Thoracic Cancer · Published 2026-07-01 · DOI 10.1111/1759-7714.70359
Anand Shah, Pranav Gwalani, Merry Zhai, Ritik Goyal, Joshua Kra
ABSTRACT Background The optimal sequencing of brain‐directed radiation and systemic therapy in stage IV non–small cell lung cancer (NSCLC) with brain metastases remains uncertain in the era of CNS‐active systemic agents. We evaluated survival outcomes using national real‐world data. Methods We conducted a retrospective cohort study of adults diagnosed between 2010 and 2022 with stage IV NSCLC and brain metastases in the National Cancer Database who received both brain‐directed radiation and systemic therapy. Treatment sequence was classified as radiation‐first or systemic‐first based on initiation dates. Multivariable Cox proportional hazards models, stratified by treatment era (pre‐2015 vs. 2015+), assessed associations with overall survival (OS), adjusting for demographic, clinical, tumor, and treatment factors. Propensity score matching and delayed‐entry sensitivity analyses were performed to address confounding and immortal time bias. Results Among 45 577 patients, 78.3% received radiation‐first and 21.7% received systemic therapy first. Unadjusted Kaplan–Meier analysis showed no significant difference in OS (log‐rank p = 0.624). In multivariable analysis, systemic‐first sequencing was associated with a modest increase in mortality (adjusted hazard ratio [aHR] 1.06; 95% CI: 1.04–1.09), which was consistent in propensity‐matched (HR 1.07; 95% CI: 1.04–1.11) and delayed‐entry analyses (aHR 1.09; 95% CI: 1.07–1.12). The use of systemic‐first therapy increased over time. Established prognostic factors demonstrated larger effect sizes. Conclusion Systemic‐first sequencing was associated with a modest increase in adjusted mortality; however, the effect size was small relative to established prognostic factors and likely influenced by residual confounding and selection bias. These findings support individualized, multidisciplinary treatment decisions rather than a uniform sequencing strategy.
Abstract from DOAJ. Public domain (CC0 1.0).
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Shah, A., Gwalani, P., Zhai, M., et al. (2026). Association Between Treatment Sequencing and Overall Survival in Stage IV NSCLC With Brain Metastases: A National Cancer Database Study. Thoracic Cancer. https://doi.org/10.1111/1759-7714.70359