Background
Phase III, open-label, multicenter RCT. 573 patients with newly diagnosed, histologically confirmed glioblastoma multiforme (GBM), age ≤70 years, WHO PS 0–2. Enrolled at 85 centers. First trial to establish concurrent and adjuvant temozolomide with radiotherapy as standard of care for GBM.
Interventions and follow up
Arm A: Radiotherapy alone — 60 Gy in 30 daily fractions over 6 week
Arm B: Radiotherapy (60 Gy/30 fr) + concomitant daily temozolomide 75 mg/m² (throughout RT) → 6 cycles adjuvant temozolomide 150–200 mg/m² days 1–5 every 28 day
Primary endpoint: Overall survival
mFollow up: Median 28 month
Arm B: Radiotherapy (60 Gy/30 fr) + concomitant daily temozolomide 75 mg/m² (throughout RT) → 6 cycles adjuvant temozolomide 150–200 mg/m² days 1–5 every 28 day
Primary endpoint: Overall survival
mFollow up: Median 28 month
Results
OS: 14.6 vs 12.1 months, HR 0.63 (95% CI 0.52–0.75), P<.001
2-year OS: 26.5% vs 10.4%
PFS: 6.9 vs 5.0 months, HR 0.54, P<.001
MGMT methylation (exploratory): Methylated OS 21.7 vs 15.3 months; unmethylated: 12.7 vs 11.8 months (non-significant)
2-year OS: 26.5% vs 10.4%
PFS: 6.9 vs 5.0 months, HR 0.54, P<.001
MGMT methylation (exploratory): Methylated OS 21.7 vs 15.3 months; unmethylated: 12.7 vs 11.8 months (non-significant)
Adverse events
Main adverse events: Grade 3–4 hematologic toxicity: 7% in TMZ+RT arm. Grade 3–4 fatigue: 7% vs 3%. Prophylactic PCP trimethoprim required. No significant difference in non-hematologic toxicity. No treatment-related deaths.
Conclusions
Radiotherapy plus concomitant and adjuvant temozolomide significantly improved OS (14.6 vs 12.1 months; 2-yr OS 26.5% vs 10.4%), establishing TMZ+RT as the standard of care for newly diagnosed GBM and defining the Stupp regimen.
Key Limitations
Key Limitations: Open-label design. Patients aged >70 years excluded — applicability to elderly GBM required subsequent trials (Nordic, EORTC 26062). MGMT analysis was retrospective and exploratory — not a prospectively stratified subgroup. Only ~45% of assessable patients had MGMT methylation. The absolute OS gain (~2.5 months) is modest, though the 2-year survival doubling is clinically meaningful. Many patients did not complete all 6 adjuvant cycles.
Clinical Context
Established the Stupp regimen (60Gy/30fr + concurrent daily TMZ → 6 cycles adjuvant TMZ) as the global standard of care for newly diagnosed GBM. The companion MGMT paper (Hegi, NEJM 2005) established MGMT methylation as a key predictive biomarker. Subsequent landmark trials (NOA-09, EF-14) added lomustine or TTFields to this backbone.
References