This study builds on the results of prior studies (UNITED and UNITED-3). The goal of UNITED-4 is to test whether an adaptive radiation therapy (RT) therapy approach ('dose painting'), with reduced margins, impacts approach in participants with glioblastoma impacts local control compared to standard non-adaptive RT approach. The main questions of the study are to see how this adaptive RT approach with reduced margins compares to standard RT in terms of:

• Local control
• Overall and progression-free survival
• Patterns of failure
• Toxicity, Neurological Function, and Quality of Life
• Longitudinal imaging features

The UNITED-4 study is for people diagnosed with glioblastoma (GBM) or other high-grade (aggressive) brain tumors. These tumors are typically treated with radiation therapy combined with a chemotherapy agent called temozolomide. Standard radiation for these tumours uses a wide margin around the tumor to ensure that all areas potentially at risk for the presence of cancer cells are targeted, but this approach can also damage healthy brain tissue.

The UNITED-4 trial uses a new machine called an MR-Linac, which combines a radiation machine with an magnetic resonance imaging (MRI) scanner, allowing doctors to take daily images during treatment and adjust the radiation plan in real-time. This study will personalize treatment based on fluid-attenuated inversion recovery (FLAIR) MRI imaging that shows where cancer cells might be spreading while using smaller treatment margins to protect more of the normal brain. Patients will receive either 30 treatments over 6 weeks or 15 treatments over 3 weeks, with different radiation doses delivered simultaneously to high-risk areas (tumour) and lower-risk areas (normal brain). The goal of this study is to determine if this approach maintains cancer control while potentially reducing side effects and improving quality of life compared to standard treatments. Risks include radiation side effects (expected to be no worse than standard treatment) and a possibility of tumor recurrence at treatment edges.

The study will enroll 60 patients over 24 months at Sunnybrook Health Sciences Centre.

Inclusion Criteria:

• Histopathologically confirmed, based on biopsy or surgical resection, glioblastoma or WHO grade 4 astrocytoma (IDH wild type or mutant)
• Deemed clinically appropriate for concurrent chemoradiotherapy (with temozolomide) with definitive/radical intent
• Biopsy or surgical resection performed ≤ 12 weeks prior to study entry
• Expected survival ≥ 12 weeks
• ECOG performance status of 0, 1 or 2
• Sufficient estimated glomerular filtration rate (eGFR) of ≥ 30 mL/ min/1.73 m2 to allow administration of gadolinium-based contrast agent; patients with eGFR < 30 mL/min/1.73 m2 not on dialysis may be allowed on the study after discussion of risks and benefits and approval by study neuroradiologist(s)
• Completed written informed consent
• Patient must be accessible for treatment and follow-up
• Patients with multifocal or multicentric disease will be allowed per the discretion of the radiation oncologist

Exclusion Criteria:

• Contraindications to MRI examination as per standard MRI screening policy
• Contraindication to Gadolinium-based contrast media
• Enhancing disease involving any part of the brainstem on post-gadolinium T1-weighted MRI imaging for patients being treated using the short-course 15-fraction regimen
• Inability to lie flat in a supine position for at least 30 minutes
• Inability to tolerate immobilization in a head thermoplastic mask
• Patients > 140 kg and/or a circumference > 60 cm (MRI scanner weight and bore size limits)
• Prior therapeutic cranial irradiation
• Leptomeningeal dissemination of disease
• History of other malignancies with the exception of adequately treated non-melanoma skin cancer, or curatively treated other solid tumours with no evidence of disease for ≥ 2 years
• Patients with any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol