Challenges and Novel Opportunities of Radiation Therapy for Brain Metastases in Non-Small Cell Lung Cancer

Simple Summary Lung cancer is the most common primary malignancy that tends to metastasize to the brain. Owing to improved survival of lung cancer patients, the prevalence of brain metastases is a matter of growing concern. Brain radiotherapy remains the mainstay in the management of metastatic CNS disease. However, new targeted therapies such as the tyrosine kinase or immune checkpoint inhibitors have demonstrated intracranial activity and promising tumor response rates. Here, we review the current and emerging therapeutical strategies for brain metastases from non-small cell lung cancer, both brain-directed and systemic, as well as the uncertainties that may arise from their combination. Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.