Survival benefits in non-small cell lung cancer during the immune checkpoint inhibitor era: integrating lymph node
Yuntao Feng1, Qijue Lu2, Yichen Dong1
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Background:
Lung cancer remains a global health challenge, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Since 2015, immunotherapy, specifically immune checkpoint inhibitors (ICIs), has significantly shifted treatment paradigms in advanced NSCLC, yet the prognostic role of lymph node metastatic burden remains underexplored. This study evaluates the survival benefit associated with the ICI era in advanced NSCLC and explores the prognostic value of lymph node burden metrics across disease stages.
Methods:
Using Surveillance, Epidemiology, and End Results data (SEER, 2010-2021), we identified advanced NSCLC patients and divided them into two cohorts based on the treatment era: pre-ICI era cohort (2010-2014) and ICI-introduction era cohort (2015-2021). Overall survival (OS) and cancer-specific survival (CSS) were analyzed in this advanced-stage population. Lymph node burden was assessed using the number of positive lymph nodes (NPLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS). Mediation analysis and SHapley Additive exPlanations (SHAP) modeling were used to evaluate their contribution to survival benefits. Additionally, we independently assessed the prognostic value of LNR and LODDS for OS and CSS, both in advanced-stage patients and a separate validation cohort of early-stage NSCLC with nodal metastasis, to evaluate their clinical utility beyond anatomical staging.
Results:
In patients with advanced NSCLC, the ICI-introduction era cohort demonstrated significantly improved OS and CSS compared to the pre-ICI era cohort, with adjusted hazard ratios (HRs) of 0.80 [95% confidence interval (CI): 0.75-0.85] and 0.76 (95% CI: 0.71-0.81), respectively. Mediation analysis indicated that LNR and LODDS partially explained these survival benefits. Besides, each 1% increase in LNR and each unit increase in LODDS were associated with an 87% (HR =1.87, 95% CI: 1.69-2.06) and 19% (HR =1.19, 95% CI: 1.16-1.22) increase in all-cause mortality risk, respectively. In early-stage NSCLC, both LNR and LODDS were strongly associated with mortality risk, and their integration with anatomical staging provided additional prognostic insight. Kaplan-Meier and Cox regression analyses confirmed enhanced survival stratification when combining rate-based lymph node metrics with anatomic staging.
Conclusions:
The approval and integration of immunotherapy has contributed, to some extent, to improved OS in advanced NSCLC at the population level, potentially mediated in part by reductions in metastatic lymph node burden. The rate-based metrics can also improve survival stratification in early-stage NSCLC, informing refinements to Tumor-Node-Metastasis (TNM) staging and personalized treatment strategies.
Insights
Immune checkpoint inhibitors (ICIs) improved survival in advanced non-small cell lung cancer (NSCLC). Lymph node burden metrics like LNR and LODDS partially explain these benefits and enhance staging for early-stage NSCLC.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality.
- Immune checkpoint inhibitors (ICIs) have transformed advanced NSCLC treatment since 2015.
- The prognostic impact of lymph node metastatic burden requires further investigation.
Purpose of the Study:
- To evaluate survival benefits of the ICI era in advanced NSCLC.
- To explore the prognostic value of lymph node burden metrics (NPLN, LNR, LODDS).
- To assess the clinical utility of LNR and LODDS in early-stage NSCLC.
Main Methods:
- Analysis of SEER data (2010-2021) comparing pre-ICI (2010-2014) and ICI (2015-2021) eras.
- Assessment of overall survival (OS) and cancer-specific survival (CSS).
- Application of mediation and SHAP analyses for lymph node burden metrics.
Main Results:
- The ICI era showed significantly improved OS and CSS in advanced NSCLC.
- LNR and LODDS partially mediated ICI survival benefits and independently predicted mortality.
- LNR and LODDS improved survival stratification in early-stage NSCLC when combined with TNM staging.
Conclusions:
- Immunotherapy contributes to improved NSCLC survival, partly via reduced lymph node burden.
- Rate-based lymph node metrics enhance prognostic insights beyond anatomical staging.
- These metrics can refine NSCLC staging and personalize treatment strategies.
