Memantine Hydrochloride and Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases

Official Title

A Randomized Phase III Trial of Memantine and Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Patients With Brain Metastases

Summary:

This randomized phase III trial compares memantine hydrochloride and whole-brain radiation therapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiation therapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumour cells and shrink tumours. Using radiation techniques, such as intensity modulated radiation therapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.

Trial Description

Primary Outcome:

  • Time to neurocognitive failure, as measured by neurocognitive decline on HVLT-R, COWA, and TMT Parts A and B
Secondary Outcome:
  • Health outcomes, as measured by the EQ-5D-5L
  • Incidence of adverse events (AE) as measured by CTCAE v4.0
  • Intracranial progression defined as progression in the brain or death
  • Overall survival
  • Preservation of neurocognitive function, as measured by neurocognitive decline on HVLT-R, COWA, and TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP) score
  • Symptom burden, as measured by the MDASI-BT
  • Time to intracranial progression
PRIMARY OBJECTIVES:
I. Determine whether the addition of whole-brain radiation therapy with hippocampal avoidance (HA-WBRT) increases time to neurocognitive failure at months 2, 4, 6, and 12 as measured by neurocognitive decline on a battery of tests: the Hopkins Verbal Learning Test-Revised (HVLT-R) for Total Recall, Delayed Recall, and Delayed Recognition, Controlled Oral Word Association (COWA), and the Trail Making Test (TMT) Parts A and B. SECONDARY OBJECTIVES:
I. Determine whether the addition of HA-WBRT preserves neurocognitive function at months 2, 4, 6, and 12 as separately measured by each test, the HVLT-R for Total Recall, Delayed Recall, and Delayed Recognition; COWA; and TMT Parts A and B. II. Evaluate the potential benefit of HA-WBRT in symptom burden, as measured by the M. D. Anderson Symptom Inventory-Brain Tumour Module (MDASI-BT). III. Assessment of quality adjusted survival and cost analysis using the five-level version of the EuroQol five-dimensional (EQ-5D-5L). IV. Compare cumulative incidence of progression and overall survival after WBRT versus HA-WBRT. V. Compare adverse events between the treatment arms according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 criteria. TERTIARY OBJECTIVES:
I. Collect serum, plasma, and imaging studies for future translational research analyses. II. Evaluate magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry at baseline and 6 months as potential predictors of neurocognitive decline and differential benefit from HA-WBRT as compared to WBRT. III. Association of symptom burden and anxiety/depression with neurocognitive function. IV. Evaluate the potential correlation between the prognostic scoring systems Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) and the diagnosis-specific graded prognostic assessment (DS-GPA) and neurocognitive function at baseline and overtime. OUTLINE:

Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for 24 weeks. Patients undergo WBRT daily over approximately 2 weeks (10 fractions). ARM II: Patients receive memantine hydrochloride as in Arm I. Patients undergo HA-WBRT using intensity modulated radiation therapy (IMRT) daily over approximately 2 weeks (10 fractions). After completion of study treatment, patients are followed up at 12 months.

View this trial on ClinicalTrials.gov

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Resources

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