Molecular Subtype, Not Treatment Sequence, Drives Low-Grade Glioma Survival

Long-term follow-up of a randomized phase 3 trial shows that initial treatment with radiotherapy or temozolomide (Temodar) produces similar survival outcomes in patients with high-risk low-grade glioma, but molecular subtype—not treatment assignment—determines prognosis, according to results published in the Journal of Clinical Oncology.¹

The mature analysis of EORTC 22033-26033 (NCT00182819), with a median follow-up of 13.1 years, found no significant difference in progression-free survival (PFS) or overall survival (OS) between patients randomly assigned to standard radiotherapy or dose-dense temozolomide, regardless of molecular subgroup.

Study Design

Between 2005 and 2012, investigators enrolled 478 patients with clinical high-risk WHO grade 2 glioma across 78 institutions in 19 countries. Patients were randomly assigned to radiotherapy (28 fractions of 1.8 Gy; n = 240) or dose-dense temozolomide (75 mg/m² daily for 21 of 28 days, up to 12 cycles; n = 238). The primary end point was PFS; OS and molecular analyses were key secondary end points.

Key Findings

Median OS was 6.6 years with radiotherapy vs 8.0 years with temozolomide (HR, 0.84; 95% CI, 0.67-1.05; P =.12). Median PFS was 3.6 years with radiotherapy vs 3.1 years with temozolomide (HR, 1.12; 95% CI, 0.93-1.36; P =.23).

Tumor tissue from 351 of 478 patients (73%) was reclassified according to 2021 World Health Organization criteria. Among 178 patients with IDH-mutant, noncodeleted astrocytoma, median OS was 6.6 to 6.7 years regardless of treatment arm. Among 109 patients with IDH-mutant, 1p/19q-codeleted oligodendroglioma, median OS was 12.9 years with radiotherapy and 14.9 years with temozolomide (HR, 0.88; 95% CI, 0.52-1.49; P =.63).

A notable exception emerged among 64 patients with IDH-wild type tumors, now recognized as a distinct, more aggressive entity resembling molecular glioblastoma. In this subgroup, survival favored temozolomide: median OS was 2.5 years with radiotherapy vs 4.7 years with temozolomide (HR, 0.47; 95% CI, 0.27-0.82; P =.0068).

The authors also revisited age as a prognostic factor. When IDH-wild type tumors were excluded, the previously accepted cutoff of 40 years lost its prognostic significance; patients 40 years or older in the IDH-mutant population fared significantly better than younger patients (HR, 0.54; 95% CI, 0.40-0.72; P <.0001).

Clinical Context

The trial authors noted that combined-modality therapy—radiotherapy plus chemotherapy—has since become standard of care for IDH-mutant astrocytoma, based on other randomized trials including RTOG 9802 and ECOG-ACRIN E3F05.^2,3 A third study arm testing combined-modality treatment was not included in this trial's original design, which the authors acknowledged, in retrospect, as a missed opportunity.

At disease progression, treatment crossover was common: 72% of patients in the radiotherapy arm received alkylator-based chemotherapy, while 68% in the temozolomide arm received radiotherapy.

Implications

The authors concluded that molecular classification should guide individualized treatment decisions rather than a uniform single-modality approach. They noted that emerging IDH-targeted agents, including vorasidenib (Voranigo) may further reshape first-line strategies for IDH-mutant glioma.

The authors cautioned that the small size and heterogeneity of the IDH-wild type subgroup (n=64) limit definitive conclusions, and called for additional molecular subclassification to guide treatment in this population.

“As the field further refines molecular risk stratification and advances toward biology-guided treatment paradigms, the insights offered in this mature EORTC 22033-26033 data set will continue to shape how we select, sequence, and individualize treatment for patients with IDH-mutant [low-grade glioma],” wrote Ariel Marciscano, MD, and Helen Shih, MD, MS, MPH, AM, FASTRO, in an accompanying commentary.⁴

REFERENCES

1. Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide versus radiotherapy as first-line therapy for low-grade glioma: mature results of a randomized phase III trial (EORTC 22033-26033/NCIC-CTG/TROG/MRC-CTU). J Clin Oncol. 2026. doi:10.1200/JCO-25-02735.

2. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med. 2016 Apr 7;374(14):1344-55. doi: 10.1056/NEJMoa1500925. PMID: 27050206; PMCID: PMC5170873.

3. Schiff D, O'Neill A, Brown P, et al. LTBK-07. PROGRESSION-FREE AND OVERALL SURVIVAL RESULTS OF ECOG-ACRIN E3F05: A PHASE 3 INTERGROUP TRIAL OF RADIATION ± TEMOZOLOMIDE FOR GRADE II GLIOMAS. Neuro Oncol. 2024 Nov 11;26(Suppl 8):viii1–2. doi: 10.1093/neuonc/noae165.1303. PMCID: PMC11584974.

4. Marciscano A and Shih H. Biology Over Monotherapy: Mature Results From European Organisation For Research and Treatment of Cancer 22033-26033 Reaffirm Molecular Stratification, Not Treatment Sequence, Defines Prognosis in Low-Grade Glioma. J Clin Oncol. 0, JCO-26-00771
DOI:10.1200/JCO-26-00771