Integrating Chinese herbal medicine in advanced lung cancer: A multicenter real-world study using target trial emulation

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, particularly in advanced stages. While Chinese herbal medicine (CHM) is often used as part of integrative treatment, its long-term impacts on stage IV NSCLC are not fully elucidated. Methods: This retrospective cohort study used a multi-institutional dataset from the Chang Gung Research Database with a target trial emulation design. Patients newly diagnosed with stage IV NSCLC between January 1, 2011, and December 31, 2021, were enrolled and followed for up to 10 years. Overall survival (OS) and cancer-specific survival (CSS) were estimated using Kaplan–Meier analysis with overlap weighting. Core CHMs and their biomedical pathways were explored through network pharmacology analysis. Results: A total of 6395 patients were analyzed, with approximately 18.1 % using CHM during treatment. Integrative CHM use was associated with more favorable outcomes, with higher 10-year OS rates (8.2 % vs. 3.4 % with overlap weighting; p-value < 0.001) and CSS rates (11.5 % vs. 4.4 % with overlap weighting; p-value < 0.001). Integrative CHM use with EGFR-TKI linked to the highest 10-year OS rate at 9.6 %. Core CHMs, including Hedyotis diffusa Willd., Morus alba l., QZJFT, Kochia scoparia (l.) Schrad. with Sophora flavescens Ait., were associated with reduced mortality risk, targeting metabolic and immune pathways. Conclusion: As the first study applying target trial emulation and network pharmacology analysis on real-world databases, this study highlights that integrative CHM, particularly alongside EGFR-TKI therapy, may have better outcomes in stage IV NSCLC patients, providing critical insights for clinical application and research.