Lung cancer remains a predominant contributor to cancer-related mortality. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all cases, with 20%–30% of patients presenting with stage III disease at diagnosis (1). For those with locally advanced (LA) NSCLC (stage IIIA-C), multimodal therapy is the cornerstone of treatment (2–4). Individuals with stage IIIN2 NSCLC are usually treated with concurrent or sequential chemoradiotherapy (CRT), and some may get immunotherapy (5). This is especially true for patients with unresectable cancer (IIIA4, IIIB). Alternatively, a surgical approach, involving either double or triple modality treatment, may be employed for patients with resectable stage III NSCLC (IIIA3) (6). A very heterogeneous cohort, stage III pN2 NSCLC exhibits a variety of clinicopathological parameters, including the size of the original tumour, the number of afflicted stations or areas, the volume of the lymph nodes (big vs. non-large), and the histological subtype. The survival advantage conferred by chemotherapy in patients with fully resected NSCLC has been substantiated through numerous phase III trials and meta-analyses, which report an absolute survival benefit of 5% at 5 years (7). Postoperative Radiotherapy (PORT) refers to radiotherapy administered after surgical resection to improve locoregional control and potentially enhance survival outcomes in patients with NSCLC. For patients with stage IIB to IIIA disease, neoadjuvant or adjuvant chemotherapy is recommended. Postoperative radiation, or PORT, is frequently recommended for patients with stage III N2 NSCLC; nonetheless, there is still continuing discussion over its usefulness. Thus, we conducted an analysis of data from NSCLC patients within the N2 population, using the latest SEER database, to elucidate the role of PORT in pN2 NSCLC and explore the relationship betweenpositive lymph nodes (PLN) count and the use of PORT.

This study demonstrated an improvement in OS rates among patients with completely resected pN2, stage IIIA NSCLC treated with PORT compared to those not receiving PORT. This improvement was non-significant in patients with a PLN count of ≤1, but statistically significant in those with PLN counts >1. Patients with completely resected NSCLC and pN2 disease represent a highly heterogeneous cohort, exhibiting complex and variable treatment strategies, with survival rates ranging from 7% to 36% (8–10). With the increasing adoption of advanced radiotherapy techniques and optimized dosing regimens, many prior retrospective studies suggest that PORT may improve survival outcomes in this population (11, 12).

The role of PORT in NSCLC has been evaluated for decades, yet despite several trials and meta-analyses, its clinical benefit remains a subject of ongoing debate. The heterogeneity of results across different stages of the disease adds to this controversy. For instance, a study by Lafitte et al. (13), which focused on pN0 patients, found no significant difference in overall survival or local control between surgery combined with PORT and surgery alone. Another study by Trodella et al. similarly evaluated PORT in pN0 patients (14), using 28 fractions of 1.8 Gy to a total dose of 50.4 Gy. Although the initial results, published in 2002, indicated a positive trend for PORT in 5-year overall survival (67% vs. 58%, P = 0.046), this was not confirmed upon updating the data for reanalysis in the PORT meta-analysis (15). The latter showed a detrimental effect of PORT in patients with completely resected pN0 and pN1 NSCLC (16, 17). In the ANITA trial, which compared adjuvant chemotherapy to observation in patients with completely resected stage IB to stage IIIA NSCLC, there was a significant 8.6% improvement in 5-year OS in the chemotherapy arm (17, 18). However, post hoc analysis of the ANITA study also demonstrated a negative impact of PORT in pN0–1 patients, leading to the current recommendation against PORT in this subgroup.

Although better locoregional control with PORT has been shown in the Lung ART and PORT-C trials, this has not yet resulted in an overall survival improvement. In the study by Dautzenberg et al. (19), which remains the largest PORT meta-analysis to date, the authors reported an adverse impact of PORT on survival, with a 5-year overall survival rate of 30% in the PORT cohort compared to 43% in the control group (P = 0.002). Nevertheless, in patients with stage N2 disease, PORT has been shown to reduce local recurrence rates. The disproportionate number of deaths in patients treated with PORT is largely attributable to the high incidence of cardiac and respiratory complications, such as cardiopulmonary failure, radiation pneumonitis, and massive hemoptysis. These outcomes have been influenced by outdated radiotherapy techniques and the associated high morbidity. In light of advancements in radiotherapy, the role of PORT in resected pN2 NSCLC warrants reevaluation. Recent studies have highlighted the significant benefits of radiotherapy (20), demonstrating lower morbidity with modern radiotherapy techniques compared to cobalt units, and suggesting a substantial reduction in the risk of cardiac mortality (21).

Studies on the N2 population, however, have shown contradictory findings. A wide range of clinicopathological characteristics, including lymph node (LN) involvement (number of afflicted stations or areas), LN volume (big vs. non-large), initial tumour size, and histological subtype, characterise the extremely varied group of patients with stage III pN2 NSCLC. Local recurrence rates and prognosis have been linked to the volume and extent of N2 illness (22–25). Patients with substantial LN involvement (several N2 metastases or stations) showed increased OS with PORT, according to a recent meta-analysis by Liu et al. (22), whereas patients with single-station N2 involvement showed no benefit.

A randomized study by the Lung Cancer Study Group (LCSG) included 230 patients with resected stage II or III squamous cell carcinoma and showed that PORT significantly prolonged disease-free survival (DFS) in patients with stage N2 (22). Similarly, the Medical Research Council (MRC) trial, which had a design akin to the LCSG study, demonstrated a trend toward improved overall survival in N2 patients. A plausible explanation is that PORT may be detrimental in early-stage patients (stage I or II) but confers a survival advantage in stage N2 patients due to the higher risk of recurrence in this subgroup.

A Japanese retrospective study further explored the impact of PORT based on the number of LN stations involved. Although PORT did not significantly affect overall survival, it markedly improved DFS by reducing local recurrence in patients with multi-station N2 involvement. Consistent with these findings, Urban et al. (26). analyzed 11,324 patients from the SEER database and observed that PORT conferred a survival benefit in patients with pN2 disease when the lymph node ratio (positive lymph nodes/total resected lymph nodes) was at least 50%.

Among the known prognostic factors, LN status remains the most significant predictor of outcome in NSCLC patients. The 9th edition of the TNM classification continues to define lymph node staging based on the anatomical location of positive LNs, as in the previous 8th edition. However, in breast, gastric, and colorectal cancers, the TNM classification has evolved to incorporate the number of metastatic lymph nodes (MLNs) in staging. In NSCLC, the number of positive LNs is strongly correlated with prognosis, though this is contingent upon the adequacy of LN sampling at the time of surgery. Numerous studies have suggested that the count of positive LNs is a more robust prognostic indicator and could serve as an alternative to traditional pathologic N-staging (27, 28). It has been demonstrated that an increased number of positive LNs correlates with poorer survival outcomes, a trend more pronounced in pN2 patients compared to those with pN1 disease (29, 30). Multivariate analyses have consistently identified the number of metastatic LNs as a significant predictor of OS and DFS. In particular, among patients with ≥2 N2 lymph node metastases, PORT improved OS compared to those without PORT, while no significant difference was observed in patients with a single N2 metastasis. The findings of this study align with these results, suggesting that PORT may improve survival in patients with multiple N2 lymph node metastases.

However, several limitations of this study should be acknowledged. First, this was a retrospective analysis of data from the SEER database, rather than a prospective randomized controlled trial. Second, key prognostic variables such as smoking history, type of surgery, N2 station, and number of positive lymph nodes were not included in the analysis. This study is limited by the lack of detailed information on specific lymph node stations in the SEER database. As a result, we were unable to assess whether involvement of certain stations, such as station 7 (subcarinal lymph nodes), was associated with worse outcomes. Existing literature suggests that station 7 involvement may correlate with poorer prognosis due to its central location and potential for extensive tumor spread (31). Future studies incorporating more granular clinical data, including lymph node station information, are needed to address this limitation and further elucidate its impact on survival outcomes. While our study stratified patients based on the number of positive lymph nodes (PLN ≤1 vs. PLN >1), the SEER database does not provide detailed information on the number of involved lymph node stations (e.g., 2, 3, or 4 stations). This limits our ability to directly assess the outcomes of patients with varying degrees of lymph node station involvement. However, our findings suggest that patients with PLN >1 may derive greater survival benefits from PORT, indicating that increasing lymph node involvement likely amplifies the therapeutic effect of postoperative radiotherapy. Future studies incorporating station-level lymph node data are needed to validate and expand upon these findings. Additionally, adjuvant treatments such as chemotherapy, targeted therapy, and endocrine therapy were not considered. In addition, due to the inherent limitations of the SEER database, specific details regarding the dosing and fractionation of PORT, as well as the effects of other postoperative treatments, were unavailable. Lastly, the distinction between preoperatively known N2 and intraoperative incidental N2 is an important factor that could influence surgical and adjuvant treatment decisions. Unfortunately, the SEER database does not provide sufficient detail to make this distinction, which may be a limitation of our study. Additionally, the database lacks information on the number and location of involved lymph node stations (e.g., single-station vs. multi-station N2), which is known to significantly impact prognosis and treatment strategies. Future studies incorporating more detailed clinical and pathological data are warranted to address these gaps and provide further insights into the optimal management of stage IIIA pN2 NSCLC.

In conclusion, this study underscores the potential of PORT to enhance overall survival in patients with resectable pN2, stage IIIA non-small cell lung cancer, particularly in those with a positive lymph node count exceeding one. These findings highlight the need for further prospective studies to substantiate and expand upon these observations.