gms | German Medical Science

Objective: Epigenetic silencing of the MGMT gene has been linked to favorable prognosis in glioblastomas (GBM) after treatment according to the EORTC protocol even when stratified for the extent of surgery except for patients who undergo biopsy only. Aim of this study was to evaluate the prognostic relevance of MGMT methylation in patients with de-novo inoperable GBM who receive concomitant radiochemotherapy (RT/C) followed by adjuvant temozolomide after stereotactic biopsy.

Methods: Patients (KPS>70) with inoperable de-novo GBM were included in this prospective study. Histopathological diagnosis and molecular genetic profiling were performed by means of stereotactic specimens. MGMT methylation was detected using methylation-specific PCR and sequencing methods. Follow-up included standard clinical and neuroradiologic examinations. Tumor progression was confirmed by re-biopsy. Primary end points of the study were progression free survival (PFS) and treatment response (TR) (classified according to the Macdonald criteria); secondary end point was overall survival (OS).

Results: The MGMT methylation status was homogeneously distributed throughout each tumor (N=52). The methylated (N=26) and non-methylated (N=26) study groups were balanced with respect to KPS, tumor size, and the applied treatment protocol; however, methylated patients were younger (mean: 55 vs. 64 years, p<0.05). Methylated patients exhibited significantly prolonged PFS (median: 48 vs. 20 weeks; p<0.001) and OS (one-year survival: 74.9% vs. 30.2%; p=0.003). Multivariate analysis identified the MGMT status as the most important prognostic factor for both PFS and OS (p<0.0001). Age gained prognostic relevance only in univariate analysis (p<0.01). Partial treatment response or stable disease were seen in 23/26 methylated and in 13/26 non-methylated tumors. The difference was statistically significant (p<0.001). Median OS in patients showing treatment response (including 13 non-methylated tumors) was 68 weeks.

Conclusions: Our study confirmed intratumoral homogeneous distribution of the MGMT methylation status, and established the MGMT promoter methylation status as the strongest independent prognostic factor for both PFS and OS in inoperable patients receiving treatment according to the EORTC protocol. However, the rather high number of patients with stable disease/response with a non-methylated MGMT promoter indicates that the MGMT methylation status cannot yet be used to exclude patients from chemotherapy.