• Cognitive function, specifically memory, from baseline to 24 weeks from the start of drug treatment as measured by the Hopkins Verbal Learning Test for delayed recall (HVLT-delayed recall)
  

• Decline in cognitive function, specifically memory, from baseline to 8 weeks, 16 weeks, and 12 months from the start of treatment as measured by the HVLT-delayed recall
  
• Neurocognitive failure as measured by a battery of tests
  
• Quality-of-life as measured by the Functional Assessment of Cancer Therapy Brain subscale (FACT-Br)
  
• Progression-free survival
  

OBJECTIVES:

Primary

• Determine whether the addition of memantine hydrochloride to whole-brain radiotherapy (WBRT) preserves cognitive function, specifically memory, as measured by the Hopkins Verbal Learning Test for delayed recall (HVLT-delayed recall), over that of placebo and WBRT in patients with brain metastases at 24 weeks from the start of drug treatment.

Secondary

• Determine whether the addition of memantine hydrochloride preserves cognitive function, specifically memory, as measured by the HVLT-delayed recall at 8 weeks, 16 weeks, and 12 months from the start of drug treatment.
• Determine whether the addition of memantine hydrochloride increases time to neurocognitive failure as measured by cognitive decline on a battery of tests including the HVLT for immediate recall, recognition, and delayed recall; the Controlled Word Association Test (COWAT); the Trail Making Test Parts A and B (TMT); the Medical Outcomes Scale-Cognitive Functioning Subscale (MOS); and the Mini-Mental Status Examination (MMSE).
• Evaluate the potential benefit of memantine hydrochloride in changing and overall quality of life, as measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) subscale.
• Determine whether the addition of memantine hydrochloride increases progression-free survival.
• Determine whether the addition of memantine hydrochloride increases overall survival.
• Compare adverse events between the treatment arms according to the CTCAE v3.0 criteria.
• Collect serum, plasma, buffy coat cells, urine, and CSF for future translational research analyses.

OUTLINE: This is a multicenter study. Patients are stratified according to recursive partitioning analysis (RPA) prognostic class (class I vs class II with controlled systemic disease) and prior surgical therapy (none vs radiosurgery or surgical resection). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) 5 days a week for 3 weeks (15 fractions). Patients also receive oral memantine hydrochloride once daily beginning on day 1 of WBRT and continuing for 24 weeks.
• Arm II: Patients undergo WBRT as in arm I. Patients also receive oral placebo once daily beginning on day 1 of WBRT and continuing for 24 weeks.

After completion of study treatment, patients are followed at 6 months, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of a solid tumor malignancy within the past 5 years

  • If the original histologic proof of malignancy is > 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)

• Brain metastases must be visible on contrast-enhanced MRI or a contrast enhanced CT scan (for patients unable to undergo MRI within the past 28 days)

  • Patients unable to undergo MRI imaging because of non-compatible devices are eligible, provided the contrast-enhanced CT scans are obtained and are of sufficient quality
  • Patients who had undergone radiosurgery or surgical resection and are planning adjuvant whole-brain radiotherapy do not have to have visible disease but do need a baseline MRI
• Must have stable systemic disease (i.e. no evidence of systemic disease progression within the past 3 months)
• Patients with brain metastases at initial presentation are eligible and do not need to demonstrate 3 months of stable scans

PATIENT CHARACTERISTICS:

Inclusion

• Karnofsky performance status 70-100%
• Creatinine ≤ 3 mg/dL and creatinine clearance ≥ 30 mL/min
• Total bilirubin ≤ 2.5 mg/dL
• BUN < 20 mg/dL
• Mini-mental status exam score > 18
• Negative serum pregnancy test
• Fertile patients must practice adequate contraception

Exclusion

• Severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Pregnant or lactating women
• Prior allergic reaction to memantine hydrochloride
• Current alcohol or drug abuse
• Intractable seizures while on adequate anticonvulsant therapy (i.e., more than one seizure per month for the past 2 months)

PRIOR CONCURRENT THERAPY:

Inclusion

• At least 14 days but no more than 56 days since prior therapy for brain metastasis, including radiosurgery and surgical resection
• No systemic chemotherapy for 14 days prior, during, or for 14 days after completion of whole-brain radiotherapy (WBRT)

Exclusion

• Prior cranial radiotherapy

  • Patients may have received up to 3 prior WBRT treatments and still be registered and randomized on the protocol provided WBRT parameters meet protocol requirements
• Chronic short-acting benzodiazepine use