Fast track — ArticlesEffects 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
Introduction
For more than three decades, postoperative radiotherapy has been standard treatment for newly diagnosed glioblastoma. Pooled analysis of six randomised trials of radiotherapy versus no radiotherapy after surgery showed significant survival benefits for radiotherapy.1, 2 However, the survival advantage after radiation was small and overall survival remained poor with almost no long-term survivors. The addition of nitrosourea-based chemotherapy gave modest further benefit: a meta-analysis of 12 randomised trials of adjuvant chemotherapy for high-grade glioma showed a 35% 1-year survival rate for glioblastoma, an improvement of 6%.3
In 2004, the European Organisation for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada Clinical Trials Group (NCIC) CE3 randomised phase III trial showed the addition of concomitant and adjuvant temozolomide to standard postoperative radiotherapy improved median survival and 2-year survival relative to postoperative radiotherapy alone.4 Furthermore, patients whose tumour had a methylated promoter for the gene encoding O-6-methylguanine-DNA methyltransferase, MGMT, were more likely to benefit from the addition of temozolomide.5 Here we present long-term results on outcome and analyse known and putative prognostic and predictive factors. At the time of the initial analysis, whether the survival advantage would last over time was unclear.
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Patients
Patients were recruited from daily practice in participating centres of the European Organisation for the Research and Treatment of Cancer (EORTC) and NCIC (webappendix). Eligible patients were aged 18–70 years with newly diagnosed and histologically proven glioblastoma (WHO grade IV astrocytoma), with a WHO performance status of 0–2 and adequate haematological, renal, and hepatic function. Patients on corticosteroid treatment had to receive a stable or decreasing dose for at least 14 days
Results
Between Aug 17, 2000, and March 22, 2002, 573 patients from 85 institutions in 15 countries were randomly assigned: 286 were assigned to receive initial radiotherapy alone, and 287 to receive concomitant and adjuvant temozolomide. Characteristics of patients in the two groups were well balanced (table 1). Details of treatment delivery, tolerance, and toxicity were published previously;4 figure 1 shows the trial profile.
For 485 (85%) of 573 patients, slides or tumour tissue was available for
Discussion
For many years, attempts to improve the dismal prognosis of patients with glioblastoma—including changes to radiotherapy schedules, doses, and techniques2, 12, 13 and the addition of nitrosourea-based chemotherapy combinations—have had little success.3 In the late 1990s, temozolomide14, 15 seemed promising for the treatment of recurrent anaplastic glioma; however, in glioblastoma, the objective response rates were only 5–8%.16, 17 A pilot phase II study18 showed that concomitant temozolomide
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