A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases
A Randomized Phase III Trial of Memantine and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Patients With Brain Metastases
This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy 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 radiotherapy (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 tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy 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.
PRIMARY OBJECTIVES:
I. Determine whether the addition of whole-brain radiotherapy 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 Tumor 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.
After completion of study treatment, patients are followed up at 12 months.
Inclusion Criteria:
PRIOR TO STEP 1 REGISTRATION:
PRIOR TO STEP 2 REGISTRATION:
Exclusion Criteria:
Prior external beam radiation therapy to the brain or whole brain radiation therapy
Planned cytotoxic chemotherapy during the WBRT only; patients may have had prior chemotherapy
Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt
Severe, active co-morbidity defined as follows:
Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
Prior allergic reaction to memantine (memantine hydrochloride)
Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine)
Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per month for the past 2 months
Patients with definitive leptomeningeal metastases
Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma
Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies
Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function
Current use of (other N-methyl D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan
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