Patients with brain metastases with expected life expectancy of 3-6 months are typically treated with radiotherapy to the whole brain giving a dose of 20 Gy over a 5 day period. This study will compare this with volumetric modulated arc therapy (VMAT) which is capable of delivering 15 Gy in one single session to identified disease within the brain but sparing the normal surrounding brain tissue. Primarily the study will assess whether it is possible to recruit sufficient patient numbers to a trial of this type. It will also compare effectiveness, side effects and quality of life between the two treatment methods.

This is a Phase II prospective clinical trial. Pre treatment evaluations include estimation of life expectancy, Creatinine (GFR) and MRI brain with contrast. An assessment of cognitive function using Montreal Cognitive Assessment questionnaire, assessment of daily living activities using the Modified Barthel's index and quality of life assessment using EORTC QLQ-PAL-15 & BN-20 questionnaires will be performed in clinic. Karnofsky Performance Status will also be assessed by the clinician. If all assessments are within the eligibility criteria then the patient can be recruited. Before treatment begins a history documenting baseline symptoms using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 and a neurological examination documenting baseline deficits must be obtained.

If patient is randomized to standard treatment of whole brain radiotherapy (WBRT) then subjects will have a non-contrast CT scan using a slice thickness of 2.5 mm or less to plan radiotherapy. If patient are randomized to single fraction radiotherapy then a contrast CT will be used as this aids in identifying metastatic tumours within the brain. Also for the single fraction arm if a contrast-enhanced diagnostic MRI was obtained ≤ 10 days before the CT planning scan, with a single-plane high-resolution sequence or low-resolution sequences in two planes, it can be used for treatment planning. If the contrast-enhanced diagnostic MRI was obtained > 10 days before the CT planning scan or there is no diagnostic MRI, the subject requires a gadolinium-enhanced, high-resolution MRI sequence for fusion in the treatment planning system. During treatment, patients will have daily online cone beam CT scans to apply setup corrections to ensure treatment accuracy. To ensure minimal movement during radiotherapy all subjects will be immobilized lying on their back in a plastic headshell with an integrated bite block.

For subjects in the single-fraction arm that are not requiring steroids before radiotherapy, dexamethasone 8 mg 1 hour before the radiotherapy and for 5 days afterwards is required. For subjects in the single-fraction arm that are requiring corticosteroids for symptom management before radiotherapy, dexamethasone 8 mg before treatment and 8 mg 2 times daily for 2 days is required. Beginning three days after radiotherapy, a taper back to the pre-radiotherapy dose can be done swiftly over 4-6 days. However, for subjects who have been on dexamethasone for more than 2 weeks at this time point, slow tapering from the pre-radiotherapy dose using decrements of 0.5 - 2 mg every 3-5 days should be used to prevent a hypocortisolemia. For subjects in the 5-fraction arm, corticosteroids will be prescribed according to the preference of the treating radiation oncologist. Anti-sickness medication and steroids will be prescribed are required before each fraction in both arms.

Following therapy completion, all patients will be seen at 6 weeks, 3, 6, 9 and 12 months. At each visit history and neurological examination will be performed. Cognitive Function, Karnofsky Performance Status, Quality of life and Adverse Events will all be assessed and recorded. Activities of Daily Living and steroid use will be assessed by telephone consultation every 4 weeks (monthly) for 1 year. Steroid use will be confirmed by evaluating the pharmacy prescription database.

Patients will have contrast-enhanced MRI brain at every time point with a creatinine 1 week before each MRI to ensure safety of intravenous contrast administration. Steroid use will be recorded in a patient diary for first 6 weeks post treatment and monthly by telephone discussion.

Inclusion Criteria:

• Age ≥ 18
• Pathologically confirmed solid malignancy
• 1-10 brain or brainstem metastases on MRI with a maximum of 4 cm diameter
• Documented extracranial disease
• Anticipated median survival 3-6 months (Graded Prognostic Assessment: Appendix I)
• Available for regular clinical and imaging follow up (< 1 hour from a cancer centre)
• Montreal Cognitive Assessment score ≥ 20 (Appendix II)
• Karnofsky Performance Score (KPS) ≥ 70 (Appendix III)
• Barthel Activities of Daily Living score ≥ 90 (Appendix IV)
• Able to complete EORTC quality of life questionnaires (Appendix V)

Exclusion Criteria:

• A metastasis located within 5 mm of the optic nerves or optic chiasm
• Requiring craniotomy to relieve mass effect
• Cytotoxic systemic therapy administered within one week before radiotherapy or planned within one week after radiotherapy
• Neurological decline since starting corticosteroids
• Metastatic germinoma, small cell carcinoma, multiple myeloma, lymphoma or leukaemia
• Systemic lupus erythematosis, scleroderma, or other connective tissue disorders not in remission
• Multiple sclerosis
• Glomerular Filtration Rate < 45 ml/minute
• Contra-indications to MRI
• Pregnancy
• AST, ALT or Bilirubin > 3 times upper limit of normal
• Haemorrhagic Metastases