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BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progres