AbstractBackgroundDiagnosing and treating synchronous multiple primary lung cancers (sMPLC) are complex and challenging. This study aimed to report real‐world data on the comprehensive diagnosis and treatment of patients with early‐stage sMPLC.Materials and MethodsA single‐center cohort study was carried out and a large number of patients with early‐stage sMPLC were included. A single‐ or two‐stage surgery was performed to remove the primary and co‐existing lesions. The “X” strategies, including ablation, SBRT, and EGFR‐TKIs treatment, were applied to treat the high‐risk residual lesions. Wide panel‐genomic sequencing was performed to assess the genetic heterogeneity of the co‐existing lesions.ResultsA total of 465 early‐stage sMPLC patients with 1198 resected lesions were included. Despite most patients being histologically different or harboring different genetic alternations, about 7.5% of the patients had the same histological type and driver gene mutation changes, comprehensive re‐evaluation is thus needed. The “Surgery + X” strategy showed remarkable efficacy and safety in treating multiple lesions. Follow‐up data revealed that the T2 stage (p= 0.014) and the solid presence of a primary lesion (p< 0.001) were significantly related to tumor recurrence. And a T2‐stage primary tumor had a significantly higher rate of developing new lesions after the initial surgery (p< 0.001).ConclusionsIn real‐world practice, histopathological and radiological evaluation combined with genetic analyses could be a robust diagnostic approach for sMPLC. The “Surgery + X” treatment strategy showed remarkable efficacy, superiority, and safety in the clinical treatment of early‐stage sMPLC.