Clinical outcomes and treatment outcomes of stage IV large cell lung cancer based on two national database analysis

Background: Large cell lung cancer (LCLC) is an uncommon neuroendocrine subtype of non-small cell lung cancer with limited therapeutic options and poor prognosis. Evidence regarding survival patterns in stage IV LCLC, particularly across different treatment modalities, remains scarce. This study aimed to evaluate clinical characteristics, treatment patterns, and survival outcomes using two national cohorts. Methods: Patients with stage IV LCLC diagnosed between 2000 and 2021 were identified from the Surveillance, Epidemiology, and End Results Program (SEER) 17 registries. Eligible cases were stage IV LCLC according to the 7th or 8th TNM classification; demographic, clinicopathologic, socioeconomic, and available molecular data were collected. Kaplan-Meier analyses compared overall survival (OS) and cancer-specific survival (CSS) across treatment groups: no treatment, chemotherapy, and combined surgery plus chemotherapy. Cox proportional hazards models were used to identify independent predictors of CSS. In addition, publicly available data from the Korean National Health Insurance System (KNHIS) were analyzed to assess the impact of epidermal growth factor receptor (EGFR) mutation on survival. Results: A total of 3,478 patients were included. In the SEER cohort, 3-year OS differed substantially by treatment modality: 2.2% with no treatment, 7.1% with chemotherapy, and 13.3% with surgery plus chemotherapy. Similar trends were observed for CSS. In multivariable analysis, age >65 years (hazard ratio (HR) 1.16 [95% confidence interval (CI) 1.08-1.25], p<0.0001), male sex (HR 1.17[95% CI 1.09-1.26], p<0.0001), and low household income (HR 1.18[95% CI 1.08-1.30], p<0.0001) were independently associated with higher cancer-related mortality. Compared with chemotherapy alone, surgery combined with chemotherapy reduced mortality (HR 0.78[95% CI 0.70-0.87], p<0.0001). Among the KNHIS cohort, EGFR mutations were detected in 303 of 666 patients (45.5%); however, the presence of EGFR mutation did not confer a significant survival benefit among patients who received chemotherapy (HR 0.821 [95% CI 0.63-1.07], p=0.146). Conclusions: Despite the overall poor prognosis, treatment significantly influences outcomes in stage IV LCLC. Chemotherapy provides a clear survival benefit, and multimodal therapy that includes surgery offers the greatest improvement, potentially reflecting increased access to molecular testing and targeted therapy. Further investigation- including the potential benefits of tyrosine-kinase inhibitors in EGFR-mutated disease, systematic evaluation of other actionable mutations, and ongoing studies of immunotherapy after platinum-based regimens- is needed to define optimal management strategies for this rare subtype.