Stereotactic Radiosurgery or Hippocampus Avoidance Whole-Brain Radiation Therapy with Memantine in Treating Patients with 5 or more Brain Metastases

Inclusion Criteria

• Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained =< 30 days from randomization
• Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy
• The largest brain metastasis must measure < 2.5 cm in maximal diameter * The total tumor volume must be 30 cm^3 or less; lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2); alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume
• Center must have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a center at which the trial is open which can treat with using one of these systems
• Patient must be >= 18 years of age
• Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance; the baseline assessment must be completed within required timelines, prior to randomization * Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions; patients must be fluent in English or French, and fully testable in one of those languages * A patient that is able but unwilling to complete the questionnaires will be considered ineligible
• ECOG performance status 0, 1, or 2
• Creatinine clearance must be >= 30 ml/min within 28 days prior to registration
• The neurocognitive testing examiner must have credentialing confirming completion of the neurocognitive testing training
• The enrolling facility is credentialed by Imaging and Radiation Oncology Core (IROC) to perform SRS and HA-WBRT - or have access to a center where these treatments are credentialed and the study is open; the treating center must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients; the treating center must have completed intensity-modulated radiation therapy (IMRT) credentialing of the specific IMRT system(s) to be used in study patients for the purposes of HA-WBRT
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements; each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate * A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures
• Patients must be accessible for treatment and follow-up; investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
• In accordance with Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 14 days of patient enrollment
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method; a woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy / vasectomized partner; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected; for example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers; patient will be considered eligible if an ultrasound is negative for pregnancy

Exclusion Criteria

• Pregnant or nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception
• Inability to complete a brain MRI
• Known allergy to gadolinium
• Prior cranial radiation therapy
• Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT
• Primary germ cell tumor, small cell carcinoma, or lymphoma
• Widespread definitive leptomeningeal metastasis; this includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumor cells
• A brain metastasis that is located =< 5 mm of the optic chiasm or either optic nerve
• Surgical resection of a brain metastasis (stereotactic biopsies will be allowed)
• Prior allergic reaction to memantine, or hypersensitivity to any excipients of memantine
• Current alcohol or drug abuse
• Current use of N-methyl-D-aspartate (NMDA) antagonists, such as amantadine, ketamine, or dextromethorphan
• Diagnosis of chronic liver disease / cirrhosis of the liver (e.g. Child-Pugh class B or C)
• Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e. unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension)
• Current active or uncontrolled urinary tract infections (UTI)
• History of epilepsy or seizures, and not currently taking anti-epileptic medication
• Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines
• Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging