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Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide
  1. Niklas Thon1,
  2. Sabina Eigenbrod2,
  3. Eva M Grasbon-Frodl2,
  4. Juergen Lutz3,
  5. Simone Kreth4,
  6. Gabriele Popperl5,
  7. Claus Belka6,
  8. Hans A Kretzschmar2,
  9. Joerg-Christian Tonn1,
  10. Friedrich W Kreth1
  1. 1Department of Neurosurgery, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  2. 2Center for Neuropathology and Prion Research, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  3. 3Department of Clinical Radiology, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  4. 4Department of Anaesthesiology, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  5. 5Department of Nuclear Medicine, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  6. 6Department of Radiation Oncology, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany
  1. Correspondence to Professor Dr Friedrich W Kreth, Department of Neurosurgery, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 Munich, Germany; fkreth{at}med.uni-muenchen.de

Abstract

Background Patients with non-resectable glioblastoma generally exhibit a poor prognosis, even after radiotherapy plus concomitant and adjuvant temozolomide (XRT/TMZ→TMZ). Unfortunately, no data are available concerning the predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for this important subpopulation. For clarification, a prospective study was conducted.

Methods Adult patients with a non-resectable glioblastoma were included. A molecular stereotactic biopsy technique was used for tumour characterisation combining histopathological diagnosis with small sample size adjusted methylation-specific PCR (MSP) and sodium bisulfite sequencing. Treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m2)→TMZ (150–200 mg/m2 per day for 5 days of every28-day cycle). The primary end point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR). Patients were categorised in the Radiation Therapy Oncology Group (RTOG)-recursive partitioning analysis (RPA) Classes III (N=4), IV (N=12), V (N=28) and VI (N=12).

Results and discussion The success rates of MSP and sequence analyses were 100%. The MGMT promoter was methylated in 30/56 tumours, which was associated with an increased PFS (median 56 versus 20 weeks; hazard ratio 0.15; range 0.07 to 0.33; p<0.0001), higher frequency of TR (93.3% vs 46.2%; p=0.0008) and increased OS (median 104 vs 28 weeks; hazard ratio 0.18; range 0.08 to 0.38; p<0.0001). The transient perioperative morbidity was 1.8%.

Conclusion MGMT promoter methylation has a predominant favourable influence even for the important subpopulation with non-resectable glioblastoma. The molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid both over- and undertreatment.

  • GBM
  • glioblastoma
  • MGMT
  • temozolomide
  • biopsy
  • epigenetic silencing

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Footnotes

  • Parts of the study have been presented as an oral presentation at the SNO's 13th Annual Scientific Meeting, Lake Las Vegas Resort, 22–23 November 2008, and as a poster presentation at the 2009 AACR Annual Meeting, 18–22 April 2009, Denver, Colorado.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the German Glioma Network.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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