PDF: CATNON
(2021)Objective
Concurrent and/or adjuvant temozolomide added to radiotherapy — to evaluate overall survival benefit and effect of IDH mutation status in 1p/19q non-co-deleted anaplastic glioma.
Study Summary
• Concurrent temozolomide during radiotherapy did NOT improve survival (median 66.9 vs 60.4 months; HR 0.97; p=0.76) — the second interim analysis declared futility.
• Clinical benefit was dependent on IDH mutation status, establishing adjuvant temozolomide as standard of care for IDH-mutant 1p/19q non-codeleted anaplastic glioma while de-prioritizing concurrent temozolomide in this molecular subtype.
Intervention
2×2 factorial design: radiotherapy alone; RT + concurrent temozolomide 75 mg/m²/d; RT + 12 cycles adjuvant temozolomide 150-200 mg/m² days 1-5 of 28-day cycle; RT + both concurrent and adjuvant TMZ.
Inclusion Criteria
Adults ≥18 years with newly diagnosed 1p/19q non-co-deleted anaplastic glioma, WHO performance status 0-2.
Study Design
Arms: RT alone vs RT + concurrent TMZ vs RT + adjuvant TMZ vs RT + both (1:1:1:1)
Patients per Arm: RT alone 189; RT + concurrent 188; RT + adjuvant 186; RT + both 188 (N=751 total)
Outcome
• Concurrent TMZ vs no concurrent TMZ — median OS: 66.9 mo (45.7-82.3) vs 60.4 mo (45.7-71.5); HR 0.97 (99.1% CI 0.73-1.28); p=0.76 (FUTILITY declared)
• Clinical benefit strongly dependent on IDH1/IDH2 mutational status
• Grade 3-4 hematologic toxicity: 0% (RT alone), 9% (concurrent), 15% (adjuvant/both)
• No treatment-related deaths reported
Clinical Question
Does concurrent temozolomide, adjuvant temozolomide, or both added to radiotherapy improve survival in 1p/19q non-co-deleted anaplastic glioma, and is effect modified by IDH status?
Bottom Line
Adjuvant temozolomide added to radiotherapy significantly improved overall survival (median 82.3 vs 46.9 months; HR 0.64, p<0.0001) in 1p/19q non-co-deleted anaplastic glioma, while concurrent temozolomide did NOT add benefit (HR 0.97, p=0.76). Clinical benefit was strongly dependent on IDH mutational status — establishing adjuvant TMZ as the standard of care for IDH-mutant disease.
Major Points
- Phase 3, multicenter, open-label, 2×2 factorial randomized trial
- 137 institutions in Australia, Europe, and North America
- 751 adults with newly diagnosed 1p/19q non-co-deleted anaplastic glioma (WHO PS 0-2), randomly assigned 1:1:1:1
- RT: 59.4 Gy in 33 fractions (3D conformal or IMRT)
- Concurrent TMZ: 75 mg/m²/d during RT
- Adjuvant TMZ: 12 cycles of 150-200 mg/m² on days 1-5 of 28-day cycles
- Both arms: concurrent during RT + 12 adjuvant cycles
- Stratified by institution, WHO PS, age, 1p LOH, oligodendroglial elements, and MGMT methylation status
- Primary endpoint: overall survival adjusted by stratification factors (ITT)
- Second interim analysis (Dec 2019) triggered when 2/3 of required events observed
- Median follow-up 55.7 months (IQR 41.0-77.3)
- Concurrent TMZ: FUTILITY declared — median OS 66.9 vs 60.4 months; HR 0.97 (99.1% CI 0.73-1.28); p=0.76
- Adjuvant TMZ: SIGNIFICANT benefit — median OS 82.3 vs 46.9 months; HR 0.64 (95% CI 0.52-0.79); p<0.0001
- Grade 3-4 hematologic toxicities: 0% RT-alone, 9% concurrent, 15% adjuvant (or both arms combined)
- No treatment-related deaths reported
- Key finding: clinical benefit depended on IDH1/IDH2 mutational status — IDH-mutant patients benefit most; IDH-wildtype outcomes distinct
- This analysis changed practice: adjuvant TMZ is the cornerstone; concurrent TMZ has no added benefit in this molecular subtype
- Final definitive 2023/2024 publications refined IDH subgroup recommendations
Study Design
- Study Type
- Phase 3, multicenter, open-label, randomized, 2×2 factorial design
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 751
- Follow-up
- Median 55.7 months at second interim analysis
- Centers
- 137
- Countries
- Australia, Europe (multiple), USA, Canada
Primary Outcome
Definition: Overall survival, adjusted for stratification factors (ITT)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| No adjuvant TMZ: median OS 46.9 mo (37.9-56.9) | Adjuvant TMZ: median OS 82.3 mo (67.2-116.6) | - | p<0.0001 for adjuvant TMZ; p=0.76 for concurrent TMZ (futility) |
Limitations & Criticisms
- Open-label design may affect time-to-event assessments
- Second interim analysis for concurrent TMZ declared futility on a prespecified boundary
- Long enrollment period (2007-2015) introduces evolving imaging and pathology standards
- IDH mutation status not required at enrollment (available retrospectively in most patients)
- Standard 59.4 Gy dose and fractionation may differ from current practice in some centers
- Results are specific to non-codeleted tumors; do NOT extend to 1p/19q codeleted anaplastic oligodendroglioma (use PCV per EORTC 26951/RTOG 9402)
Citation
Lancet Oncology 2021;22(6):813-823