Decreased overall survival in patients with brain metastases from non-small cell lung cancer with radiotherapy dose on the neurogenic niches

Background: Non-small cell lung cancer (NSCLC), the most common type of lung cancer frequently leads to brain metastases (BMs), which are associated with a poor prognosis. Radiotherapy is the main treatment for BMs, but irradiates healthy tissue, including neural stem cells (NSCs). NSCs reside in neurogenic niches, mainly the subventricular zone (SVZ) and the subgranular zone (SGZ) within the hippocampus (HPC), which support neurogenesis and brain repair. Radiation damage to NSCs may influence overall survival (OS). Our study aims to evaluate the impact of any radiotherapy dose on NSCs on OS in patients with BMs from NSCLC, with lesion contact explored as a secondary aim. Methods: We retrospectively included 138 NSCLC patients with BMs and delineated NSC regions on T1 MR-images. Kaplan-Meier (KM) analysis and Cox regression assessed associations between OS, mean radiotherapy dose to SVZ and HPC, and lesion contact. Results: Higher radiotherapy dose on the SVZ and HPC were significantly associated with reduced OS, with a hazard ratio (HR) of 1.306 ([95% CI 1.043-1.635], p = 0.019) and 1.222 ([95% CI 1.008-1.483], p = 0.041), respectively. Lesion contact with neurogenic niches was also independently significant (SVZ: HR 1.968 [95% CI 1.094-3.542], p = 0.023 and HPC: HR 5.751 [95% CI 1.733-19.07], p = 0.004), although lesion contact was uncommon. Conclusion: Unintended radiotherapy dose to neurogenic niches is independently associated with worse OS in NSCLC patients with brain metastases, and tumor contact with these regions also shows an adverse association. These findings support considering the SVZ and hippocampus as organs-at-risk in SRS planning and motivate prospective validation in larger, controlled cohorts.