Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.
BACKGROUND
In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years.


METHODS
Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353.


RESULTS
Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy.


CONCLUSIONS
Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide.


BACKGROUND
EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
Stupp
Roger
R
Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. roger.stupp@chuv.ch
Hegi
Monika E
ME
Mason
Warren P
WP
van den Bent
Martin J
MJ
Taphoorn
Martin J B
MJ
Janzer
Robert C
RC
Ludwin
Samuel K
SK
Allgeier
Anouk
A
Fisher
Barbara
B
Belanger
Karl
K
Hau
Peter
P
Brandes
Alba A
AA
Gijtenbeek
Johanna
J
Marosi
Christine
C
Vecht
Charles J
CJ
Mokhtari
Karima
K
Wesseling
Pieter
P
Villa
Salvador
S
Eisenhauer
Elizabeth
E
Gorlia
Thierry
T
Weller
Michael
M
Lacombe
Denis
D
Cairncross
J Gregory
JG
Mirimanoff
René-Olivier
RO
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide