department of Neurology, Heidelberg University Medical Center; National Center for Tumor Diseases Heidelberg, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Antje
authors: A
authors: Wick
authors: Department of Neurosurgery, Ludwig Maximilian University of Munich, Munich, Germany.
authors: Oliver
authors: O
authors: Schnell
authors: Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
authors: Peter
authors: P
authors: Hau
authors: Division of Clinical Neuro-Oncology, Department of Neurology, University of Bonn Medical Center, Bonn, Germany.
authors: Ulrich
authors: U
authors: Herrlinger
authors: Department of Neurosurgery, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors: Michael C
authors: MC
authors: Sabel
authors: Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Hans-Georg
authors: HG
authors: Wirsching
authors: Department of Neurosurgery, Saarland University, Homburg, Germany.
authors: Ralf
authors: R
authors: Ketter
authors: Dr. Senckenberg Institute for Neuro-Oncology, University Hospital Frankfurt, Frankfurt, Germany.
authors: Oliver
authors: O
authors: Bähr
authors: Department of Neurology, Heidelberg University Medical Center; National Center for Tumor Diseases Heidelberg, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Michael
authors: M
authors: Platten
authors: Department of Neurosurgery, Ludwig Maximilian University of Munich, Munich, Germany.
authors: Jörg C
authors: JC
authors: Tonn
authors: Department of Neurology, University Hospital Bochum, Bochum, Germany.
authors: Uwe
authors: U
authors: Schlegel
authors: Department of Oncology, Medical University Vienna, Vienna, Austria.
authors: Christine
authors: C
authors: Marosi
authors: Department of Neurosurgery, University Hospital Cologne, Cologne, Germany.
authors: Roland
authors: R
authors: Goldbrunner
authors: Department of Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Roger
authors: R
authors: Stupp
authors: Department of Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Krisztian
authors: K
authors: Homicsko
authors: Department of Oncology, Hospital Linz, Austria.
authors: Josef
authors: J
authors: Pichler
authors: Department of Neurosurgery, University Hospital Freiburg, Germany.
authors: Guido
authors: G
authors: Nikkhah
authors: Department of Neurosurgery, University Hospital Leipzig, Germany.
authors: Jürgen
authors: J
authors: Meixensberger
authors: Department of Neurosurgery, University Hospital Berlin Charité, Germany.
authors: Peter
authors: P
authors: Vajkoczy
authors: Department of Neuroradiology, University Hospital Zurich, Zurich, Switzerland.
authors: Spyros
authors: S
authors: Kollias
authors: Clinical Trial Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
authors: Johannes
authors: J
authors: Hüsing
authors: Department of Neuropathology, Heinrich Heine University Düsseldorf, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Guido
authors: G
authors: Reifenberger
authors: Department of Neurology, Heidelberg University Medical Center; National Center for Tumor Diseases Heidelberg, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Wick
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide