Background
Randomized, open-label phase 3 intergroup trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU; N=478). Clinically high-risk WHO grade 2 low-grade glioma. Compared single-modality first-line therapy: dose-dense temozolomide vs radiotherapy. Mature long-term analysis with post hoc molecular reclassification per WHO 2021 criteria (analyzable tissue in 73%).
Results
Interventions and follow up: Arm A: Temozolomide 75 mg/m2 PO daily x21 of 28 days, up to 12 cycles (dose-dense)
Arm B: Radiotherapy 50.4 Gy (28 x 1.8 Gy)
Primary endpoint: PFS
mFollow up: NR (mature analysis)
Results: PFS: no significant difference between arms
OS: no significant difference between arms
OS, astrocytoma IDHmt/non-codeleted (n=178): median 6.6-6.7 yr irrespective of arm (P=.93)
OS, oligodendroglioma IDHmt/1p19q-codeleted (n=109): 12.9 yr (RT) vs 14.9 yr (TMZ) (HR 0.88; 95% CI 0.52-1.49; P=.63)
OS, IDH-wildtype (n=64): 2.5 yr (RT) vs 4.7 yr (TMZ) (HR 0.47; 95% CI 0.27-0.82; P=.0068)
Age: patients ≥40 yr fared better than <40 yr, challenging age alone as a negative prognostic factor
Arm B: Radiotherapy 50.4 Gy (28 x 1.8 Gy)
Primary endpoint: PFS
mFollow up: NR (mature analysis)
Results: PFS: no significant difference between arms
OS: no significant difference between arms
OS, astrocytoma IDHmt/non-codeleted (n=178): median 6.6-6.7 yr irrespective of arm (P=.93)
OS, oligodendroglioma IDHmt/1p19q-codeleted (n=109): 12.9 yr (RT) vs 14.9 yr (TMZ) (HR 0.88; 95% CI 0.52-1.49; P=.63)
OS, IDH-wildtype (n=64): 2.5 yr (RT) vs 4.7 yr (TMZ) (HR 0.47; 95% CI 0.27-0.82; P=.0068)
Age: patients ≥40 yr fared better than <40 yr, challenging age alone as a negative prognostic factor
Adverse events
Mature analysis: no new safety data reported (NR)
Primary report (Lancet Oncol 2016): hematologic toxicity predominated in the TMZ arm; acute toxicity low with RT
Primary report (Lancet Oncol 2016): hematologic toxicity predominated in the TMZ arm; acute toxicity low with RT
Conclusions
Choice of initial single-modality therapy (dose-dense TMZ vs RT alone) did not affect PFS or OS in any molecular subtype of high-risk grade 2 glioma. The OS signal favoring TMZ in IDH-wildtype tumors and the challenge to the age-40 prognostic cutoff are hypothesis-generating; combined-modality therapy (not tested here) has since become standard for IDH-mutant astrocytoma.
Key Limitations
Post hoc molecular reclassification with tissue available in only 73%; subgroup analyses underpowered and exploratory (IDH-wildtype n=64, likely enriched for molecular glioblastoma); single-modality design now outdated with no RT + chemotherapy arm; accrual era predates WHO 2021 classification and IDH inhibitors.
Clinical Context
RT + PCV (RTOG 9802) and RT + TMZ (CATNON) remain standards for high-risk IDH-mutant grade 2-3 glioma; vorasidenib (INDIGO, FDA-approved 2024) is now an option for residual/recurrent IDH-mutant grade 2 glioma. These mature data support molecularly tailored initial strategies but do not change standard of care.