Commentary on: Beneficial outcomes of surgical combination therapy for patients with N3M0 non-small cell lung cancer: a retrospective cohort study

Dear Editor, We have read with great interest your article titled “Beneficial outcomes of surgical combination therapy for patients with N3M0 non-small cell lung cancer: a retrospective cohort study” published in the International Journal of Surgery[1]. Using a large sample from the SEER database and applying multivariable adjustment, propensity score matching, and subgroup analyses, your study explores the role of surgery within multimodal treatment for N3M0 non-small cell lung cancer (NSCLC) and concludes that integrating surgery into comprehensive treatment strategies may benefit selected patients. The study is well designed, employs appropriate statistical methods, and provides valuable real-world evidence for this clinically controversial area. However, while acknowledging its contributions, we believe several key limitations and potential biases warrant further discussion, and we would like to offer suggestions for future research. First, although the SEER database offers advantages such as a large sample size and population representativeness, it lacks critical clinical prognostic variables, including performance status, detailed comorbidity indices, smoking history, and pulmonary function parameters. These factors directly influence surgical candidacy and postoperative recovery and are important confounders for survival outcomes. We recommend that this limitation be more thoroughly acknowledged in the discussion, along with its implications for the generalizability of the conclusions. Second, the study did not incorporate tumor molecular profiling or information on targeted therapies, which are crucial in contemporary NSCLC management. For patients with adenocarcinoma, the status of driver mutations such as EGFR or ALK and the corresponding use of targeted agents can significantly affect prognosis and may alter the role and timing of local treatments, including surgery[2]. The lack of a significant survival benefit from surgery in the adenocarcinoma subgroup (especially T3-4) might be partly explained by the inability to stratify patients based on molecular subtypes and receipt of targeted therapy. Future studies should, where feasible, integrate molecular data to more precisely define which patients are likely to benefit from surgery. Third, while the “surgical recommendation” variable used in the study helps to indirectly control for some unmeasured confounding, SEER does not capture the specific reasons behind the recommendation (e.g., contraindications due to comorbidities, patient refusal, or rapid disease progression). Therefore, the survival difference between the “recommended but not operated” group and the “recommended and operated” group could still be influenced by unmeasured health disparities rather than solely attributable to surgery itself. Caution is warranted when interpreting these results, and future prospective studies are encouraged to systematically document the clinical rationale behind surgical decisions. Furthermore, the definition of N3 disease in the study is broad, encompassing a heterogeneous population ranging from contralateral mediastinal to supraclavicular nodal involvement. Different N3 substations (e.g., N3a vs. N3c) may have distinct biological behaviors and prognoses, and their responses to treatment could also differ. The SEER data do not provide this level of granularity, which limits the clinical precision of the study’s conclusions. We suggest that this point be explicitly acknowledged in the discussion, and future studies should be encouraged to analyze outcomes based on more detailed nodal staging. Methodologically, although propensity score matching was applied, the potential for time-dependent confounding was not sufficiently addressed. For instance, surgical patients might have undergone surgery only after demonstrating a favorable response to induction chemotherapy/radiotherapy; thus, their better survival could be partly attributable to that response rather than to surgery alone. Consideration of methods such as marginal structural models, which better handle time-dependent confounding, might strengthen causal inference. Finally, we agree with the authors on the importance of individualized, multidisciplinary treatment. Based on your findings, we suggest future research directions include conducting prospective registry studies to collect more comprehensive clinical, molecular, and treatment details; performing cost-effectiveness analyses and quality-of-life assessments to fully evaluate the value of surgery within multimodal therapy; and utilizing more refined nodal substation data to explore optimal treatment combinations for different N3 subgroups. In summary, the study provides valuable evidence to inform treatment decisions for N3M0 NSCLC. By acknowledging the above limitations and addressing them in future research, the field can move toward more precise and personalized clinical practice guidelines. Ethical approval Not appliclable. Consent Not applicable. Author contributions J.C., and C.L.: contributed to the drafting of the initial manuscript. Y.R.: conducted a critical review of the article.