Neurocognitive Dysfunction in Brain Tumor Patients following Radiation Therapy: A Review of Biological Hypotheses, Current Treatment Outcomes, and Novel Therapeutic Strategies

Given the difficulty of surgical resection of brain neoplasms located adjacent to vital structures of the brain as well as the challenges posed by the blood-brain-barrier for the efficacy of chemotherapeutic agents, whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are often turned to for patients with brain metastases as well as primary brain neoplasms. Though radiation therapy may be successful in local control of these tumors, many patients experience treatment-related neurocognitive issues, later in life. In this review, we examine cognitive dysfunction in brain tumor patients following radiation therapy, with an emphasis on the pediatric population. Articles were found using NCBI’s PubMed and relevant search terms. We first review the hypotheses regarding the biological mechanisms underlying these neurologic manifestations such as neuroinflammation, extracellular matrix disruption, and inhibition of angiogenesis. Cognitive defects and related effects on health-related quality of life in brain tumor patients treated with radiotherapy are then discussed. We also address novel treatment strategies aimed at minimizing neurocognitive delays such as hippocampal-sparing radiotherapy planning, intensive chemotherapy regimens, and the growing field of proton therapy. Possible molecular therapeutic targets are discussed as well as preclinical studies examining human embryonic and neural stem cell transplantations. Finally, we examine the role of aerobic exercise, multidisciplinary rehabilitation, and other interventions that may help to curb the negative effects of radiotherapy on cognitive development and function.