Recommended optimal range for the count of examined lymph nodes and lymph node ratio for postoperative adjuvant radiotherapy in patients with pN2 non-small cell lung cancer: a multicenter retrospective cohort investigation

Introduction

Globally, lung cancer remains the foremost cause of cancer-related mortality, with more than 1.5 million new cases diagnosed each year, approximately 85% of which are non-small cell lung cancer (NSCLC) (1). Surgery is the preferred treatment for early-stage NSCLC (2); however, only around 20% of tumors are amenable to potentially curative surgical intervention. Even among those patients who undergo complete resection, the 5-year survival rate hovers around a mere 40% (3). To enhance local and regional disease control and improve survival outcomes, researchers have explored postoperative adjuvant radiotherapy (PORT) as a therapeutic strategy.

Despite the complete resection of operable NSCLC, patients remain at substantial risk of recurrence, which can be both distant and localized (4). Consequently, adjuvant chemotherapy and radiotherapy have been scrutinized in randomized trials, although these studies have frequently yielded inconclusive results. The role of postoperative radiotherapy has been evaluated over decades, and despite numerous trials and meta-analyses, its efficacy remains a matter of debate. The seminal meta-analysis on PORT, focused on data from 1998, encompassed nine randomized trials and reached conclusions that are well-known among clinicians: PORT is deleterious in early-stage disease (stage I or II) but shows no significant adverse effects in patients with stage N2 disease (5). Another analysis of the National Cancer Database (NCDB) by Mikell et al., which included patients with pN2 NSCLC who had undergone surgical resection and adjuvant chemotherapy, indicated that PORT was associated with improved survival, with no interaction observed between the benefit of PORT and the number of positive lymph nodes (6). However, this analysis did not consider the total number of examined lymph nodes (ELNs).

Lymph node status is a critical prognostic factor in patients with resected NSCLC. The current approach adopted by the American Joint Committee on Cancer (AJCC) determines lymph node status based on the anatomical location of the affected lymph nodes, under the premise that metastasis progresses from lymph nodes nearest to the primary tumor to more distant nodes (7,8). Given the significance of accurate lung cancer staging for the timely initiation of appropriate treatments, assessments based on lymph node count and lymph node ratio (LNR) have been proposed as complements to anatomical staging (9). A higher LNR is correlated with an increased risk of recurrence, suggesting that such patients might benefit from more aggressive postoperative treatment or rigorous follow-up (10,11). The prognostic superiority of LNR over simply the number of positive lymph nodes (PLNs) or the total number of resected lymph nodes has been demonstrated in various cancers, including colorectal cancer (10,12,13).

Our objective was to investigate the impact of PORT on survival, stratified by adequate postoperative ELNs count and LNR, in patients with pN2 NSCLC who had also received adjuvant chemotherapy. This investigation was conducted by analyzing data from a large, population-based multicenter database. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1573/rc).

Methods

Data source

We meticulously extracted data from the Surveillance, Epidemiology, and End Results (SEER) 17 registry study database (https://seer.cancer.gov/), which encompasses data spanning from 2015 to 2019. The SEER 17 database encompasses registry centers across the United States, including both major urban and rural areas. The collection of cancer data begins with the identification of patients diagnosed with or treated for cancer at various healthcare facilities, such as hospitals, outpatient clinics, radiology departments, physicians’ offices, laboratories, surgery centers, and other providers, including pharmacists. All fifty states have enacted legislation mandating the reporting of newly diagnosed cancers to a central registry. These cancer registries then review the reported cases to ascertain if the information meets legal reportability criteria. When it does, the registry extracts pertinent cancer information from the medical records of these cases, in accordance with the North American Association of Central Cancer Registries (NAACCR) Data Standards.

Cohort selection

Our study encompassed patients with pN2 stage NSCLC who underwent surgical intervention and pathological biopsy of resected lymph nodes. We excluded patients lacking data on the count of ELNs, pathological grading, positive lymph nodes, T-stage, and survival status. Ultimately, our analysis utilized a robust multicenter database, providing a reliable dataset for investigating the prognostic significance of ELNs and LNR in NSCLC. LNR was defined as the ratio of PLNs to ELNs.

Patients were stratified into two groups: those with ELNs <10 and those with ELNs ≥10. This division was informed by previous studies suggesting that an ELNs count of 10 or more is associated with improved prognostic accuracy and reduced risk of understaging (14). Patients with fewer than 10 examined nodes may have a higher likelihood of occult residual disease, thus potentially benefiting more from additional therapeutic measures such as PORT. This cutoff enabled us to evaluate the impact of PORT in cases where limited nodal examination could influence recurrence risk and survival outcomes.

We then examined the impact of PORT on overall survival (OS) within the total cohort, as well as within the ELNs <10 and ≥10 subgroups. Further analysis was conducted on the ELNs ≥10 cohort to assess the effect of PORT on OS across different LNR values. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Statistical analysis

X-tile software was employed for the stratification of the LNR. The software categorized LNR into three distinct groups based on survival outcomes: LNR ≤0.2, >0.2 to <0.53, and ≥0.53 (Figure S1). The variables included in the analysis were the year of diagnosis, age, gender, race, histology, grading, T-stage, type of surgery, PORT, LNR, and ELNs. Univariate analyses were conducted to evaluate the impact of each covariate on OS. The Cox proportional hazards model was then utilized to ascertain the effect of PORT on OS, adjusting for potential confounders. Additionally, the influence of PORT on OS across different LNR groups was examined within the Cox model, stratified by ELNs (ELNs <10 and ≥10).

Results

Baseline characteristics of the study participants

A total of 1,875 patients with stage pN2 NSCLC who underwent surgery between 2015 and 2019 were identified using the aforementioned selection criteria. Of these, 782 patients (41.71%) received PORT, while 1,093 patients (58.29%) did not. Patients who underwent PORT were more likely to be younger, with 457 (58.44%) being of advanced age, and predominantly of Caucasian ancestry, comprising 624 (79.80%) of the group (Table 1).

Within the PORT cohort, the LNR ≤0.2 group accounted for 35.04% of patients, the LNR >0.2 to <0.53 group constituted 42.97%, and the LNR ≥0.53 group represented 21.99% of patients. Furthermore, patients with ELNs ≥10 were predominant in both the PORT group (60.74%) and the non-PORT group (66.42%) (Table 1).

COX proportional hazards model demonstrates the survival benefit of PORT

The Cox proportional hazards model revealed a significant survival advantage associated with PORT. In the unadjusted model, mortality was 22% higher in the non-PORT group compared to the PORT group [hazard ratio (HR) =1.22, 95% confidence interval (CI): 1.02–1.46, P=0.03]. When adjusting for age, sex, and race, mortality remained 21% higher in the non-PORT group (HR =1.21, 95% CI: 1.01–1.45, P=0.03). Further adjustments for primary site, grade, histology, T-stage, type of surgery, LNR category, and ELNs category indicated a 31% increase in mortality in the non-PORT group compared to the PORT group (HR =1.31, 95% CI: 1.09–1.58, P=0.004) (Table 2).

Moreover, in the fully adjusted model, mortality rates among the LNR groups were ranked in descending order: the LNR ≥0.53 group exhibited the highest mortality, followed by the LNR >0.2 to <0.53 group, and the LNR ≤0.2 group, which had the lowest mortality (Table 2).

COX proportional hazards model stratified by ELNs and LNR

We examined the impact of PORT on OS by stratifying patients according to ELNs and LNR. The analysis revealed that in the fully adjusted model, within the ELNs <10 group, the mortality rate in the non-PORT cohort was 4.15 times greater than in the PORT cohort when the LNR was ≤0.2 (HR =4.15, 95% CI: 1.14–15.08, P=0.03). For an LNR ranging from >0.2 to <0.53, the mortality rate in the non-PORT group was 1.12 times higher than in the PORT group (HR =1.12, 95% CI: 0.70–1.78, P=0.64). Conversely, when LNR was ≥0.53, the non-PORT group exhibited a mortality rate 1.83 times higher than that of the PORT group (HR =1.83, 95% CI: 1.14–2.95, P=0.01) (Table 3).

In the ELNs ≥10 group, when LNR was ≤0.2, the mortality rate in the non-PORT group was 0.82 times that observed in the PORT group (HR =0.82, 95% CI: 0.57–1.18, P=0.28). For an LNR of >0.2 to <0.53, the mortality rate in the non-PORT group was 1.58 times higher than in the PORT group (HR =1.58, 95% CI: 1.09–2.28, P=0.02). When LNR was ≥0.53, the mortality rate in the non-PORT group was 2.67 times higher than that in the PORT group (HR =2.67, 95% CI: 1.41–5.05, P=0.002) (Table 3).

Kaplan-Meier survival curves stratified by ELNs and LNR

To further elucidate the impact of PORT on OS across different ELNs counts and LNR, we generated Kaplan-Meier survival curves stratified by ELNs and LNR to PORT.

In the ELNs <10 strata, survival curves demonstrated a marked distinction between the PORT and non-PORT groups when LNR was ≤0.2 (P=0.03) and when LNR was ≥0.53 (P=0.02), with the PORT group exhibiting a significantly superior survival rate compared to the non-PORT group (Figure 1).

Figure 1 KM stratification curves by PORT group, participants with ELNs <10 groups, stratified by LNR. (A) All LNR; (B) LNR ≤0.2; (C) LNR >0.2 and <0.53; (D) LNR ≥0.53. KM, Kaplan-Meier; PORT, postoperative radiotherapy; ELNs, examined lymph nodes; LNR, lymph node ratio.

In the ELNs ≥10 strata, survival curves also revealed a clear separation between the PORT and non-PORT groups when LNR was >0.2 and <0.53 (P=0.006) and when LNR was ≥0.53 (P=0.03), with the PORT group showing a pronounced survival advantage over the non-PORT group (Figure 2).

Figure 2 KM stratification curves by PORT group, participants with ELNs ≥10 groups, stratified by LNR. (A) All LNR; (B) LNR ≤0.2; (C) LNR >0.2 and <0.53; (D) LNR ≥0.53. KM, Kaplan-Meier; PORT, postoperative radiotherapy; ELNs, examined lymph nodes; LNR, lymph node ratio.

Discussion

Following the complete resection of NSCLC, adjuvant chemotherapy has become the gold standard of care for patients with stage II and III disease, including the elderly (15). However, its use in stage I patients remains contentious (16). Despite this, the challenge of local control persists, as 20–40% of these patients may experience localized regional recurrence. The role of PORT has been a subject of debate for decades. Despite extensive evaluation through numerous trials and meta-analyses, its efficacy remains controversial.

The seminal meta-analysis from 1998 established that PORT is detrimental for patients with early-stage disease (stage I or II), while it showed no significant adverse effects in stage N2 patients. Subsequent randomized trials, including those by the Lung Cancer Study Group (LCSG), revealed that the 5-year survival rate was approximately 40% in both the surgical and PORT groups (17), with no notable difference in OS. Nevertheless, subgroup analyses indicated that PORT extended disease-free survival (DFS) for patients with stage N2 disease. The Medical Research Council (MRC) study, which mirrored the LCSG trial’s design, also suggested a trend toward improved OS in stage N2 patients. Similarly, a phase III trial in China involving 366 patients with N1 or N2 resections found a lower rate of local recurrence in the PORT group (12.7%) compared to the control group (33.2%, P=0.01), though survival rates were comparable (5-year survival rates of 42.9% for the PORT group versus 40.5% for the control group, P=0.56).

Research into other malignancies has underscored the benefits of adjuvant radiotherapy in patients with high LNR. For instance, Zhu et al.’s NCDB study demonstrated a survival benefit from adjuvant radiotherapy for pancreatic cancer patients with 2–3 positive lymph nodes or an LNR of 0.15–0.25 (18). Kim et al. found that adjuvant radiotherapy could enhance cancer-specific survival in patients with prostate adenocarcinoma post-radical prostatectomy (19). Similarly, Polterauer et al. (20) reported improved OS in vulvar cancer patients with LNR >20% after inguinal lymph node dissection.

Lymph node metastasis and its anatomical location in NSCLC patients critically influence prognosis and treatment strategies (9). The TNM system’s current classification for NSCLC, as outlined in the 8th edition of the AJCC Staging Manual, does not consider the number of involved lymph nodes, focusing solely on anatomical location (21-25). Evidence suggests a correlation between the number of lymph nodes retrieved [limited (<10) or sufficient (≥10)] and survival prognosis, potentially leading to staging migration and compromised survival assessment accuracy (14). Consequently, we have established ELNs threshold of 10 as indicative of adequate lymph node dissection. We eschewed a smaller threshold to avoid instability in the LNR. For instance, an LNR of 33% derived from a single positive node out of three dissected nodes may be inaccurate. In patients with ELNs ≥10, PORT did not correlate with improved OS.

The LNR has emerged as a robust independent prognostic indicator across various solid tumors (12,26-28). For NSCLC, recent studies from the United States and China affirm that increased LNR predicts poorer survival outcomes. One Chinese study, encompassing 254 pN0, 115 pN1, and 111 pN2 patients, found LNR to be an independent prognostic factor comparable to pN (29). Another Chinese study involving 71 pN1 and 230 pN2 patients demonstrated that LNR stratification into high (LNR >18%, pN2), intermediate (LNR >18%, pN1 or LNR <18%, pN2), and low (LNR <18%, pN1) categories was effective for prognosis prediction. Our analysis indicated that PORT offered the most significant survival benefit in patients with ELNs <10 and LNR ≤0.2, with no confirmed benefit in other categories (30).

In patients with ELNs <10, those with a low LNR (≤0.2) who did not receive PORT exhibited significantly higher mortality rates, even exceeding those in the high LNR group (LNR >0.53). This finding appears contradictory to the usual association of higher LNR with increased mortality. We hypothesize that in patients with limited ELNs, a low LNR generally indicates a smaller tumor burden; however, insufficient lymph node examination may lead to undetected microscopic residual disease, which increases the risk of recurrence or distant metastasis. In this context, PORT could play a critical role by targeting these hidden microscopic lesions, effectively reducing recurrence risk and thereby improving survival outcomes. Thus, even in the low LNR group, patients who do not receive PORT may still experience elevated mortality, suggesting that PORT offers substantial survival benefits in cases with low tumor burden but limited lymphatic assessment. Additionally, although low LNR patients typically have fewer affected lymph nodes, indicating a relatively stable disease state, PORT as a preventive measure could further mitigate the risk of recurrence. Our findings demonstrate that PORT serves as a valuable adjunctive therapy in low LNR patients, not only compensating for the limitations of lymph node examination but also providing a proactive preventive benefit in patients with minimal tumor burden. Therefore, despite the overall low tumor burden, low LNR patients who forgo PORT exhibit higher mortality rates, further supporting the utility of PORT in this patient population.

Retrospective evaluations of PORT based on the number of involved lymph node stations support these findings. Urban et al. (14) analyzed 11,324 patients from the SEER database and validated that PORT is advantageous for patients with pN2 disease when the LNR is ≥50% of the resected nodes. Given the evolution in radiotherapy techniques since this data was collected, modern modalities may further mitigate PORT-related toxicity. Our study, encompassing patients diagnosed from 2015 to 2019, validated the efficacy of contemporary radiotherapy techniques. By integrating the radiotherapy model into our analyses, we accounted for advancements in technology. Our current study reveals that high LNR is consistently associated with worsening OS, reaffirming previous research. Technological advancements in radiotherapy, improved staging [e.g., accurate positron emission tomography/computed tomography (PET/CT)], enhanced surgical techniques, and systemic adjuvant or neoadjuvant chemotherapy have the potential to bolster PORT’s role in enhancing local recurrence-free survival and potentially OS.

Recent data from the Lung ART trial demonstrated that PORT was not associated with a significant increase in DFS compared with no PORT in patients with completely resected stage IIIAN2 NSCLC (31). Specifically, the study reported a 3-year DFS rate of 47% in the PORT group versus 44% in the control group, indicating no substantial benefit of PORT in extending DFS (31). However, it is noteworthy that our study focuses on the subset of patients with limited ELNs, where PORT might play a crucial role in targeting potential microscopic diseases. In patients with lower LNR and limited lymphatic examination, PORT could help mitigate the risk of undetected residual disease, potentially explaining the survival benefit observed in our cohort. Thus, while Lung ART suggests that PORT may not be universally beneficial, its application in carefully selected subgroups, such as patients with low ELNs and specific LNR profiles, may warrant further investigation.

The SEER database’s extensive sample size allows for the detection of modest correlations and supports complex multivariate analyses, making it highly applicable to community settings. However, it lacks detailed data on smoking history, performance status, preoperative staging methods, level of lymph node dissection, resection completeness, lymphatic and/or vascular invasion, recurrence patterns, and chemotherapy usage. Additionally, it does not differentiate between intact lymph nodes and fragments. In summary, our study delineates the optimal range of ELNs and LNR for PORT suitability in stage N2 NSCLC patients through dual stratification. ELNs

Conclusions

Our findings indicate that the number of ELNs and the LNR could serve as valuable criteria for selecting pN2 NSCLC patients who may benefit from PORT. PORT has been linked to improved survival outcomes in pN2 stage NSCLC, with a particular emphasis on its efficacy in patients with ELNs <10 and an LNR of ≤0.2. We advocate for the application of PORT in these specific patient subsets to optimize therapeutic outcomes.

Acknowledgments

We hereby thank the participants for their time and energy in the data collection phase of SEER project.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1573/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1573/prf

Funding: This study was funded by the Scientific and Technological Research Project by the Jiangxi Provincial Department of Education (No. GJJ2200185).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1573/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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