This is an international multi-centre, open-label, randomized phase III trial comparing stereotactic radiosurgery (SRS) to whole brain radiotherapy (WBRT) in patients with 5 to 15 brain metastases.
• To compare the overall survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT.
• To compare the neurocognitive progression-free survival in patients with five to fifteen brain metastases who receive SRS compared to patients who receive WBRT.
Patient/treatment Related Secondary Outcomes
• To compare time to central nervous system (CNS) failure (local, distant, and leptomeningeal) in patients who receive SRS compared to patients who receive WBRT.
• To evaluate if there is any difference in CNS failure patterns (local, distant, or leptomeningeal) in patients who receive SRS compared to patients who receive WBRT.
• To evaluate number of salvage procedures following SRS in comparison to WBRT.
• To evaluate the individual cognitive test results following SRS in comparison to WBRT.
• To tabulate and descriptively compare the post-treatment adverse events associated with the interventions.
• To evaluate the time delay to (re-)initiation of systemic therapy in patients receiving SRS in comparison to WBRT.
• To prospectively validate a predictive nomogram for distant brain failure [Ayala-Peacock 2014].
• To compare the estimated cost of brain-related therapies in patients who receive SRS compared to patients who receive WBRT:
- Comparison based on payer rates (Medicare for US / provincial heath authorities in Canadian jurisdictions with activity-based funding).
Quality of Life Endpoints
• To evaluate patient’s quality of life, as assessed by the EORTC QLQ-C30 + BN20, EQ-5D, ECOG performance status, for those who receive SRS compared to those who receive WBRT.
• Collect plasma to evaluate whether detectable somatic mutations in liquid biopsy can enhance prediction of the overall survival and development of new brain metastases.
• Analysis of serum samples for inflammatory biomarker C-reactive protein and brain-derived-neurotrophic factor (BDNF) to elucidate molecular/genomic mechanisms of neurocognitive decline and associated radiographic changes.
• Collect whole-brain dosimetry in SRS patients to be prospectively correlated with cognitive toxicity, intracranial control and radiation necrosis (hippocampal dosimetry will be retrospectively assessed).
• Collect imaging parameters and workflow details relating to the radiosurgery planning MRIs (including timing of MR prior to radiosurgery, magnet field strength, contrast type/dose/timing, use of image post-processing, and formal reviewed by radiology) to be prospectively correlated with tumour control outcomes (local control, intracranial control).
• Evaluate serial changes in imaging features found in routine MRI images (T2w changes, morphometry) that may predict tumour control and/or neurocognitive outcomes