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Life sciences · Journal article
Cancers · October 16, 2026
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Stage III/N2 non-small-cell lung cancer (NSCLC) can often be treated with either surgery-based multimodality therapy or definitive chemoradiotherapy. Historical randomized trials showed that surgery improved local control without demonstrating an overall-survival benefit; neither platform demonstrated superiority, although none was designed to establish equivalence. In the immunotherapy era, both pathways have improved through separate evidence streams: perioperative trials compared immunotherapy with chemotherapy-based surgical controls, and PACIFIC compared durvalumab with placebo after chemoradiotherapy. Neither stream determines which complete modern pathway is better for a patient eligible for both, and cross-trial comparisons are confounded by differences in populations, randomization points, and endpoint definitions. This review distinguishes three questions that are often conflated: whether direct comparative evidence exists, how large any relative treatment effect may be, and whether sufficient clinical equipoise exists to justify randomization. Technical resectability, physiological operability, and irradiability define eligibility for a platform, not comparative benefit, and no current biomarker has been shown to modify the relative effect of the two platforms. Comparative uncertainty is most visible in multistation, bulky, or anatomically complex N2 disease, the most practicable starting point for randomization; superiority of either platform, however, has not been demonstrated at either end of the N2 spectrum. A staged randomized comparison of the complete modern pathways, with prespecified analyses of candidate treatment-effect modifiers, is proposed as a reasoned research strategy.