MGMT promoter methylation as a predictive biomarker for response to radiotherapy versus chemotherapy in malignant astrocytomas in the elderly: The NOA-08 trial.

Abstract

2000 Background: In a few years more than half of the patients with glioblastoma will be older than 65 years of age and thus be classified as elderly. The current standard of care in elderly patients with glioblastoma (GB) or anapestic astrocytoma (AA) is resection or biopsy followed by involved-field radiotherapy (RT). The role of primary chemotherapy is poorly defined. The NOA-08 trial compared efficacy and safety of RT to temozolomide (TMZ) in patients with newly diagnosed AA or GB. Methods: Patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score > 60 were randomized to receive RT or TMZ. The primary endpoint was overall survival (OS). The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Results: Patient characteristics in the intention-to-treat population [N=373 (178 patients RT, 195 patients TMZ)] were balanced. All histologic diagnoses (11% AA and 89% GB) were centrally confirmed. Median OS [HR=1.09 (95% CI: 0.84-1.42)] and event-free survival (EFS) [hazard ratio (HR)=1.15 (0.92-1.43)] of TMZ versus RT did not differ between both arms. Non-inferiority of TMZ compared with RT was significant (p<0.05). Extent of resection, but not age or diagnosis of AA were associated with prolonged EFS and OS. DNA repair protein O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation in tumor tissue was associated with prolonged OS [HR=0.67 (0.38-1.29)]. Patients with MGMT promoter methylation had longer EFS when treated with TMZ (8.4 months [5.5-11.7] versus RT (4.6 [4.2-5] months) whereas patients without MGMT promoter methylation had longer EFS when treated with RT (4.6 [3.7-6.3] versus 3.3 [3-3.5] months). This effect persisted for OS. Conclusions: NOA-08 demonstrates the non-inferiority of TMZ compared with RT in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ.

Treatment of Elderly Patients With Glioblastoma

“…e Analysis was limited by the small sample size for this treatment (n = 2). Median overall survival with 95% CI (horizontal lines) for each treatment cohort for the NOA-08 trial, 5 the Nordic trial, 6 the German Glioma Network study, 9 the Association des Neuro-Oncologues d'Expression Française (ANOCEF) trial, 10 European Organisation for Research and Treatment of Cancer (EORTC)-National Cancer Institute of Canada Clinical Trials Group (NCIC), 11 and the study by Rønning et al 12 Dashed line indicates mean overall survival for all patients treated; shaded area, 95% CI for mean overall survival for all patients treated. had no effect on OS in patients treated with radiotherapy in either the Nordic trial or the NOA-08 trial.…”

“…The NOA-08 trial 5 and the Nordic trial 6 were the only randomized trials comparing radiotherapy alone with temozolomide monotherapy for patients aged 65 years or older. The NOA-08 trial studied 373 patients with newly diagnosed GBM or anaplastic astrocytoma and a Karnofsky Performance Status score of 60 or greater.…”

“…The results of several recent studies 5,6 have suggested that treatment with temozolomide alone for elderly patients with GBM may be a reasonable alternative to radiotherapy. In particular, this option may be most relevant in elderly patients who harbor O 6 methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation.…”

Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide Era

“…5 Acceptance in the neuro-oncology community of single-modality adjuvant strategies for elderly patients with GBM generally arises from the challenges that older patients may have in completing aggressive multimodality therapies, 14,19 concerns for increased RT-related central nervous system effects in older patients, 20 and the reports of randomized trials showing no OS advantage of RT alone over temozolomide alone. 2,3 In the NOA-08 trial, 373 patients older than 65 years were randomized to dose-dense temozolomide alone vs standard RT alone (60 Gy/30 Fx) and demonstrated no significant differences in survival. 3 Similarly, the Nordic trial randomized 342 patients 60 years or older (later amended to ≥65 years) to standard dose temozolomide alone, hypofractionated RT alone (34 Gy/10 Fx), or standard fractionation RT alone (60 Gy/30 Fx), and demonstrated a prolongation in median OS with either temozolomide alone or hypofractionated RT alone over standard fractionation RT.…”

“…Although level I evidence exists to support an overall survival (OS) advantage of RT over best supportive care (BSC), 1 2 randomized trials evaluating elderly populations have demonstrated no advantage of RT alone over CT alone with temozolomide, and subgroup analyses from each of these trials suggest that CT may be the more important single-modality therapy for patients with O 6 -methylguanine-DNA methyltransferase (MGMT) promoter-methylated tumors. 2,3 Nevertheless, elderly patients who present with a favorable performance status are often suitable candidates for combined-modality therapy (CMT) with both RT and CT, which is offered as the standard of care for younger patients. [4][5][6] At present, no randomized data are available for elderly patients with GBM to clarify the effect on OS of CMT vs RT alone or CT alone.…”