The N2 dilemma in stage III NSCLC: toward a quantitative framework for trial design

Stage III non-small-cell lung cancer (NSCLC) represents one of the most clinically and methodologically challenging entities in thoracic oncology, where anatomical staging, biological behavior, and treatment strategies intersect without full alignment. Despite substantial advances in multimodality therapy, including chemo-immunotherapy and refined surgical techniques, the field continues to face a fundamental limitation: the lack of a reproducible and universally accepted definition of mediastinal nodal disease, particularly N2 involvement. This misalignment is not merely conceptual but has direct consequences on trial validity and interpretability. Importantly, two distinct but interconnected sources of heterogeneity should be recognized. The first is biological heterogeneity, reflecting intrinsic differences in tumor biology, including molecular alterations, immune microenvironment, and treatment responsiveness. The second is measurement heterogeneity, resulting from variability in imaging acquisition, nodal staging techniques, interpretation, and reporting across institutions. While biological heterogeneity requires integration of biomarkers, measurement heterogeneity demands standardized quantitative assessment. The framework proposed here is intended to address both dimensions.The recent multisocietal effort led by the European Organization for Research and Treatment of Cancer (EORTC) represents a significant attempt to standardize the definition of technical resectability in stage III NSCLC [1]. This initiative is timely and necessary, given the increasing number of clinical trials exploring perioperative and multimodal strategies. However, while the consensus successfully frames resectability as a multidisciplinary, context-dependent decision, it also exposes, rather than resolves, the ambiguity surrounding N2 disease, which remains the central determinant of treatment allocation. Specifically, important aspects remain only partially operationalized, including the definition of bulky nodal disease, the distinction between single-and multi-station involvement, and the incorporation of functional imaging into resectability assessment.In contrast, contiguous and non-contiguous disease describe direct versus anatomically discontinuous mediastinal nodal spread. These unresolved issues inevitably leave room for interinstitutional variability. In this context, the present perspective should be interpreted as a complementary, operational extension of the EORTC framework, aimed at enhancing its applicability in clinical trial design rather than challenging its conceptual foundation. Indeed, N2 disease is widely recognized as a biologically and clinically heterogeneous condition, encompassing a spectrum of scenarios that differ substantially in prognosis and therapeutic implications [2]. The current classification into single-station, multi-station, bulky, and invasive disease reflects an attempt to capture this heterogeneity. Yet these categories lack precise, reproducible definitions. In particular, the concept of "bulky" N2 disease remains inconsistently defined, often relying on arbitrary size thresholds that have not been prospectively validated against biological aggressiveness, surgical complexity, or patient outcomes. Throughout this article, bulky disease refers to nodal disease with an extensive tumor volume likely to compromise complete surgical resection. This definitional imprecision extends beyond semantics and introduces important methodological challenges for trial validity. Eligibility criteria based on loosely defined nodal characteristics inevitably introduce misclassification bias, reduce inter-study comparability, and limit the external validity of trial results. In multicentre settings, variability in imaging interpretation, staging techniques, and institutional expertise further amplifies this problem, undermining the very objective of harmonization.Moreover, the persistent uncertainty surrounding multi-station N2 disease underscores the limitations of the current categorical approach. Divergences between expert opinion, survey responses, and real-world case assessments suggest that the existing framework is insufficiently granular [3]. As long as multi-station involvement is treated as a binary variable rather than a quantitative, spatial continuum, its integration into trial design will remain problematic.The reliance on multidisciplinary team (MDT) discussion as a compensatory mechanism, although clinically appropriate, introduces an additional layer of variability. MDT decisions are inherently influenced by local expertise, surgical philosophy, and institutional resources. For example, a patient with single-station, borderline bulky N2 disease on imaging may be considered resectable in a high-volume surgical center, while being directed toward definitive chemoradiotherapy in another institution with different expertise or thresholds. While this flexibility is essential in clinical practice, it conflicts with the need for reproducibility and standardization in research contexts. A framework that depends on subjective consensus cannot serve as a reproducible or auditable foundation for trial eligibility criteria. Rather than replacing multidisciplinary decision-making, quantitative tools should provide standardized, reproducible inputs to support MDT deliberations while preserving expert clinical judgment. Taken together, these limitations expose a structural inconsistency between clinical decision-making and trial design.These considerations suggest that the current paradigm for defining N2 disease is reaching its limits.A shift toward a more quantitative and biologically informed classification is needed. A pragmatic way forward would be to operationalise N2 disease using a composite, trial-ready framework integrating: (i) nodal burden (number of stations and absolute number of involved nodes), (ii) volumetric nodal assessment rather than diameter-based thresholds