Hippocampal Sparing Whole Brain Radiotherapy vs Conventional Whole Brain Radiotherapy in Patients With Brain Metastases

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1-10 Brain Metastases

Conditions
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Brain Metastases

Intervention / Treatment
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* Radiation: Hippocampal sparing whole brain radiotherapy
* Radiation: Conventional whole brain radiotherapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hippocampal sparing whole brain RT<br>30 Gy in 10 fractions hippocampal sparing whole brain radiotherapy will be administered by Helical Tomotherapy, IMRT, or VMAT | Radiation: Hippocampal sparing whole brain radiotherapy<br>* 30 Gy in 10 fractions hippocampal sparing whole brain radiotherapy will be administered by Helical Tomotherapy, IMRT, or VMAT<br>|
| Active Comparator: Control: Conventional whole brain RT<br>30 Gy in 10 fractions conventional whole brain radiotherapy will be administered | Radiation: Conventional whole brain radiotherapy<br>* 30 Gy in 10 fractions conventional whole brain radiotherapy will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total recall assessed using Hopkins Verbal Learning Test-Revised (HVTLR) at 4 months | A decline in total recall will be assessed as being clinically significant if there is at least a 5 point decrease in total recall score at 4 months, compared to baseline [Jacobson 1991, Brandt 1998] | 4 months after completion of WBRT or HS-WBRT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurocognitive function | NCF, using a 30-60 min test battery (Memory - HVLT-R, Wechsler Memory Scale (logical memory subtest), Rey figure test, Wechsler digit span; Attention - Test of Everyday Attention (map search subtest), Trail Making Test (Parts A and B); Language - Graded Naming Test); this may be revised in the light of forthcoming recommendations on NCF assessment in brain metastases trials by the RANO (Revised Assessment in Neuro-oncology) working party | 2, 4, 6, 12 and 24 months after completion of WBRT or HS-WBRT | 
| Quality of life | Quality of life will be assessed using EORTC QLQ C30 and BN20 and EuroQol EQ-5D questionnaires | 2, 4, 6, 9, 12, 18 and 24 months after completion of WBRT or HS-WBRT | 
| Length of time functionally independent | The duration of functional independence will be assessed as the time for which the Karnofsky Performance Status ≥ 70 | 2, 4, 6, 9, 12, 18 and 24 months after completion of WBRT or HS-WBRT | 
| Local control of surgery/SRS treated metastases, local and distant intracranial control (treated and new metastases), and disease control within the hippocampal regions | Incidence of metastases within the perihippocampal region, local control, and intracranial control will be assessed on the basis of MRI imaging | 2, 4, 6, 9, 12, 18 and 24 months after completion of WBRT or HS-WBRT | 
| Overall survival | Date of death will be determined from the medical records, or from the GP | followed up until 24 months after completion of WBRT or HS-WBRT | 
| Steroid and antiepileptic medication requirements | Steroid and antiepileptic medication use will be recorded in patient diaries and assessed at clinic visits | 2, 4, 6, 9, 12, 18 and 24 months after completion of WBRT or HS-WBRT | 
| Acute and late side effects of radiotherapy | Acute and late side effects of radiotherapy will be assessed using NCI CTCAE scale v4.03 | 2, 4, 6, 9, 12, 18 and 24 months after completion of WBRT or HS-WBRT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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whole brain RT, hippocampal sparing, neurocognitive function