Radiation to Neurogenic Zones Worsens NSCLC Survival

Radiation-induced damage to specific sensitive areas of the brain, the subventricular zone (SVZ) and the subgranular zone (SGZ) within the hippocampus (HPC), may significantly shorten a patient’s life, according to a groundbreaking study out of University Medical Center Utrecht in the Netherlands.¹ These findings stem from an analysis of potential links between overall survival (OS), mean radiotherapy (RT) dose to the SVZ and HPC, and lesion contact among patients originally treated for non–small cell lung cancer (NSCLC) who developed brain metastases.

They published their results in Technical Innovations and Patient Support in Radiation Oncology, focusing on the SVZ because not much is known of its role in metastatic brain disease.

NSCLC is the most common type of lung cancer,² and brain metastases are a frequent complication, with estimates ranging from 10% to upwards of 30%.^3-5 The neural stem cells that are housed in the SVZ and SGZ play important roles in neurogenesis and brain repair mechanisms, the study authors note, as well as cognitive functioning (ie, learning and memory). They are also highly sensitive to radiation, with damage purportedly interfering with the brain’s recovery and brain metastases implicated in shortened patient survival depending on treatment history and actionable mutations. Primary treatment methods are localized RT or surgery plus RT.

Fifty percent of the patients were male and female, their median (IQR) age was 67 years (60-74), the most common World Health Organization performance status was 1 (62.3%), adenocarcinoma was the most common type of lung cancer (73.9%), and most did not know their mutation status for BRAF (69.6%), EGFR (56.5%), ALK (81.2%), HER2 (78.1%), or KRAS (73.2%). Unilateral vs bilateral tumor contact was more common (97% vs 3%), and median RT doses were 1.50 Gy (0.87-2.70) in the SVZ and 1.22 Gy (0.1-23) in the HPC.

Radiation-Induced Patient Survival

The investigators focused on patients treated with stereotactic radiosurgery at UMC Utrecht between December 2014 and April 2020 (N = 138). To investigate the potential links between unintended radiation delivered to the SVZ and HPC while the actual tumor was being targeted and OS in patients being treated for NSCLC, they used virtual brain grafting, a form of advanced MRI processing, to map the areas of the brain affected.

“Images were denoised, segmented, and as part of the processing pipeline, all MRIs, and subsequently all related elements, such as masks or dose distribution, were reoriented into a common stereotactic space using the standard MNI template, specifically the MNI152 6th‑generation nonlinear asymmetric version, without any resizing of the images,” they explained.

Their results were striking. Overall median OS from the start of RT to death was 8.4 months (range, 0.23-64.7) for the 107 patients who died. The patients with adenocarcinoma had an OS that was close to twice as long as the patients who had squamous cell carcinoma, at 9.6 vs 5.1 months, but still not considered a statistically significant advantage (HR, 1.23; 95% CI, 0.71-2.16; P .459).

Higher radiation doses to both the SVZ and HPC significantly reduced OS. Specifically, for every unit of Gy dose increase on the SVZ, the risk of death increased by close to 30% (HR, 1.306; 95% CI, 1.043-1.635; P = .019), and for every unit increase on the HPC, the risk of death rose by 22% (HR, 1.222; 95% CI, 1.008-1.483; P = .041).

The study authors also looked at outcomes from tumors that touched these zones, finding that patients with tumors that contacted the SVZ had a median OS of 5.7 months compared with 9.6 months (P = .019) seen among patients whose tumors were farther away. For patients with tumors that made contact with the HPC, their OS was even shorter, at 3.2 vs 8.6 months (P = .0257) for patients whose tumors were farther away.

As the authors noted, “Unintended RT 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.”

Multivariable Cox regression analyses also showed that SVZ and HPC contact were associated with significantly worse OS:

• SVZ: 97% (HR, 1.968; 95% CI, 1.094-3.542; P = .023)
• HPC: 475% (HR, 5.751; 95% CI, 1.733-19.07; P = .004)

Real-World Implications

The authors explain that their findings suggest the SVZ and HOC should be classified as “organs-at-risk,” with current RT planning primarily focused on tumor destruction and sparing major organs, such as the optic nerves and brainstem. With practical implications for future cancer care, the authors note that if radiation can be directed away from areas it is not meant to touch, patient cognitive functioning can be preserved and life potentially extended.

They also acknowledge technical challenges inherent in some cases: what if tumors are so close to these zones that sparing them is impossible without compromising the tumor treatment itself? Therefore, future studies should focus on dosimetric feasibility and evaluate how to avoid these areas of the brain in real-world clinical settings.

Limitations on their findings are that it was retrospective and focused on a relatively small patient population. New investigations need to be larger and prospective to confirm their findings and better understand the biological mechanisms at play.

References

1. Cialdella F, Bruil DE, van der Boog ATJ, et al. Decreased overall survival in patients with brain metastases from non-small cell lung cancer with radiotherapy dose on the neurogenic niches. Tech Innov Patient Support Radiat Oncol. 2026:37:100380. doi:10.1016/j.tipsro.2026.100380
2. Lung cancer types. Johns Hopkins Medicine. Accessed February 18, 2026. https://www.hopkinsmedicine.org/health/conditions-and-diseases/lung-cancer/lung-cancer-types
3. Solomon B. Brain metastases in non-small cell lung cancer. UpToDate. Updated November 11, 2025. Accessed February 18, 2026. https://www.uptodate.com/contents/brain-metastases-in-non-small-cell-lung-cancer/print
4. NSCLC and brain metastasis: understanding the hidden journey from lungs to brain. Boehringer Ingelheim. Accessed February 18, 2026. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/nsclc-and-brain-metastasis-understanding-hidden-journey-lungs-brain
5. Winslow N, Boyle J, Miller W, Wang Y, Geoffroy F, Tsung AJ. Development of brain metastases in non-small-cell lung cancer: high-risk features. CNS Oncol. 2024;13(1):2395804. doi:10.1080/20450907.2024.2395804