PDF: Stupp Protocol
(2005)Objective
To determine whether concurrent temozolomide with radiotherapy followed by adjuvant temozolomide improves overall survival compared with radiotherapy alone in newly diagnosed glioblastoma
Study Summary
• 2-year OS: 26.5% vs 10.4%
• Median PFS: 6.9 months vs 5.0 months; HR 0.54 (95% CI 0.45-0.64), P<0.001
• 2-year PFS: 10.7% vs 1.5%
• Grade 3/4 hematologic toxicity in 7% of RT+TMZ patients during concomitant phase
• Benefit consistent across all prognostic subgroups
• Established the Stupp protocol as standard of care for newly diagnosed GBM
Intervention
Radiotherapy (60 Gy in 30 fractions over 6 weeks) plus concomitant daily temozolomide (75 mg/m2/day, 7 days/week) followed by 6 cycles of adjuvant temozolomide (150-200 mg/m2, days 1-5 of 28-day cycle) vs radiotherapy alone (60 Gy in 30 fractions)
Inclusion Criteria
Age 18-70 years; newly diagnosed, histologically confirmed glioblastoma (WHO grade IV); WHO performance status 0-2; adequate hematologic, renal, and hepatic function; stable or decreasing corticosteroids for >=14 days before randomization
Study Design
Arms: Array
Patients per Arm: RT+TMZ: 287; RT alone: 286
Outcome
• 2-year OS: 26.5% vs 10.4%
• Median PFS: 6.9 vs 5.0 months; HR 0.54 (0.45-0.64), P<0.001
• 2-year PFS: 10.7% vs 1.5%
• Grade 3/4 hematologic toxicity (concomitant phase): 7%
• Grade 3/4 neutropenia: 4%; thrombocytopenia: 3%
Bottom Line
Adding temozolomide to radiotherapy improved median overall survival from 12.1 to 14.6 months (HR 0.63, P<0.001) and 2-year survival from 10.4% to 26.5%, with manageable toxicity (7% grade 3/4 hematologic events during concomitant phase), establishing the Stupp protocol as the global standard of care for newly diagnosed glioblastoma.
Major Points
- This was the first phase 3 trial to demonstrate a significant overall survival benefit from adding chemotherapy to radiotherapy in glioblastoma, fundamentally changing the treatment paradigm.
- 573 patients from 85 centers in 15 countries were randomized; 84% had undergone debulking surgery, and the median age was 56 years.
- The primary endpoint — overall survival — showed a 37% relative reduction in the risk of death with RT+TMZ (HR 0.63; 95% CI 0.52-0.75; P<0.001), translating to a 2.5-month median survival benefit.
- The 2-year overall survival rate was 26.5% with RT+TMZ vs 10.4% with RT alone — a clinically meaningful 2.5-fold improvement at a landmark time point.
- Median progression-free survival was also significantly improved: 6.9 months vs 5.0 months (HR 0.54; 95% CI 0.45-0.64; P<0.001), with 2-year PFS of 10.7% vs 1.5%.
- The survival benefit was consistent across all predefined prognostic subgroups, including age, sex, WHO performance status, extent of surgery, and use of corticosteroids.
- Temozolomide was well tolerated: only 7% of patients developed grade 3 or 4 hematologic toxicity during the concomitant phase. During adjuvant therapy, 14% had grade 3/4 hematologic events. The main reason for not completing adjuvant cycles was disease progression (39%), not toxicity.
- A companion translational study (Hegi et al., same issue of NEJM) showed that MGMT promoter methylation was the strongest predictor of benefit from temozolomide, establishing a critical biomarker for treatment decision-making.
Study Design
- Study Type
- Randomized, multicenter, open-label, phase 3 trial
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 573
- Follow-up
- Median 28 months
- Centers
- 85
- Countries
- 15 countries
Primary Outcome
Definition: Overall survival: 14.6 vs 12.1 months; HR 0.63 (95% CI 0.52-0.75); P<0.001 | 2-year OS: 26.5% vs 10.4%
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.63 (0.52-0.75) | P<0.001 |
Citation
N Engl J Med 2005;352:987-96