Elsevier

The Lancet Oncology

Volume 13, Issue 9, September 2012, Pages 916-926
The Lancet Oncology

Articles
Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(12)70265-6Get rights and content

Summary

Background

Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma.

Methods

Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m2 on days 1–5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623.

Findings

342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1–9·5; n=93] vs 6·0 months [95% CI 5·1–6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52–0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5–8·6; n=98], HR 0·85 [0·64–1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3–9·4; n=119] vs 7·4 months [6·4–8·4; n=123]; HR 0·82, 95% CI 0·63–1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21–0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37–0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0–11·4] vs 6·8 months [5·9–7·7]; HR 0·56 [95% CI 0·34–0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69–1·38]; p=0·81). As expected, the most common grade 3–4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3–5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed.

Interpretation

Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide.

Funding

Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.

Introduction

Glioblastoma is the most frequent primary brain tumour and is mainly seen in people older than 60 years. Median survival is less than 1 year.1, 2 Chemoradiotherapy with temozolomide became the standard of care in 2004, but its introduction was based on a pivotal study in which patients were aged 70 years or younger; increasing age was found to be a negative prognostic factor.3, 4 Elderly and frail patients might, therefore, not be viewed as candidates for combined therapy, and extensive treatment might not be seen as justifiable owing to the short survival.5, 6, 7, 8, 9, 10

Alternatives to the standard 6 weeks of radiotherapy that are associated with similar or improved survival and quality of life would be beneficial. Outpatient treatment or short treatment times could also lessen demands on medical resources and reduce the risk of treatment being withheld. Chemotherapy with temozolomide, an oral alkylating agent, has been efficacious as a treatment for glioma with low risk of toxic effects11, 12, 13 and hypofractionated radiotherapy has been advocated.14, 15 In contrast to radiotherapy, temozolomide chemotherapy can be administered from local hospitals and can be started quickly after diagnosis.

To define an evidence-based treatment recommendation for patients aged 60 years or older with glioblastoma, the Nordic Clinical Brain Tumour Study Group (NCBTSG) did a randomised trial to compare survival, health-related quality of life, and safety with single-agent temozolomide chemotherapy, hypofractionated radiotherapy, or standard radiotherapy.

Section snippets

Patients

Between Feb 2, 2000, and June 18, 2009, we recruited patients from 28 centres treating patients with brain tumours (mainly oncology departments) in Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey, to which patients were referred after neurosurgery. Patients with newly diagnosed, histologically confirmed glioblastoma (WHO grade IV astrocytoma) and aged 60 years or older were eligible. To resemble the characteristics of patients seen in clinics, patients with WHO performance

Results

342 patients were enrolled overall. 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, and standard radiotherapy n=100) and constitute the cohort for comparisons with standard radiotherapy. 51 further patients from four centres that did not offer standard radiotherapy were randomised across only the temozolomide (n=26) or hypofractionated radiotherapy (n=25) groups. Thus, 242 patients were assessed in comparisons of temozolomide (n=119

Discussion

Our trial confirms that the overall prognosis for elderly patients with glioblastoma is poor, particularly in patients older than 70 years treated with standard radiotherapy (panel). We found that temozolomide chemotherapy is a potential alternative to radiotherapy in elderly and frail patients. Of note is that a substantial number of patients were unable to complete the planned standard radiotherapy regimen, which could partly explain the inferior survival in this group. Radiotherapy was

References (29)

  • BA Kohler et al.

    Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system

    J Natl Cancer Inst

    (2011)
  • T Bergenheim et al.

    Registration on regional basis of patients with primary brain tumors. Regional differences disclosed

    Lakartidningen

    (2007)
  • R Stupp et al.

    Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

    N Engl J Med

    (2005)
  • G Minniti et al.

    Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients

    J Neurooncol

    (2008)
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