Management and survival outcomes of patients with postoperative recurrence of non-small cell lung cancer at isolated ipsilateral hilar or mediastinal lymph node

Introduction

Although surgical resection remains the most effective treatment for patients with early-stage non-small cell lung cancer (NSCLC), 5-year disease-free survival rates based on the 7^th edition of the tumor-node-metastasis (TNM) classification (1) were reported to be 84.3% for stage IA, 65.8% for stage IB, 49.7% for stage IIA, 46.3% for stage IIB, and 27.8% for stage IIIA, according to data from the largest national cancer registry in Japan (2). Recent multi-institutional studies have reported that postoperative recurrence at hilar or mediastinal lymph nodes (LNs) occurred as the initial recurrence site in 30.9–41.8% of patients who underwent resection for stage I–III NSCLC (3,4), indicating that recurrence at an ipsilateral hilar or mediastinal LN is not uncommon. Recurrence at ipsilateral hilar and mediastinal LNs, which are contiguously located, is classified as locoregional recurrence (5).

The management of postoperative recurrence of NSCLC confined to a hilar or mediastinal LN remains controversial. Several international guidelines do not provide specific recommendations for this scenario (6,7), except for the National Comprehensive Cancer Network (NCCN) guidelines (8), which recommend chemoradiotherapy or chemotherapy alone in cases of prior radiotherapy for mediastinal LN recurrence, similar to the approach for unresectable NSCLC with N2 status. In addition, the role of molecular targeted therapy and immune checkpoint inhibitors (ICIs) in this setting remains unclear.

The current literature on managing isolated hilar or mediastinal LN recurrence lacks randomized trials and prospective studies. Several single-institution retrospective studies with small sample sizes suggest a variety of management approaches in this setting (9-13), although much of the data appear outdated. As the management of isolated ipsilateral hilar or mediastinal LN recurrence of NSCLC is often discussed in multidisciplinary teams (14), real-world data are expected to help guide treatment decisions.

In this study, we used a multi-institutional database to investigate the long-term survival outcomes of patients with isolated ipsilateral hilar or mediastinal LN recurrence after surgical resection for NSCLC, with reference to current guidelines. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-809/rc).

Methods

Patients and data collection

A retrospective chart review was conducted using a multi-institutional database to identify all consecutive patients who underwent surgical resection for pathological stage I–IIIA NSCLC at 10 acute care hospitals between January 2014 and December 2016. Patients were included if they (I) had isolated ipsilateral hilar or mediastinal LN recurrence as the initial recurrence; (II) had no other recurrence; and (III) received any form of anticancer treatment. Clinical staging was determined based on radiological findings at the time of initial presentation. Standard imaging typically included contrast-enhanced whole-body computed tomography (CT), contrast-enhanced brain magnetic resonance imaging (MRI), and ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET). Chest MRI was not routinely performed. If mediastinal LNs measured ≥1 cm in diameter on CT or showed increased FDG uptake on PET-CT, tissue sampling was generally performed prior to surgery. Endobronchial ultrasound-guided transbronchial needle aspiration was the first choice and video-assisted mediastinoscopy was the second choice, in accordance with the European Society for Medical Oncology guidelines (7). Pathological staging was based on the 7th edition of the TNM classification (1), as it was in use until December 2016. Postoperative adjuvant chemotherapy was administered in accordance with the Japan Lung Cancer Society guidelines (6).

The following clinical data were collected: age, sex, smoking history, body mass index, pulmonary function at the time of initial pulmonary resection, Charlson Comorbidity Index (15), details of pulmonary resection, histology, and pathological stage of lung cancer, treatment for recurrence, and follow-up information. Postoperative surveillance typically included chest CT every 3–6 months after surgery, with brain MRI performed for symptomatic patients, in accordance with the NCCN and European Society for Medical Oncology guidelines (7,8). PET-CT was performed when CT revealed enlarged LNs. Invasive sampling was not routinely conducted, in accordance with the NCCN guidelines (8). Patients who developed recurrence and received post-recurrence treatment were followed up every 3–6 months, similar to the postoperative surveillance schedule. Follow-up data were censored as of June 2024.

The management of LN recurrence was discussed by a multidisciplinary team, based on a comprehensive assessment of patient condition, performance status, pulmonary function, and social background. Most patients received chemotherapy, with or without radiotherapy. Chemotherapy mainly consisted of platinum-based doublet regimens. Tyrosine kinase inhibitors (TKIs) were occasionally selected as first-line therapy when driver gene alterations were identified. Surgical resection was rarely performed according to location of the LN. Local radical therapy (LRT) included complete surgical resection and radiotherapy.

This study was approved by the Kyoto University Institutional Review Board (June 22, 2020; reference number: R2504), and other institutions were informed and agreed with the study. The requirement for patient consent was waived in view of the retrospective study design. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and Good Clinical Practice guidelines as defined by the International Conference on Harmonization.

Statistical analysis

Descriptive statistics were reported as frequencies and percentages for categorical variables and as medians with interquartile ranges (IQRs) for continuous variables. Categorical variables were compared using Fisher’s exact test, whereas continuous variables were compared using the Mann-Whitney U test for two groups or the Kruskal-Wallis test for three groups. Median follow-up was calculated using the reverse Kaplan-Meier method for potential follow-up (16). Post-recurrence survival (PRS) was defined as the time from recurrence diagnosis to death from any cause or the last known date the patient was alive. PRS was analyzed using the Kaplan-Meier method, and differences between survival curves were assessed using a two-tailed log-rank test. Data were processed and analyzed using R software (version 3.3.2; R Foundation for Statistical Computing, Vienna, Austria). All P values were two-sided, with values <0.05 considered statistically significant.

Results

A total of 2,921 consecutive patients undergoing surgical resection for NSCLC were reviewed, and 67 patients (2.3%) with isolated ipsilateral hilar or mediastinal LN recurrence were analyzed in this study (Table 1). Among them, 16 had driver gene alterations, including epidermal growth factor receptor (EGFR) del19 (n=9), EGFR L858R (n=4), other EGFR mutations (n=2), and anaplastic lymphoma kinase rearrangement (n=1). Neoadjuvant chemoradiotherapy was administered to one patient, and adjuvant radiotherapy to two patients. The median disease-free interval (DFI) between the primary operation and recurrence detection was 14.7 months (IQR, 7.5–26.0 months). Treatment options did not significantly differ between patients with hilar and mediastinal LN recurrence (P=0.14; Table S1). Table 2 presents the clinicopathological characteristics of patients receiving LRT (n=16), chemotherapy (n=30), and chemoradiotherapy (n=21). EGFR mutations were more frequently detected in patients receiving chemotherapy (P=0.08), although no other factors showed significant differences among the three groups. There were no significant differences in patient characteristics between the surgical resection and radiotherapy groups (Table S2).

The median follow-up period after LN recurrence was 51.5 months. Two- and 5-year PRS rates were 69.2% and 34.2%, respectively (Figure 1). Five-year PRS rates in patients with hilar and mediastinal LN recurrences were 31.0% and 34.7%, respectively (P=0.57, log-rank test; Figure 2A), pathological stage I and ≥ II NSCLC were 35.4% and 33.5%, respectively (P=0.77, log-rank test; Figure 2B), adenocarcinoma and squamous cell carcinoma were 50.2% and 22.0%, respectively (P=0.002, log-rank test; Figure 2C), presence and absence of EGFR mutations were 33.0% and 33.6%, respectively (P=0.19, log-rank test; Figure 2D), and DFI (<1 year) and DFI (≥1 year) were 29.7% and 37.1%, respectively (P=0.61, log-rank test; Figure 2E).

Figure 1 Kaplan-Meier curve for PRS in all patients. PRS, post-recurrence survival.

Figure 2 Kaplan-Meier curves for PRS by LN recurrence site (A), pathological stage of primary lung cancer (B), histology (C), EGFR mutations (D), and DFI (E). DFI, disease-free interval; EGFR, epidermal growth factor receptor; LN, lymph node; PRS, post-recurrence survival.

In regard to treatment for isolated recurrence, 5-year PRS rates were 32.9% in patients receiving LRT, 12.6% in those receiving chemotherapy, and 55.0% in those receiving chemoradiotherapy (Figure 3A). The survival curve for patients receiving chemotherapy tended to be worse than that for those receiving chemoradiotherapy (P=0.13, log-rank test; Figure 3A).

Figure 3 Kaplan-Meier curves for PRS by treatment type (LRT, chemotherapy, or chemoradiotherapy) for isolated recurrence (A) and in patients with EGFR mutations by treatment type (TKI or other treatments) for isolated recurrence (B). EGFR, epidermal growth factor receptor; LRT, local radical therapy; PRS, post-recurrence survival; TKI, tyrosine kinase inhibitor.

In the subgroup analysis of EGFR-mutated adenocarcinoma (Table S3), the survival curve for patients receiving a TKI as first-line treatment tended to be worse than that for those receiving other first-line treatments consisting of surgical resection (n=1), radiotherapy (n=2), and chemoradiotherapy (n=1), although the sample size was small (P=0.06, log-rank test; Figure 3B).

Discussion

In this study, we evaluated the long-term survival outcomes of patients with isolated ipsilateral hilar or mediastinal LN recurrence after surgical resection for NSCLC. Our data showed that a variety of treatments were administered, differing from the NCCN guidelines for mediastinal LN recurrence (8), whereas no specific recommendations exist for hilar LN recurrence. Among our patients, those receiving chemoradiotherapy had more favorable PRS; however, meaningful comparisons of treatment effects were challenging owing to differences in patient covariates, such as performance status, smoking history, driver gene mutations, and recurrence site.

To the best of our knowledge, this is the first study to investigate survival outcomes specifically in patients with isolated ipsilateral hilar or mediastinal LN recurrence after surgical resection for NSCLC. Postoperative recurrence at an intrathoracic LN is occasionally observed in patients undergoing resection for NSCLC (3,4), yet surprisingly, data on treatment in this setting remain limited. Table 3 summarizes findings from similar studies conducted over the past decade (9-13). Notably, none of these studies documented follow-up periods for patients with isolated intrathoracic LN recurrence (9-13), and all were based on single-institution experiences with small sample sizes, making them more susceptible to selection bias. Our multi-institutional study, with a larger sample size, provides valuable insights to help guide the management of patients with isolated ipsilateral hilar or mediastinal LN recurrence. Although analyzing both hilar and mediastinal LN recurrences together may be debated, our data, consistent with previous studies (11,12), showed no significant difference in PRS between these groups.

A previous study reported that DFI is associated with tumor aggressiveness in patients with locoregional recurrence of NSCLC (17). In our study, a longer DFI was not a favorable prognostic factor, consistent with other studies focusing solely on intrathoracic LN recurrence (10-13), suggesting that the malignant potential of intrathoracic LN recurrence differs from that of locoregional recurrence. Furthermore, the pathological stage of primary lung cancer was not associated with prognosis in our study, aligning with previous findings (9-13). These results support the consideration of aggressive treatment for ipsilateral LN recurrence, regardless of DFI or pathological stage.

Previous studies did not evaluate the role of LRT in patients with postoperative intrathoracic LN recurrence of EGFR-mutated adenocarcinoma (18,19). Although those studies found no significant difference in PRS between LRT and systemic therapy, which primarily consisted of EGFR-TKIs, 26–70% of patients had multiple sites of recurrence. In our study, although only 15 patients with EGFR mutations were included, which resulted in limited statistical power to draw meaningful conclusions, the survival curves suggested that LRT may be prioritized to systemic therapy, such as EGFR-TKIs, for isolated ipsilateral hilar or mediastinal LN recurrence of EGFR-mutated adenocarcinoma. Further prospective studies involving larger patient cohorts across multiple institutions are needed to validate the present findings.

This study has some limitations. First, it was retrospective and non-randomized, using a limited database that lacked data on pulmonary function tests such as diffusing capacity for carbon monoxide and tumor markers other than carcinoembryonic antigen. Second, the diagnosis of recurrence was not routinely confirmed by invasive sampling in accordance with the NCCN guidelines (8), and treatment indications were not standardized across institutions. Although the specific reasons why some patients received surgical resection or radiotherapy alone remain unclear, impaired performance status after the initial operation may have influenced treatment decisions. Third, 16% of initial pulmonary resections for NSCLC were sublobar, potentially leading to an incomplete assessment of LN metastases. However, this limitation is unavoidable in a real-world database, as 12–18% of initial operations were sublobar resections in similar studies (10,13). Finally, not all patients in our study, or in previous studies (9-13), underwent gene alteration analysis. In particular, programmed death-ligand 1 (PD-L1) expression was not assessed, as testing was performed in only 25% of patients, resulting in too small a number of patients receiving ICIs to allow for any definitive conclusions. However, this limitation is difficult to address, as the study cohort consisted of patients treated between 2014 and 2016—prior to the widespread use of ICIs. Moreover, adjuvant therapy for NSCLC with driver mutations or high PD-L1 expression has shown promising results with the use of targeted therapies (20,21) or ICIs (22), which might change recurrence patterns of NSCLC and their management. Despite these limitations, this is the first study to investigate treatment for isolated ipsilateral hilar or mediastinal LN recurrence after surgical resection for NSCLC, based on the largest patient cohort using a real-world database.

Conclusions

Our data suggest that various treatments are administered for isolated ipsilateral hilar or mediastinal LN recurrence after surgical resection for NSCLC, differing from current guideline recommendations, yet associated with acceptable survival outcomes. Careful discussion within the multidisciplinary team is essential for management, although genetic information may help guide treatment selection.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-809/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-809/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-809/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-809/coif). M.H. serves as an unpaid editorial board member of Journal of Thoracic Disease from February 2025 to January 2026. The other 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. This study was approved by the Kyoto University Institutional Review Board (June 22, 2020; reference number: R2504), and other institutions were informed and agreed with the study. The requirement for patient consent was waived in view of the retrospective study design. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and Good Clinical Practice guidelines as defined by the International Conference on Harmonization.

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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