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.
- epigenetic silencing
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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.