Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness.

Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, more than one- third of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis.

The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the result of phase III randomized trials suggested hippocampal avoidance plus Memantine significantly reduce the risk of neurocognitive impairment at 6 months from 68.2% in control arm with standard WBRT to 59.5% in experimental arm. In the investigator's prior investigation, patients received conformal WBRT with bilateral hippocampal avoidance also had significant less declines in verbal memory at 6 months.

Previous studies showed the right and left hippocampus exert different neurocognitive functions. Several retrospective studies also demonstrated that the radiation dose to the left hippocampus is more related to neurocognitive impairment. Planning study and investigation showed that by avoiding the left hippocampus alone, the radiation dose to the spared unilateral hippocampus is further decreased. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with bilateral or unilateral hippocampal avoidance and memantine.

Inclusion Criteria:

• Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
• Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration
• Patients with brain metastasis who have not been or will not be treated with SRS, or have received SRS for ≤ 5 intracranial metastatic lesion(s)
• No evidence of diffuse leptomeningeal metastasis on gadolinium- enhanced MRI within 30 days prior registration
• Age ≥ 20 years
• Karnofsky Performance Status ≥ 60%
• Life expectancy of ≥ 6 months.
• Women of childbearing potential and male participants must practice adequate contraception
• Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

Exclusion Criteria:

• Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3Gy to 40% of the volume of bilateral hippocampus from prior radiosurgery

• Serum creatinine > 2.0 mg/dL within 30 days prior registration

• Serum urea nitrogen > 20 mg/dL within 30 days prior registration

• Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia

• Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:

  1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
  2. Transmural myocardial infarction ≤ 6 months prior to registration
  3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
  4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
  5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
  6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  7. Uncontrolled psychiatric disorder

• Will receive any other investigational agent or chemotherapy during WBRT

• Current use of Memantine HCL or Allergy to Memantine HCL

• Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic

• Pregnant or breast-feeding women