Elsevier

The Lancet Oncology

Volume 13, Issue 7, July 2012, Pages 707-715
The Lancet Oncology

Articles
Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(12)70164-XGet rights and content

Summary

Background

Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma.

Methods

Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241.

Findings

Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, pnon-inferiority=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, pnon-inferiority=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight).

Interpretation

Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.

Funding

Merck Sharp & Dohme.

Introduction

Gliomas account for half of all intrinsic brain tumours. WHO grade IV glioblastomas are the most malignant variant of glioma and make up around half of such tumours. At a population level, median survival for patients with glioblastoma remains less than 6 months, and age is the most important therapy-independent prognostic factor.1 In a few years, more than half of patients with glioblastoma will be elderly (older than 65 years).2 Anaplastic astrocytoma (WHO grade III), a less common malignant glioma with an overall better prognosis than grade IV glioblastoma, shares molecular features and poor outcome with glioblastomas in the elderly.3, 4

The current standard of care in elderly patients with glioblastoma or anaplastic astrocytoma is resection or biopsy followed by involved-field radiotherapy.5 The classic radiotherapy treatment schedule is 60 Gy in 30 fractions of 2·0 Gy, although hypofractionated schedules, such as 15 fractions of 2·66 Gy, are used in some centres.6 Concomitant and adjuvant radiochemotherapy with the alkylating agent temozolomide has become the standard of care in non-elderly patients with glioblastoma.7 The benefit from this treatment, however, is largely restricted to patients with tumours exhibiting promoter methylation of the O6-methylguanine-DNA methyltransferase gene (MGMT), which encodes a DNA repair protein associated with alkylator resistance.8, 9 Increasing age is associated with decreasing benefit from chemotherapy10 and an increasing risk of cognitive side-effects from cranial irradiation.2 Moreover, the tolerability of combined radiotherapy and temozolomide seems to be reduced in the elderly.11 Temozolomide chemotherapy alone has shown promising results in elderly patients with glioblastoma.12, 13 We have previously reported encouraging progression-free survival at 6 months in patients with recurrent glioblastoma treated with a 1 week on, 1 week off regimen.14 On the basis of these results the German Neuro-oncology Working Group (NOA) has done a randomised, phase 3 trial (NOA-08) to assess whether dose-dense temozolomide alone is inferior to radiotherapy alone in the management of newly diagnosed glioblastoma or anaplastic astrocytoma in elderly patients, and to investigate the role of MGMT promoter methylation.

Section snippets

Patients

Between May 15, 2005, and Nov 2, 2009, we recruited patients from 23 university centres across Germany and one in Switzerland. Eligible patients had de-novo anaplastic astrocytoma or glioblastoma that were histologically confirmed locally after biopsy or resection, age older than 65 years, and a Karnofsky performance score of 60 or more. Histological diagnoses were confirmed centrally at study entry by the Brain Tumour Reference Centre, German Society for Neuropathology and Neuroanatomy,

Results

Of 584 patients screened, 412 were eligible for enrolment (figure 1). 39 patients were excluded after randomisation and, therefore, the analysis population for efficacy endpoints (received at least one dose of dose-dense temozolomide or one fraction of radiotherapy) consisted of 373 patients. Central review of disease revealed that 40 (11%) patients had anaplastic astrocytoma and 331 (89%) had glioblastoma. The per-protocol population consisted of 362 patients, after 11 patients were excluded

Discussion

We have shown that temozolomide alone is non-inferior to radiotherapy alone as treatment for newly diagnosed malignant gliomas in elderly patients. MGMT promoter methylation status seems to be a relevant biomarker to indicate patients who might be undertreated with radiotherapy alone. Temozolomide could, therefore, broaden the spectrum of treatment available for the increasing population of elderly patients with malignant gliomas.

The current standard care for anaplastic astrocytoma or

References (31)

  • 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)
  • M Weller et al.

    MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

    Nat Rev Neurol

    (2010)
  • AE Sijben et al.

    Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme

    J Neurooncol

    (2008)
  • M Glantz et al.

    Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas

    Cancer

    (2003)
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    See appendix for authors of the Study Group

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