Background
Phase III, open-label, multicenter RCT (EORTC 22033-26033). 477 patients with high-risk, supratentorial low-grade glioma (age ≥40 OR subtotal resection) — parallel design to RTOG 9802 but testing TMZ vs RT rather than RT+PCV vs RT. The central question: can TMZ monotherapy replace RT for high-risk LGG, avoiding radiation toxicity? MGMT, IDH, and 1p/19q assessed prospectively.
Interventions and follow up
Arm A: Radiotherapy — 50.4 Gy in 28 fractio
Arm B: Temozolomide — 75 mg/m² days 1–21 every 28 days, 12 cycle
Primary endpoint: Progression-free survival
mFollow up: Median 48 month
Arm B: Temozolomide — 75 mg/m² days 1–21 every 28 days, 12 cycle
Primary endpoint: Progression-free survival
mFollow up: Median 48 month
Results
PFS (overall): Median 3.3yr (TMZ) vs 4.2yr (RT), HR 1.16 (95% CI 0.9–1.5), P=.22 — not significant
1p/19q codeleted PFS: RT superior (HR 1.86, 95% CI 1.21–2.87, P=.0139)
IDH mutant non-codeleted PFS: TMZ and RT similar (HR 0.98)
IDH wild-type PFS: Very short PFS regardless of treatment — RT may be slightly better
1p/19q codeleted PFS: RT superior (HR 1.86, 95% CI 1.21–2.87, P=.0139)
IDH mutant non-codeleted PFS: TMZ and RT similar (HR 0.98)
IDH wild-type PFS: Very short PFS regardless of treatment — RT may be slightly better
Adverse events
Main adverse events: TMZ arm: grade 3–4 hematologic toxicity 3%. RT arm: well-tolerated acute toxicity, risk of neurocognitive effects long-term. Both arms well-tolerated overall. No treatment-related deaths.
Conclusions
TMZ monotherapy did not improve PFS vs RT in high-risk LGG overall. Molecular subgroup analysis showed 1p/19q codeleted patients did better with RT than TMZ (possibly reflecting the superior benefit of RT+PCV in codeleted tumors). TMZ and RT were roughly equivalent in IDH-mutant non-codeleted patients (now classified as IDH-mutant astrocytoma), supporting the concept that chemotherapy and RT are interchangeable for this subtype — but not additive alone without combination.
Key Limitations
Key Limitations: TMZ monotherapy arm — not RT+TMZ combination. No PCV arm for direct comparison in 1p/19q codeleted patients (where RT+PCV is the gold standard). The 1p/19q codeleted finding favoring RT is unexpected and may reflect the absence of the best regimen (RT+PCV) rather than RT superiority over TMZ. OS data were not mature at time of this report. The IDH wild-type patients had very poor prognosis — likely reclassified as GBM equivalent under WHO 2021.
Clinical Context
EORTC 22033-26033 did not establish TMZ as superior to RT for LGG. The key practice-relevant finding is molecular: 1p/19q codeleted LGG responds differently to TMZ vs RT, supporting that these patients require RT+PCV (not TMZ monotherapy). For IDH-mutant non-codeleted LGG, chemotherapy and RT are likely both needed (as shown by RTOG 9802 and CATNON). Modern treatment of LGG is guided by IDH+1p/19q status with combined modality therapy for high-risk patients.
References