The purpose of this study is to evaluate whether sparing the hippocampi during whole brain radiotherapy following neurosurgery or stereotactic radiosurgery in patients with brain metastases from a systemic tumour helps preserve brain function.

Inclusion Criteria:

• Age ≥ 16 years

• Karnofsky Performance Status (KPS) ≥ 70

• Brain metastases from systemic malignancy which has been histologically confirmed (from the primary or any metastatic site)

• In total, at most 10 distinct brain metastases based on MRI imaging with contrast at any prior time-points

• Each of the brain metastases to have been treated by complete or incomplete surgical excision or by SRS in line with UK SRS commissioning guidelines which in addition for STS treated patients means:

  • Patient selection for SRS by the appropriate MDT(s),
  • No pressure symptoms which would be best relieved by surgery,
  • Life expectancy from extracranial disease greater than 6 months,
  • Gross tumour volume at time of SRS ≤ 20 cc.

• Ability to comply with the following timelines:

  • Randomisation 1 - 4 weeks (+/- 3 days, but only acceptable if accounting for logistical issues) after neurosurgery or last SRS fraction,
  • Start of WBRT or HS-WBRT 4 - 6 weeks (+ 3 days, but only acceptable if accounting for logistical or planning treatment issues) after neurosurgery or last SRS fraction.

• Ability to complete the NCF test battery (including ability to speak English).

• Willing and able to give consent and to comply with treatment and follow up schedule.

Exclusion Criteria:

• Metastases from small cell carcinoma from any site, haematological malignancy, or central nervous system malignancy,

• Leptomeningeal metastases,

• Contraindication to MRI imaging with contrast,

• Prior radiotherapy to the brain (apart from a single course of SRS for brain metastases completed within 1-4 weeks (+/- 3 days) of randomisation and within 4-6 weeks (+3 days) of start of the HIPPO trial treatment),

• Prior neurosurgery for brain metastases (apart from a single operation within 1-4 weeks (+/- 3 days) of randomisation and within 4-6 weeks (+3 days) of start of HIPPO trial treatment), except that one or more earlier operations not immediately preceding HIPPO trial entry will be allowed if:

  • there is no evidence of residual tumour at the resection site on contrast MRI imaging, or
  • residual tumour at the resection site has been treated by SRS immediately prior to entering the HIPPO trial,

• One or more metastases currently or previously within 5 mm of either hippocampus,

• One or more metastases within the brainstem,

• One or more SRS treated metastases in close proximity to critical normal organs, unless the local investigator is satisfied that the dose already received by the critical organ allows for subsequent delivery of the HIPPO protocol radiotherapy doses,

• Disease specific graded prognostic assessment (DS-GPA) score ≤ 1.0 for any of the histologies for which DS-GPA has been defined,

• Past medical history of dementia which is thought to be unrelated to the brain metastases,

• Women of childbearing potential who are known to be pregnant, or are unwilling to use an acceptable method of contraception from the time of informed consent until completion of the course of radiotherapy.