The purpose of this study is to determine whether oral memantine daily for 6 months, when compared to
placebo, is associated with reduction in decline of cognitive function at 12 months in children ages 4-18
receiving cranial radiotherapy (RT) for primary central nervous system tumors and to correlate protective
effects of memantine with imaging biomarkers. Radiotherapy is a proven curative therapeutic tool in the
treatment of primary brain tumors. However, cranial RT results in significant cognitive morbidity. The
mechanisms of radiation-induced injury result in a picture that is a combination of the small vessel disease
seen with vascular dementia as well as neurodegenerative diseases like Alzheimer’s dementia. Ischemia
and injury can induce excessive NMDA stimulation and lead to excitotoxicity, and pre- clinical data suggests
that selective blocking of the NMDA receptor can restore long-term potentiation and restore learning in both
models of ischemia as well as models of radiation injury. Memantine is a non- competitive, low-affinity, open-
channel NMDA blocker, which has been shown to be neuroprotective in pre- clinical models. In two placebo-
controlled phase III trials, memantine proved to be effective treatment for Alzheimer’s and vascular
dementia, especially for patients with small-vessel disease. Memantine has also proven effective in reducing
cognitive dysfunction in adults receiving whole-brain radiotherapy for brain metastases. Memantine delayed
time to cognitive decline and reduced the rate of decline in memory, executive function and processing
speed. Importantly, cognitive function in patients receiving memantine remained stable even after
memantine was discontinued; suggesting memantine had a protective effect rather than simply a therapeutic
effect. In this study, we propose evaluating the efficacy of memantine in preventing cognitive dysfunction in
pediatric patients receiving cranial radiation through the clinical trial mechanism of the Children’s Oncology
Group. This study is novel in that children will undergo early cognitive evaluations (baseline prior to
radiation, 3, 6, and 12 months post-radiation) with a brief computerized testing battery that we will correlate
with formal cognitive testing as well with long-term cognitive function (30 and 60 months) assessed with both
methods. If successful, this study will provide validated early cognitive assessment time points that correlate
with late cognitive toxicity and result in an framework for accelerated study design that will allow for early
assessment of efficacy for future neuro-protectant trials. Dose- and volume-dependent reduction in brain
volume is seen after radiotherapy exposure and is associated with cognitive decline. We hypothesize that
neuroprotection with memantine will also preserve relevant brain volume and this will correlate with domain-
specific improvements in cognitive function. We will use quantitative volumetric MRI analysis to correlate
protective effects of memantine with brain substructure (white matter, hippocampus, frontal lobes etc) volume
changes over time and correlate with cognitive assessments. Radiographic analysis will provide proof-of-
principle for the mechanism of action of memantine as well as a biomarker that can be utilized in future trials
of radio-protectants, which is especially important for young patients or patients not neurologically capable of
completing cognitive assessments but who may benefit the most from neuroprotective interventions.
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