Radiotherapy and Temozolomide Produce Comparable Long-Term Outcomes in High-Risk Low-Grade Glioma

Clinical Summary: 

• Design/Population: This randomized trial compared upfront radiotherapy with dose-dense temozolomide in patients with clinically high-risk WHO grade 2 low-grade glioma. Long-term outcomes were subsequently analyzed according to the 2021 WHO molecular classification.
• Key Outcomes: Initial treatment with radiotherapy or temozolomide resulted in comparable progression-free survival and overall survival across molecularly defined glioma subtypes. Molecular classification provided greater prognostic value than age alone, although patients with IDH-wild-type tumors experienced longer overall survival with temozolomide.
• Clinical Relevance: These findings suggest that molecular subtype should guide prognostic assessment in low-grade glioma and underscore the need for individualized treatment strategies as newer therapies become available.

Long-term follow-up of a phase 3 trial showed that initial treatment with either radiotherapy or dose-dense temozolomide produced comparable survival outcomes in patients with clinically high-risk low-grade glioma, while molecular classification emerged as a stronger predictor of prognosis.

“Prognosis in low-grade gliomas remains highly variable, and treatment-related late toxicity is a concern,” stated Brigitta Baumert, MD, PhD, Haaglanden Medisch Centrum, The Hague, The Netherlands, and coauthors. “This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers.”

In this international trial, 478 patients with clinically high-risk low-grade glioma were randomized to receive either 28 fractions of 1.8 Gy radiotherapy (n = 240) or 75 mg/m² of once-daily dose-dense temozolomide for 21 days of each 28-day cycle for up to 12 cycles (n = 238). The primary end point was progression-free survival (PFS), with overall survival (OS) and molecular analyses serving as key secondary end points. Tumor tissue from 351 patients (73%) was available for post hoc molecular reclassification according to the 2021 WHO criteria.

After a median follow-up of 13.1 years, there were no significant differences in PFS or OS between the treatment arms. Median PFS was 3.6 years in the radiotherapy arm and 3.1 years in the temozolomide arm (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.93 to 1.36; P = .23), while median OS was 6.6 years and 8 years, respectively (HR, 0.84; 95% CI, 0.67 to 1.05; P = .12).

Long-term outcomes remained comparable after molecular reclassification. Among patients with IDH-mutant, 1p/19q-noncodeleted astrocytoma (n = 178), median OS was 6.6 years in the radiotherapy arm and 6.7 years in the temozolomide arm (P = .93). Among patients with IDH-mutant, 1p/19q-codeleted oligodendroglioma (n = 109), median OS was 12.9 years and 14.9 years, respectively (HR, 0.88; 95% CI, 0.52 to 1.49; P = .63).

Investigators also reported significantly longer OS in the temozolomide arm among the 64 patients with IDH-wild-type tumors (4.7 vs 2.5 years; HR, 0.47; 95% CI, 0.27 to 0.82; P = .0068), although they noted this exploratory subgroup should be interpreted cautiously.

Molecular classification also reshaped the prognostic significance of age. After excluding IDH-wild-type tumors, age 40 years or older was no longer associated with worse outcomes. Instead, older patients experienced significantly better survival than younger patients, challenging the longstanding use of age alone as a high-risk feature in low-grade glioma.

“When single-modality cytotoxic treatments with [temozolomide] or [radiotherapy] are considered for patients with IDHmut glioma, this study shows that the sequence of chemotherapy or [radiotherapy] has no overall effect on outcome,” concluded Dr Baumert et al. “Future research may allow to tailor the choice of primary treatment to individual tumor characteristics (molecular subtype, location, and size) and patient preference.”

“Molecular classification of gliomas is shifting previously reported prognostic and predictive criteria, thereby impacting the considerations for initial treatment to maximize the therapeutic ratio and outcomes,” added Journal of Clinical Oncology associate editor Caroline Chung, MD, MD Anderson Cancer Center, Houston, Texas. 

Source: 

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. Published online: July 2, 2026. doi: 10.1200/JCO-25-02735