• Roger Stupp, Monika E Hegi, Warren P Mason, Martin J van den Bent, Martin J B Taphoorn, Robert C Janzer, Samuel K Ludwin, Anouk Allgeier, Barbara Fisher, Karl Belanger, Peter Hau, Alba A Brandes, Johanna Gijtenbeek, Christine Marosi, Charles J Vecht, Karima Mokhtari, Pieter Wesseling, Salvador Villa, Elizabeth Eisenhauer, Thierry Gorlia, Michael Weller, Denis Lacombe, J Gregory Cairncross, René-Olivier Mirimanoff, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, and National Cancer Institute of Canada Clinical Trials Group.
• Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. roger.stupp@chuv.ch
• Lancet Oncol. 2009 May 1; 10 (5): 459466459-66.

BackgroundIn 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.MethodsAdult 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.FindingsBetween 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.InterpretationBenefits 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.FundingEORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

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