Elsevier

The Lancet Oncology

Volume 10, Issue 5, May 2009, Pages 459-466
The Lancet Oncology

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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

https://doi.org/10.1016/S1470-2045(09)70025-7Get rights and content

Summary

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.

Findings

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.

Interpretation

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.

Funding

EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

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.

Section snippets

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

References (51)

  • TT Batchelor et al.

    AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients

    Cancer Cell

    (2007)
  • MD Walker et al.

    Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery

    N Engl J Med

    (1980)
  • LA Stewart

    Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials

    Lancet

    (2002)
  • R Stupp et al.

    Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

    N Engl J Med

    (2005)
  • ME Hegi et al.

    MGMT gene silencing and benefit from temozolomide in glioblastoma

    N Engl J Med

    (2005)
  • SJ Pocock et al.

    Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial

    Biometrics

    (1975)
  • LS Freedman et al.

    On the use of Pocock and Simon's method for balancing treatment numbers over prognostic factors in the controlled clinical trial

    Biometrics

    (1976)
  • RO Mirimanoff et al.

    Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial

    J Clin Oncol

    (2006)
  • LM Lamers et al.

    Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study

    Cancer

    (2008)
  • DG Gonzalez et al.

    Accelerated radiotherapy in glioblastoma multiforme: a dose searching prospective study

    Radiother Oncol

    (1994)
  • R Miralbell et al.

    Accelerated radiotherapy, carbogen, and nicotinamide in glioblastoma multiforme: report of European Organization for Research and Treatment of Cancer trial 22933

    J Clin Oncol

    (1999)
  • CS Brock et al.

    Phase I trial of temozolomide using an extended continuous oral schedule

    Cancer Res

    (1998)
  • WK Yung et al.

    A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse

    Br J Cancer

    (2000)
  • R Stupp et al.

    Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide

    J Clin Oncol

    (2002)
  • W Wick et al.

    A novel tool to analyse MRI recurrence patterns in glioblastoma

    Neuro Oncol

    (2008)
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