Background
Phase III, open-label, multicenter RCT (EORTC 26062-22061 / NCIC CTG CE.6). 562 patients with newly diagnosed GBM, age ≥65 years. First phase III trial specifically powered to evaluate the addition of temozolomide to a hypofractionated RT regimen in elderly GBM. MGMT promoter methylation status prospectively evaluated in 354 patients.
Interventions and follow up
Arm A: Hypofractionated radiotherapy alone — 40 Gy in 15 fractions over 3 week
Arm B: Hypofractionated radiotherapy (40 Gy/15fr) + concomitant and adjuvant temozolomide (75 mg/m² concurrent; 150–200 mg/m² days 1–5 every 28 days, 12 cycles maximum)
Primary endpoint: Overall survival
mFollow up: Not reported; all patients deceased
Arm B: Hypofractionated radiotherapy (40 Gy/15fr) + concomitant and adjuvant temozolomide (75 mg/m² concurrent; 150–200 mg/m² days 1–5 every 28 days, 12 cycles maximum)
Primary endpoint: Overall survival
mFollow up: Not reported; all patients deceased
Results
OS: 9.3 vs 7.6 months, HR 0.67 (95% CI 0.56–0.80), P<.001
PFS: 5.3 vs 3.9 months, HR 0.50 (95% CI 0.41–0.60), P<.001
MGMT methylated OS: 13.5 vs 7.7 months, HR 0.53, P<.001
MGMT unmethylated OS: 10.0 vs 7.9 months, HR 0.75, P=.055 (P interaction=.08)
PFS: 5.3 vs 3.9 months, HR 0.50 (95% CI 0.41–0.60), P<.001
MGMT methylated OS: 13.5 vs 7.7 months, HR 0.53, P<.001
MGMT unmethylated OS: 10.0 vs 7.9 months, HR 0.75, P=.055 (P interaction=.08)
Adverse events
Main adverse events: Grade 3–4 AEs more common with TMZ addition: fatigue, hematologic toxicity. Grade 3–4 neutropenia 9% vs 0%. Grade 3–4 thrombocytopenia 11% vs 0%. No treatment-related deaths. QoL maintained similarly between arms without clinically significant difference.
Conclusions
Adding temozolomide to hypofractionated RT (40 Gy/15fr) significantly improved OS (9.3 vs 7.6mo) and PFS in elderly GBM patients ≥65yr. Benefit was strongest in MGMT-methylated patients (OS 13.5 vs 7.7mo). MGMT-unmethylated patients showed a trend toward OS benefit (10.0 vs 7.9mo) but interaction test was not significant.
Key Limitations
Key Limitations: Open-label design. MGMT interaction test for TMZ benefit did not reach statistical significance (P=.08) — the MGMT-unmethylated subgroup may still have some benefit or it may reflect type II error given the sample size. Maximum of 12 TMZ cycles is more aggressive than standard 6 cycles. Patients were not stratified by KPS or extent of resection — performance status heterogeneity may affect interpretation. No comparison with TMZ alone (relevant given Nordic trial data).
Clinical Context
This trial established hypoRT+TMZ (40Gy/15fr + TMZ) as the standard of care for elderly GBM patients ≥65yr. For MGMT-methylated patients, the benefit is unambiguous and this combination is recommended. For MGMT-unmethylated patients, hypoRT±TMZ is used — the Nordic trial suggests TMZ alone may be inferior in MGMT-unmethylated tumors, but no head-to-head comparison exists. MGMT methylation testing is now standard for all elderly GBM patients to guide adjuvant therapy intensity.
References
References: Perry JR et al, NEJM 2017 (EORTC 26062)