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

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 O(6)-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. 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/m(2))→TMZ (150-200 mg/m(2) per day for 5 days of every 28-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).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; p0.0001), 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; p0.0001). The transient perioperative morbidity was 1.8%.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.