Revisiting nature of stage III non-small cell lung cancer: Anatomically defined, biologically systemic.

Stage III non-small cell lung cancer (NSCLC) is traditionally viewed as a locally advanced disease based on anatomic imaging. It is increasingly recognized as a systemic illness with localized manifestations, as evidenced by high rates of distant recurrence despite aggressive local therapy. Recent landmark trials (e.g., ADAURA, ALINA, PACIFIC, and KEYNOTE 671) have demonstrated that prolonged systemic treatment, including adjuvant targeted therapy in oncogene-driven NSCLC and consolidation immune checkpoint inhibition after chemoradiotherapy, significantly improves survival outcomes. In contrast, intensifying local therapy alone has exhibited limited benefit or even potential harm. Supporting this shift, detection of circulating tumor DNA and circulating tumor cells indicates the presence of micrometastatic disease at the time of diagnosis. We propose an integrated "sandwich" therapeutic framework encompassing three sequential phases: 1) induction with biomarker-guided systemic therapy (e.g., targeted agents or chemoimmunotherapy) to control micrometastases; 2) local consolidation with surgery or radiotherapy tailored to the post-induction tumor extent; and 3) systemic consolidation with prolonged maintenance therapy to eradicate residual disease. This approach underscores the necessity of treating stage III NSCLC as a systemic disease from the outset, integrating prolonged, biomarker-directed systemic strategies within a multimodal curative-intent framework to address both the local and systemic components of the disease.