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2B or Not 2B: Multiple Positive Nodal Stations, Regardless of Location, Are Associated with Worse Overall and Disease-Free Survival in Clinical Stage I Non-Small Cell Lung Cancer
Nahom Seyoum1, Daniel B. Eaton2, Nikki E. Rossetti1, Martin W. Schoen2, Theodore S. Thomas2, Su-Hsin Chang3, Yan Yan3, Mayank Patel2, Ana A. Baumann Walker3, Daniel Kreisel1, Bryan F. Meyers1, Benjamin D. Kozower1, Brendan T. Heiden1, Varun Puri1, Whitney Brandt
1Department of Surgery, Division of Cardiothoracic Surgery, Washington University in St Louis School of Medicine, St. Louis, MO, 2Veterans Affairs St. Louis Health Care System, Saint Louis, MO, 3Department of Public Health, Washington University in St Louis School of Medicine, St. Louis, MO
Background: Multiple prior studies have demonstrated worse survival among patients with multistation N2 non-small cell lung cancer (NSCLC). Accordingly, the American Joint Commission on Cancer 9th edition revised nodal staging to distinguish single-station (N2a) from multistation (N2b) disease. However, it remains unclear whether involvement of multiple nodal levels, regardless of anatomic location, reflects increased metastatic burden and, consequently, worse survival in patients with NSCLC. We aimed to address this knowledge gap by comparing overall survival (OS) and disease-free survival (DFS) across patterns of nodal involvement following curative-intent resection.
Methods: We conducted a retrospective cohort study of Veterans with clinical stage I (cStage I) NSCLC who underwent curative-intent surgical resection between 2006 and 2020. Inclusion required pathologic evaluation of at least one hilar/intrapulmonary (N1) and one mediastinal (N2) nodal station. Patients who underwent neoadjuvant therapy were excluded. Follow-up was available through January 15, 2025. Patients were classified into five groups based on pathologic nodal involvement: single-station N1, single-station N2, concurrent N1 and N2 positivity, multistation N1, and multistation N2 disease. OS and DFS were estimated using Kaplan-Meier methods.
An adjusted analysis was then performed among pathologically upstaged patients. Nodal involvement was collapsed into three burden-based categories based on 5-year OS rates from the univariable analysis: single-station nodal disease (one positive N1 or one positive N2 station), combined N1-N2 disease (one positive N1 and one positive N2 station), and multistation nodal disease (>1 positive N1/N2 station). Multivariable Cox regression was used to estimate adjusted hazard ratios (aHRs) for OS and DFS.
Results: Of the 7,296 Veterans with cStage I NSCLC included, 6,663 (91.3%) had no pathologic nodal involvement, while 633 (8.7%) had at least one positive lymph node (Table 1). Among upstaged patients, 370 (5.1%) had single-station N1 disease, 95 (1.3%) had single-station N2 disease, and 69 (1.0%) had concurrent single-station N1 and N2 involvement. Multistation nodal disease was less common, with 58 (0.8%) demonstrating multistation N1 disease and 41 (0.6%) multistation N2 disease. Patients with N2 involvement were more likely to receive adjuvant therapy (42.1% with single-station N2 disease and 39.0% with multistation N2 disease) compared with patients with single-station N1 disease (32.7%), concurrent N1 and N2 disease (27.5%), or multistation N1 disease (31.0%).
On univariable analysis, 5-year OS was highest among patients with single-station N1 (49.2%) and single-station N2 disease (48.4%), intermediate among those with concurrent N1/N2 involvement (30.4%) or multistation N1 disease (27.4%), and lowest among those with multistation N2 disease (18.8%) (p < 0.0001) (Figure 1a). A similar graded pattern was observed for DFS, with 5-year DFS of 34.0%, 27.3%, 20.3%, 12.5%, and 9.8%, respectively (p < 0.0001) (Figure 1b).
After multivariable adjustment for age, extent of resection, pathologic characteristics, and receipt of adjuvant therapy, combined N1-N2 disease was associated with significantly worse OS (aHR 1.70, 95% CI 1.27-2.28) and DFS (aHR 1.92, 95% CI 1.45-2.53), as was multistation nodal disease (OS: aHR 1.62, 95% CI 1.29-2.03; DFS: aHR 1.59, 95% CI 1.28-1.97). Receipt of adjuvant therapy was not independently associated with either outcome on multivariable analysis.
Conclusion: Among patients with clinical stage I NSCLC, survival outcomes were strongly associated with the number of positive lymph node stations, independent of receipt of adjuvant therapy. If validated, these findings suggest that upstaging of patients with multistation nodal involvement, regardless of nodal level, may be warranted.
Figure 1: Overall and Disease-Free Survival by Pattern of Pathologic Nodal Involvement in Clinical Stage I NSCLC
Table 1: Baseline Clinicodemographic and Tumor Characteristics by Pattern of Pathologic Nodal Involvement
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