Background
Phase III multicenter RCT (NOA-04), N=318 newly diagnosed anaplastic gliomas (anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma). Randomized 2:1:1 to determine whether initial chemotherapy (PCV or TMZ) could replace RT at diagnosis, using a sequential strategy with crossover at progression. First trial to report IDH1 mutation as a prognostic factor in anaplastic gliomas.
Interventions and follow up
Arm A (RT first, 2:1:1): Conventional RT (54–60 Gy) at diagnosis; PCV or TMZ at progression
Arm B (PCV first): PCV (procarbazine + CCNU + vincristine) × up to 4 cycles at diagnosis; RT at progression
Arm C (TMZ first): TMZ (200 mg/m² days 1–5 every 4 weeks) × up to 8 cycles at diagnosis; RT at progression
Primary endpoint: Time to treatment failure (TTF = progression after RT and one chemotherapy regimen in sequence)
mFollow up: NR; all endpoints mature
Arm B (PCV first): PCV (procarbazine + CCNU + vincristine) × up to 4 cycles at diagnosis; RT at progression
Arm C (TMZ first): TMZ (200 mg/m² days 1–5 every 4 weeks) × up to 8 cycles at diagnosis; RT at progression
Primary endpoint: Time to treatment failure (TTF = progression after RT and one chemotherapy regimen in sequence)
mFollow up: NR; all endpoints mature
Results
TTF: HR 1.2 (95% CI 0.8–1.8) — no difference RT-first vs chemotherapy-first
PFS: HR 1.0 (95% CI 0.7–1.3) — equivalent
OS: HR 1.2 (95% CI 0.8–1.9) — equivalent
IDH1 mutation (HR for PFS vs IDH WT): HR 0.48 (95% CI 0.29–0.77)
MGMT methylation: Associated with improved PFS in chemotherapy arms
PFS: HR 1.0 (95% CI 0.7–1.3) — equivalent
OS: HR 1.2 (95% CI 0.8–1.9) — equivalent
IDH1 mutation (HR for PFS vs IDH WT): HR 0.48 (95% CI 0.29–0.77)
MGMT methylation: Associated with improved PFS in chemotherapy arms
Adverse events
PCV arm: More hematologic toxicity and neuropathy than TMZ arm
RT-first arm: Expected acute RT toxicities
Overall: AEs consistent with known profiles; extent of resection was the strongest surgical prognostic factor
RT-first arm: Expected acute RT toxicities
Overall: AEs consistent with known profiles; extent of resection was the strongest surgical prognostic factor
Conclusions
Initial RT vs initial chemotherapy (PCV or TMZ) achieved comparable TTF, PFS, and OS in anaplastic gliomas when used sequentially with crossover at progression — supporting that timing of RT does not affect overall outcome. IDH1 mutation was identified as a powerful positive prognostic factor.
Key Limitations
Histology-based (pre-molecular) enrollment; many cases would be reclassified under WHO 2016/2021. Sequential crossover design tests timing rather than head-to-head modality efficacy. Did not stratify by 1p/19q codeletion at randomization. Predates the survival-superior RT-plus-chemotherapy approach later established by CATNON and CODEL.
Clinical Context
Landmark for establishing IDH1 mutation as a dominant prognostic biomarker in anaplastic glioma. Current standard for anaplastic gliomas favors combined RT plus chemotherapy (per CATNON/RTOG 9402/EORTC 26951) rather than the sequential single-modality strategy tested here.