Predominant influence of MGMT methylation in non-resectable GBM after radiotherapy plus temozolomide

Niklas Thon (1) , Sabina Eigenbrod (2) , Eva Maria Grasbon-Frodl (2) , Juergen Lutz (3) , Simone Kreth (4) , Gabriele Poepperl (5) , Claus Belka (6) , Hans A Kretzschmar (2) , Joerg Christian Tonn (1) , Friedrich-Wilhelm Kreth (1)

1 Department of Neurosurgery, University of Munich
2 Center for Neuropathology and Prion Research, University of Munich
3 Department of Clinical Radiology, University of Munich
4 Department of Anaesthesiology, University of Munich
5 Department of Nuclear Medicine, University of Munich
6 Department of Radation Oncology, University of Munich

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. Adult patients with a non-resectable glioblastoma were included. Molecular stereotactic biopsy technique was used for tumour characterization 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 75mg/m2)→ TMZ (150 to 200mg/m2 per day for 5 days of every 28-day cycle). Primary end point was progression free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR). Patients were categorized 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). 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% versus 46.2%; p=0.0008), and increased OS (median, 104 versus 28 weeks; hazard ratio, 0.18; range, 0.08 to 0.38; p<0.0001). Transient perioperative morbidity was 1.8%. In conclusion, MGMT promoter methylation has predominant favourable influence even for the important subpopulation with non-resectable glioblastoma. Molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid therapeutic nihilism.

Mots clés: NEUROONCOLOGY

Niklas Thon, Sabina Eigenbrod, Eva Maria Grasbon-Frodl, Juergen Lutz, Simone Kreth, et al.. Predominant influence of MGMT methylation in non-resectable GBM after radiotherapy plus temozolomide. Journal of Neurology, Neurosurgery and Psychiatry, 2010, 82 (4), pp.441. ⟨10.1136/jnnp.2010.214593⟩. ⟨hal-00578711⟩