Memantine for the Prevention of Radiation Induced Cognitive Dysfunction in Brain Metastatic Patients; A Randomized Placebo-Controlled Trial

Brain metastasis are the most common intracranial tumors in adults, accounting for significantly more than one-half of brain tumors. The incidence of brain metastasis may be increasing, due to both improved detection of small metastases by magnetic resonance imaging (MRI) and increased survival of patients with solid tumors.

The primary approaches to the treatment of brain metastasis include surgery and whole brain radiotherapy (WBRT). In WBRT, the entire brain and the brain stem are irradiated. With the improvement of technologies, new approaches like, stereotactic radiosurgery (SRS) and Hippocampal Avoidance whole brain radiotherapy (HA-WBRT) can be used to mitigate the normal tissue damage. However, neurocognitive impairments, including learning, memory, spatial processing and dementia is still persist in all type of radiation.

Around 50 to 90 % of individuals who receive brain irradiation exhibit cognitive decline which occurs mainly because of the accelerated atherosclerosis and mineralizing micro angiopathy in small vessels following radiation can lead to vascular insufficiency and the infarction ischemia caused by this vascular insufficiency leads to significant rise in the level of extracellular glutamate.

Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N Methyl D Aspartate (NMDA) receptor, which is involved in learning and memory. Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity and that contribute to the development of cognitive failure.If an agent that would preserve the cognitive functions of patients receiving radiotherapy, that will improve the quality of life of cancer survivors. One such pharmacological agent is memantine by blocking the effect of excessive levels of glutamate that could cause neuronal dysfunction

Memantine is an antagonist of NMDA type glutamate receptors (Approved for the treatment of Alzheimer’s), modulates neuronal transmission and synaptic plasticity which blocks the effect of excessive levels of glutamate that could cause neuronal dysfunction. For memantine few trials have been conducted so far to find out the effectiveness of such agent in preserving cognitive functions following brain irradiation. In a Randomized Control Trial (RTOG 0614), memantine was appeared to be well tolerated and showed a better cognitive function over time in Americans, although theP value for the primary endpoint of delayed recall at 24 weeks was borderline significant. This lack of significance was likely attributed to be the result of marked loss to follow up.

However, the almost significant findings would be beneficial in patients because cognitive decline causes a severe decline in the quality of life of these patients. The National Cancer Comprehensive Network’s(NCCN) consensus guidelines now include the use of memantine with WBRT as a result of the RTOG 0614 trial. No trails have been conducted so far to find out the role of memantine in SRS therapy and also effectiveness of such neuroprotective agent like memantine in all type of radiation therapy is poorly understood in Indian patients and neither studied so far.

Here in, first in India, initiating a placebo controlled randomized trial to evaluate the effectiveness of memantine in preserving cognitive functions following brain irradiation in Indian patients.