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

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION:

• Brain metastases outside a 5-mm margin around either hippocampus must bevisible on contrast-enhanced magnetic resonance imaging (MRI) performed =< 21days prior to Step 1 registration; an allowed exception, regarding ability toimage brain metastases, would be that patients who had undergone radiosurgeryor surgical resection and are planning adjuvant WBRT do not have to havevisible disease but do need a pre-surgery MRI or computed tomography (CT) scandemonstrating brain metastases; however, the brain metastases could not havebeen within 5 mm of either hippocampus

• Patients must have a gadolinium contrast-enhanced three-dimensional spoiledgradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbofield echo (TFE) axial MRI scan with standard axial and coronal gadoliniumcontrast-enhanced T1-weighted sequence and axial T2/FLAIR sequenceacquisitions; to yield acceptable image quality, the gadoliniumcontrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan shoulduse the smallest possible axial slice thickness not exceeding 1.5 mm; theassociated coronal and sagittal contrast-enhanced T1 sequences can be up to 2.5mm in slice thickness; this MRI must be obtained =< 21 days prior to step 1registration; the vendor specific MRI protocols are available for download fromthe Alzheimer's Disease Neuroimaging Initiative (ADNI)

• Patients must provide study-specific informed consent prior to registration

• PRIOR TO STEP 2 REGISTRATION:

• The following baseline neurocognitive assessments must be completed prior toStep 2 registration: HVLT-R, TMT, and COWA;

• Pathologically (histologically or cytologically) proven diagnosis of solidtumor malignancy within 5 years prior to Step 2 registration

• History and physical examination within 28 days prior to Step 2 registration

• Karnofsky performance status of >= 70 within 28 days prior to Step 2registration

• Serum creatinine =< 3 mg/dL (265 umol/L) and creatinine clearance >= 30 ml/min

• Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. < 20mg/dL)

• Total bilirubin =< 2.5 mg/dL (43 umol/L)

• Patients may have had prior therapy for brain metastasis, includingradiosurgery and surgical resection; patients must have completed prior therapyby at least 14 days prior to Step 2 for surgical resection and 7 days forradiosurgery

• Negative serum pregnancy test (in women of childbearing potential) =< 14 daysprior to Step 2; women of childbearing potential and men who are sexuallyactive must practice adequate contraception while on study

• Patients who are primary English or French speakers are eligible

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 priorchemotherapy

• Radiographic evidence of hydrocephalus or other architectural distortion of theventricular system, including placement of external ventricular drain orventriculoperitoneal shunt

• Severe, active co-morbidity defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Chronic obstructive pulmonary disease exacerbation or other acute respiratoryillness precluding study therapy at the time of registration

• Severe hepatic disease defined as a diagnosis of Child-Pugh class B or Chepatic disease

• Renal tubular acidosis or metabolic acidosis

• Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive areeligible, provided they are under treatment with highly active antiretroviraltherapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 daysprior to registration; Note also that HIV testing is not required foreligibility for this protocol

• Pregnant or lactating women, or women of childbearing potential and men who aresexually active and not willing/able to use medically acceptable forms ofcontraception

• 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 seizureper 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 devicesor foreign bodies

• Contraindication to gadolinium contrast administration during MR imaging, such asallergy or insufficient renal function

• Current use of (other N-methyl D-aspartate [NMDA] antagonists) amantadine, ketamine,or dextromethorphan