STUPP

Background

Prior to this landmark phase III trial, radiotherapy alone was standard for newly diagnosed glioblastoma. STUPP (EORTC 26981-22981/NCIC CE.3) tested whether concurrent and adjuvant temozolomide (TMZ), an oral alkylating agent, added to radiotherapy improves survival.

Interventions and follow up

Arm A: Radiotherapy (60 Gy/30 fractions) + concurrent TMZ 75mg/m²/day, then 6 cycles adjuvant TMZ 150–200mg/m² days 1–5 q28d
Arm B: Radiotherapy alone (60 Gy/30 fractions)
Primary endpoint: overall survival
mFollow-up: 28mo

Results

n: 573
mOS: 14.6 vs 12.1mo (HR 0.63, 95% CI 0.52–0.75, P<.001)
2-yr OS: 26.5% vs 10.4%; 5-yr OS: 9.8% vs 1.9%
MGMT-methylated: mOS 21.7 vs 15.3mo (HR 0.51)
MGMT-unmethylated: mOS 12.7 vs 11.8mo (HR 0.69, NS)

Adverse events

Hematologic (grade 3–4): 7% during concurrent and 14% during adjuvant TMZ vs <1% (RT alone), primarily thrombocytopenia and neutropenia
Other: nausea, vomiting, fatigue, constipation generally manageable; lymphopenia warranted PCP prophylaxis; treatment-related deaths rare.

Conclusions

Concurrent and adjuvant temozolomide added to radiotherapy significantly improved OS in newly diagnosed GBM, establishing the Stupp protocol as the global standard of care for nearly two decades and identifying MGMT promoter methylation as a key predictive biomarker.

Key Limitations

Conducted before molecular reclassification of glioblastoma; the cohort by current criteria is IDH-wildtype but MGMT testing was retrospective and not universally available. Absolute survival gain remains modest, and benefit in MGMT-unmethylated tumors is limited. Predates Tumor Treating Fields (EF-14) era.

Clinical Context

The Stupp protocol (maximal safe resection → RT + concurrent/adjuvant TMZ) remains the backbone of first-line GBM therapy worldwide and is endorsed by ASCO/SNO and ESMO guidelines. MGMT methylation testing is now standard. Tumor Treating Fields (EF-14) were later added to the maintenance phase as an option.

References