Unmasking the Survival Disparity Between Large-Cell Neuroendocrine Carcinoma and Small-Cell Lung Cancer: A SEER Analysis

Background : Large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both high-grade neuroendocrine carcinomas of the lung. While SCLC has well-established treatment protocols, LCNEC remains poorly defined in clinical guidelines, leading to variability in management. Prior studies comparing their survival outcomes have yielded conflicting results, often limited by inadequate adjustment for confounders and lack of time-dependent modeling. Methods : Using the SEER database (2000–2021), we conducted a retrospective cohort study of 26,930 patients with histologically confirmed SCLC or LCNEC. Patients with stage IV disease or incomplete clinical data were excluded. Propensity score matching (PSM) was performed 1:1 based on age, sex, race, tumor stage (T/N), treatment modalities (chemotherapy, surgery, radiotherapy), and year of diagnosis. Survival was analyzed using Kaplan-Meier curves, Cox proportional hazards models, and time-dependent Cox regression incorporating histology*time interaction. Results : In the unmatched cohort, LCNEC was associated with significantly worse overall survival (OS) compared to SCLC (HR = 1.31; 95% CI, 1.23–1.39; p  < 0.0001). After PSM (n = 1898 per group), survival curves remained separated in Kaplan-Meier analysis ( p  < 0.0001). However, in the adjusted Cox model, LCNEC became associated with better OS (HR = 0.82; 95% CI, 0.73–0.93; p  = 0.0024). Time-dependent Cox analysis revealed a significant cancer type x time interaction (HRinteraction = 0.74; p  < 0.0001), indicating that the survival gap narrowed over time. Compared to patients who did not receive chemotherapy, chemotherapy was associated with improved OS (HR = 0.70); compared to no surgery, surgery was associated with improved OS (HR = 0.36); and compared to no radiotherapy, radiotherapy was associated with improved OS (HR = 0.62). Conclusions : The observed survival disadvantage of LCNEC in unadjusted analysis was largely driven by differences in stage and treatment. After rigorous adjustment and matching, LCNEC exhibited survival outcomes comparable to SCLC. These findings support managing LCNEC with SCLC-based treatment protocols and suggest that treatment disparities—not intrinsic tumor biology—are the primary drivers of prognosis.