Background
Phase III, open-label, multicenter RCT — the Nordic Brain Tumor Study Group trial. 342 patients with newly diagnosed GBM, age ≥60 years, enrolled at centers in Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. Three-arm design comparing TMZ monotherapy, hypofractionated RT, and standard RT — specifically designed for older or frailer patients where the benefit of the Stupp regimen (which excluded >70yr) was uncertain.
Interventions and follow up
Arm A: Temozolomide monotherapy — 200 mg/m² days 1–5 every 28 days, up to 6 cycle
Arm B: Hypofractionated radiotherapy — 34.0 Gy in 10 × 3.4 Gy fractions over 2 week
Arm C: Standard radiotherapy — 60.0 Gy in 30 × 2.0 Gy fractions over 6 week
Primary endpoint: Overall survival
mFollow up: Not specified; all patients deceased
Arm B: Hypofractionated radiotherapy — 34.0 Gy in 10 × 3.4 Gy fractions over 2 week
Arm C: Standard radiotherapy — 60.0 Gy in 30 × 2.0 Gy fractions over 6 week
Primary endpoint: Overall survival
mFollow up: Not specified; all patients deceased
Results
OS (TMZ vs standard RT): 8.3 vs 6.0 months, HR 0.70 (95% CI 0.52–0.93), P=.01
OS (hypoRT vs standard RT): 7.5 vs 6.0 months, HR 0.85, P=.24 — not significant
OS age >70yr (TMZ vs standard RT): HR 0.35, P<.0001
OS age >70yr (hypoRT vs standard RT): HR 0.59, P=.02
MGMT methylated (TMZ arm): 9.7 vs 6.8 months (unmethylated), P=.02
OS (hypoRT vs standard RT): 7.5 vs 6.0 months, HR 0.85, P=.24 — not significant
OS age >70yr (TMZ vs standard RT): HR 0.35, P<.0001
OS age >70yr (hypoRT vs standard RT): HR 0.59, P=.02
MGMT methylated (TMZ arm): 9.7 vs 6.8 months (unmethylated), P=.02
Adverse events
Main adverse events: Standard RT associated with worst outcomes especially in >70yr patients. Grade 3–4 AEs with TMZ: neutropenia (n=12), thrombocytopenia (n=18). Two fatal infections (one each in TMZ and standard RT arms). No significant difference in grade 3–5 toxicity between arms.
Conclusions
In elderly GBM patients (≥60yr), TMZ monotherapy improved OS vs standard RT (8.3 vs 6.0mo; HR 0.70), especially in patients >70yr. Both TMZ and hypofractionated RT were superior to standard RT in patients >70 years. MGMT methylation predicted benefit from TMZ. Standard 60-Gy RT should not be used as default in patients older than 70.
Key Limitations
Key Limitations: Open-label design. No concurrent TMZ+RT arm — the most effective regimen per Stupp was not tested here. The 3-arm randomization was not fully balanced (some patients were randomized to only 2 arms). No TMZ vs hypoRT direct comparison powered to detect survival differences. Results for patients 60–70yr less definitive; the signal is strongest for >70yr. MGMT analysis retrospective/subset.
Clinical Context
This trial established that in elderly GBM (especially >70yr), standard 60-Gy RT is inferior and TMZ monotherapy or hypoRT should be used. EORTC 26062 (Perry 2017) subsequently showed that 40Gy/15fr+TMZ is superior to 40Gy/15fr alone for all elderly patients, with particularly strong benefit in MGMT-methylated tumors. Current practice: MGMT-methylated elderly GBM → TMZ±hypoRT preferred; MGMT-unmethylated → hypoRT preferred over TMZ monotherapy.
References