Modern Stereotactic Radiotherapy for Brain Metastases from Lung Cancer: Current Trends and Future Perspectives Based on Integrated Translational Approaches

Simple Summary In the current era of precision medicine, the management of patients with brain metastases (BMs) is rapidly evolving. The technical evolution of radiotherapy, now able to offer focal ablative treatments, in combination with new systemic target therapies, is changing the therapeutic landscape in this challenging clinical setting. Moreover, the emerging role of the tumor microenvironment in influencing the response to standard therapies is revealing new potential prognostic and predictive biomarkers for patients with BMs. In this review, we offer an overview of the current trends in the treatment of BMs from lung cancer, with a secondary focus on future perspectives based on integrated translational approaches.Abstract Brain metastases (BMs) represent the most frequent metastatic event in the course of lung cancer patients, occurring in approximately 50% of patients with non-small-cell lung cancer (NSCLC) and in up to 70% in patients with small-cell lung cancer (SCLC). Thus far, many advances have been made in the diagnostic and therapeutic procedures, allowing improvements in the prognosis of these patients. The modern approach relies on the integration of several factors, such as accurate histological and molecular profiling, comprehensive assessment of clinical parameters and precise definition of the extent of intracranial and extracranial disease involvement. The combination of these factors is pivotal to guide the multidisciplinary discussion and to offer the most appropriate treatment to these patients based on a personalized approach. Focal radiotherapy (RT), in all its modalities (radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), adjuvant stereotactic radiotherapy (aSRT)), is the cornerstone of BM management, either alone or in combination with surgery and systemic therapies. We review the modern therapeutic strategies available to treat lung cancer patients with brain involvement. This includes an accurate review of the different technical solutions which can be exploited to provide a "state-of-art" focal RT and also a detailed description of the systemic agents available as effective alternatives to SRS/SRT when a targetable molecular driver is present. In addition to the validated treatment options, we also discuss the future perspective for focal RT, based on emerging clinical reports (e.g., SRS for patients with many BMs from NSCLC or SRS for BMs from SCLC), together with a presentation of innovative and promising findings in translational research and the combination of novel targeted agents with SRS/SRT.