Rationale: Standard postoperative treatment of isocitrate dehydrogenase 1/2 mutated grade 2 and 3 glioma (IDHmG) consists of radiotherapy and chemotherapy. The improving prognosis of these patients leads towards more emphasis on the long-term effects of treatment. Specifically radiotherapy has been implicated in the development of delayed neurocognitive deterioration. The impact of modern radiotherapy techniques (such as intensity modulated radiotherapy, volumetric modulated radiotherapy and proton beam therapy) and chemotherapy on general toxicity, late neurocognitive outcomes and imaging changes is currently unclear.

Objectives:

• To report treatment outcomes and radiation-induced toxicity from a prospective, multicentre observational cohort of IDHmG patients treated with radiotherapy and chemotherapy,
• To integrate radiotherapeutic dose distributions, imaging changes and neuropsychological outcome in IDHmG.
• To evaluate the Dutch selection criteria for proton therapy applied to IDHmG based on the outcomes collected in this observational study.
• To assess the impact of proton and photon therapy on health-related quality of life (HRQoL) and health-related economics (HR-E) in IDHmG patients.
• To collect genetic material for future translational research into the interaction between germline DNA, prognosis and radiation-induced toxicity.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This project is a multicentre, observational cohort of patients undergoing radiotherapy and chemotherapy for IDHmG. The protocol closely follows the local guidelines for clinical follow-up. Specific to the study are extra questionnaires and specific imaging acquired during scheduled MRI's. Routine neuropsychological investigation is standard of care in Erasmus Medical Center (Erasmus MC), but not in all participating centers. We feel the additional burden of participation in this study to be low.

Inclusion Criteria:

• Histologically confirmed glioma, World Health Organisation (WHO) grade 2 or 3, IDH mutated
• Indication for standard treatment with radiotherapy and chemotherapy. For WHO grade 2 tumors 50.4 Gy relative biological equivalent (RBE) in 28 fractions. For WHO grade 3 tumors 59.4 Gy (RBE) in 33 fractions.
• Ability to comply with the protocol, including neuropsychological testing and imaging.
• Ability to understand the requirements of the study and to give written informed consent, as determined by the treating physician.
• Written informed consent.

Exclusion Criteria:

• Any prior chemotherapy for IDHmG. This includes upfront postoperative chemotherapy.
• Any prior cranial radiotherapy, including but not limited to radiotherapy for IDHmG.
• Prior invasive malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with current prostate specific antigen (PSA) of less than or equal to 0.1 ng/mL).
• Extensive white matter disease visible on pre-therapy imaging (Fazekas grade ≥2)
• Contra-indication for magnetic resonance (MR) imaging (i.e. metal implants, claustrophobia)
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule in the participating hospitals
• Any other serious medical condition that could interfere with follow-up.
• Severe aphasia or language barrier interfering with assessing endpoints (i.e. completion of questionnaires or neurocognitive performance)

IDH mutated glioma patients, WHO grade 2 and 3, who undergo postoperative radiotherapy and chemotherapy as standard treatment.