ArticlesTemozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial
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)
- et al.
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
Lancet Oncol
(2009) - et al.
Validation of real-time MSP to determine MGMT promoter methylation in glioma
J Mol Diagn
(2008) - et al.
Health-related quality of life in patients with glioblastoma: a randomised controlled trial
Lancet Oncol
(2005) - et al.
Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up
Lancet Neurol
(2009) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004-2006
- et al.
Geriatric neuro-oncology: from mythology to biology
Curr Opin Neurol
(2011) - et al.
Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma
J Neurosurg
(2008) - et al.
Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas
Acta Neuropathol
(2010) - et al.
Radiotherapy for glioblastoma in the elderly
N Engl J Med
(2007) - et al.
Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial
J Clin Oncol
(2004)
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
MGMT gene silencing and benefit from temozolomide in glioblastoma
N Engl J Med
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Nat Rev Neurol
Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme
J Neurooncol
Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas
Cancer
Cited by (0)
- ‡
See appendix for authors of the Study Group