Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide.
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 O(6)-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/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).


CONCLUSIONS
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%.


CONCLUSIONS
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.
Thon
Niklas
N
Department of Neurosurgery, University Hospital Großhadern, Ludwig-Maximilians-Universität München, Munich, Germany.
Eigenbrod
Sabina
S
Grasbon-Frodl
Eva M
EM
Lutz
Juergen
J
Kreth
Simone
S
Popperl
Gabriele
G
Belka
Claus
C
Kretzschmar
Hans A
HA
Tonn
Joerg-Christian
JC
Kreth
Friedrich W
FW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D003131:Combined Modality Therapy / Q000379:methods*; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D017421:Sequence Analysis / Q000379:methods; D013238:Stereotaxic Techniques / Q000009:adverse effects; D016019:Survival Analysis; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide