Abstract Purpose Surgical resection (SR) and Stereotactic Body Radiation Therapy (SBRT) are established treatment modalities for early-stage non-small cell lung cancer (NSCLC). Although randomized trials have not confirmed equivalent efficacy, real-world comparative data, particularly including minimally invasive surgery (MIS), remain limited. This study evaluates mortality and complication outcomes of SBRT versus SR and MIS using a large, real-world dataset. Methods A retrospective cohort analysis was conducted using the TriNetX U.S. Collaborative Network. Patients with Stage I or II NSCLC who underwent SBRT or SR were identified, excluding small cell cases. A third cohort undergoing MIS, including segmentectomy, was analyzed separately. Outcomes were followed for 5 years post-treatment, focusing on complication rates and overall survival. Propensity score matching was performed across cohorts. Statistical analyses included Kaplan-Meier survival curves, Odds Ratios (OR), Hazard Ratios (HR), and Cox proportional hazards modeling. Descriptive statistics summarized categorical variables, and p 0.05 denoted statistical significance. Results After matching, 32,993 patients were included in both the SBRT and SR groups, and 31,101 in the MIS cohort. The median age was 69 years, with 48% male. The overall complication rate was slightly higher for SR (13%) versus SBRT (12%) OR 0.89. Common SBRT-related complications included radiation pneumonitis (7%), pulmonary fibrosis (9%), chest wall pain (14%), esophagitis (1.2%), and radiation sickness (2.2%). SR complications included persistent air leak (3.2%), pneumothorax (6.4%), post-thoracotomy pain (5%), and surgical site infection (0.1%).Median survival for SBRT was 1,236 days compared with 1,800 days for SR, corresponding to 5-year survival rates of 40% and 65%, respectively HR 2.2, p 0.0001. In the MIS subgroup, complication rates were lower (8%) than with SBRT (11%) OR 1.3, and median survival reached 2,123 days. Five-year survival was 73% for MIS versus 40% for SBRT HR 3.3, p 0.0001. Cox regression identified DLCO 40 cm³/min/mmHg HR 1.5 and ECOG 2 HR 6.7 as strong predictors of 5-year mortality (both p 0.0001). Conclusions (1) SR is associated with slightly more complications than SBRT, but MIS demonstrates the lowest morbidity. (2) Five-year survival is significantly higher for SR and MIS compared with SBRT. (3) Reduced DLCO and poor performance status strongly predict mortality and should guide treatment selection. Clinical Implications: While SBRT remains a suitable alternative for nonsurgical candidates, SR, particularly MIS offers superior long-term survival with acceptable complication rates. Careful patient selection based on pulmonary function and comorbidities is essential in early-stage NSCLC management. This abstract is funded by: NONE
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