Abstract
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Purpose
- The aim of this study was to identify subgroups of patients with pathologic N2 (pN2) non-small cell lung cancer (NSCLC) who may benefit from postoperative radiotherapy (PORT). Particular attention was given to evaluating whether extranodal extension (ENE) influences the therapeutic efficacy of PORT.
-
Materials and Methods
- A total of 231 patients with pN2 NSCLC who underwent surgical resection followed by adjuvant chemotherapy at a single institution were analyzed retrospectively. Propensity score matching was performed to compare treatment outcomes according to the receipt of PORT.
-
Results
- Propensity score matching yielded 99 matched pairs of patients with no significant differences in clinical parameters. There were no significant differences in the overall survival (OS; p=0.112) and disease-free survival (DFS; p=0.286) between the PORT and no PORT groups. However, PORT significantly improved the locoregional recurrence (LRR)–free rate (p=0.011), whereas the distant metastasis–free rate was comparable between groups (p=0.646). In subgroup analyses, PORT was associated with improved OS in patients with 1-3 positive N2 lymph nodes (p=0.013) and with significantly improved DFS among patients without ENE (p=0.046) or lymphatic invasion (p=0.032).
-
Conclusion
- Although PORT did not improve OS or DFS in the matched overall cohort, it significantly reduced LRR. Subgroup analyses suggested potential benefits in patients with limited nodal burden and in those without ENE or lymphatic invasion. These findings, however, should be interpreted cautiously given small subgroup sizes and inherent limitations of retrospective design.
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Key words: Non-small cell lung carcinoma, Radiotherapy, Propensity score, Risk factors, Extranodal extension
Introduction
Non–small cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer, the leading cause of cancer-related mortality worldwide [1]. Complete surgical resection of the primary tumor and mediastinal lymph node dissection is preferred for management of operable NSCLC. After surgery, adjuvant treatment is required to reduce the risk of locoregional and distant relapse. The survival benefit of platinum-based adjuvant chemotherapy has been demonstrated in several randomized trials; thus, it has become the standard of care for patients with stage II-IIIA NSCLC following complete resection [2].
Considering the high rate of locoregional recurrence (LRR) after complete resection and adjuvant chemotherapy in node-positive NSCLC, postoperative radiotherapy (PORT) has often been recommended, particularly for pathologic N2 (pN2) NSCLC [3]. Because patients with LRR show poorer survival compared to those who do not [4], the addition of PORT has been hypothesized to augment the survival of patients with pN2 NSCLC. The results of retrospective analyses have demonstrated that administration of PORT using advanced techniques resulted in improved survival outcomes in pN2 NSCLC patients; a post-hoc analysis of the ANITA trial [5] and the Surveillance, Epidemiology, and End Results database analysis [6] showed that the overall survival (OS) in pN2 NSCLC was significantly increased by PORT. Several studies using public databases have reported on the benefit of PORT [7,8]. Although two recent randomized trials did not demonstrate an OS benefit from PORT, they suggested a trend toward improved disease-free survival (DFS) and demonstrated that the rate of LRR was reduced by approximately 50% [9,10]. And several small retrospective studies from various institutions have also identified a subset of patients with clinicopathologic factors, such as nodal disease burden and other histologic findings, that may help in selecting appropriate candidates for PORT [11-18]. Therefore, many oncologists believe that a subset of patients with pN2 NSCLC may still benefit from PORT [19].
Extranodal extension (ENE) of regional lymph nodes is defined as the spread of metastatic cells beyond the nodal capsule into the perinodal tissue, as observed in resected specimens. It is a well-established adverse prognostic factor in head and neck cancers and breast cancer. While its prognostic significance in NSCLC remains unclear [20], a meta-analysis identified ENE as an independent poor prognostic factor for recurrence and survival in NSCLC [21]. Considering these findings, PORT is often recommended by oncologists for patients with ENE [19,22].
The aim of this study was to identify subgroups of patients with pN2 NSCLC who may benefit from PORT. Of particular interest was whether the presence or absence of ENE influences the therapeutic efficacy of PORT.
Materials and Methods
1. Study population
We retrospectively reviewed patients with NSCLC diagnosed with pN2 disease who underwent surgical resection followed by adjuvant chemotherapy between March 2010 and December 2020. Decisions regarding PORT were primarily determined by the operating thoracic surgeons, with input from radiation oncologists and medical oncologists in selected cases. Patients who underwent neoadjuvant chemotherapy, with histology other than adenocarcinoma or squamous cell carcinoma, with a positive resection margin, with less than 10 regional lymph nodes dissected, with evidence of distant metastasis at diagnosis, or with history of other cancers within 5 years prior to surgery were excluded. To avoid bias resulting from omission of PORT due to early disease recurrence, patients who showed indications of failure within one month after completion of adjuvant chemotherapy at the time the decision to administer PORT was made were also excluded. Clinicopathologic features, including age, sex, pathologic TNM stage according to the 8th edition of the American Joint Committee on Cancer (AJCC) classification, histology, extent of lung resection, adjuvant treatment, and the presence of ENE, lymphatic invasion, vascular invasion, and perineural invasion, were collected.
2. Follow-up and treatment outcomes
Following surgery and completion of adjuvant chemotherapy (with or without PORT), patients underwent a contrast-enhanced computed tomography (CT) scan to detect early recurrences. Subsequent follow-up was performed every 3 months during the first 2 years, every 6 months for the next 3 years, and annually thereafter. Each follow-up visit included history taking, physical examination, and chest CT. Additional imaging studies such as positron emission tomography (PET)–CT, brain magnetic resonance imaging, or abdominal CT were performed when clinically indicated. There were no differences in the follow-up schedule or imaging modality between the PORT and no PORT groups.
Recurrence was defined as either histologic confirmation or consecutive radiologic evidence of a tumor during follow-up. Local recurrence was defined as recurrence at the surgical bed, including the bronchial stump. Regional recurrence was defined as recurrence at regional lymph nodes within the hilum, mediastinum, or supraclavicular area. These types of recurrence were collectively defined as LRR. All other cases of recurrence were classified as distant metastasis (DM). Isolated LRR was defined as LRR occurring as the first site of failure, without evidence of concurrent DM. OS was defined as time from surgery to death from any cause. DFS was defined as time from surgery to either disease recurrence or death from any cause, whichever occurred first.
Clinicopathologic variables were collected, including age, sex, pathologic TNM stage according to the 8th edition of the AJCC classification, number of involved nodes, multiple N2 station, histologic subtype, and the presence of ENE, lymphatic invasion, vascular invasion, and perineural invasion. Subgroup analyses were conducted to assess whether PORT provided a benefit over observation within these categories. Forest plots were generated to compare treatment effects on OS, DFS, LRR, and DM across subgroups, with hazard ratios (HR) and corresponding 95% confidence intervals (CI) calculated for each variable.
The chi-squared test and Student’s t test were used for comparison of the categorical and continuous variables between two groups, respectively. The Kaplan-Meier method was used to determine OS, DFS, LRR-free rate, and DM-free rate. A p-value < 0.05 was considered statistically significant in all analyses. Propensity score matching was performed using the MatchIt R package with nearest neighbor caliper matching, and a logistic regression method was used for estimation of the propensity score. All variables with a p-value < 0.20 in comparison between patients undergoing PORT and no PORT were included in the matching.
Results
1. Patient characteristics and treatment
A total of 231 patients were eligible for inclusion in this study; of these 131 received PORT, while 100 did not. Younger age (p=0.020) and the presence of ENE (p=0.074), vascular invasion (p=0.043), and lymphatic invasion (p=0.059) were associated with a higher likelihood of receiving PORT. After propensity score matching based on these variables, 99 matched pairs of patients were selected for further analysis. All variables were evenly distributed between patients with and without PORT. Details of patient and tumor characteristics before and after propensity score matching are presented in Table 1.
Among the 198 matched patients, 189 patients (95.5%) underwent preoperative PET scanning. Surgical resection was performed via thoracoscopic and open approach in 161 (81.3%) and 37 (18.7%) patients, respectively. The majority of patients (n=176, 88.9%) underwent lobectomy, while bilobectomy and pneumonectomy were performed in 11 patients each (5.5%). The median number of dissected lymph nodes was 23 (range, 10 to 91). After surgery, platinum-based adjuvant chemotherapy was administered to all patients for a median of four cycles (range, 2 to 4 cycles). Cisplatin/vinorelbine (61.6%), followed by carboplatin/paclitaxel (23.2%) and cisplatin/paclitaxel (7.1%) were the most employed adjuvant chemotherapy regimens. PORT was initiated a median of 27 days after completion of adjuvant chemotherapy (range, 13 to 88 days). The clinical target volume (CTV) included the ipsilateral hilum, subcarinal region, ipsilateral mediastinal lymph nodes, and, in case of close resection margin, also encompassed the bronchial stump. The planning target volume (PTV) was constructed by expanding the CTV by 5-10 mm. Radiotherapy was administered using either three-dimensional conformal radiotherapy (64.6%) or intensity-modulated radiotherapy technique (35.4%). The median total dose was 50.4 Gy (range, 45.0 to 54.0 Gy), with a daily dose of 1.8-2.0 Gy. At least 95% of PTV was required to receive the prescription dose, with dose uniformity maintained between 95% and 107%.
2. Survival outcomes for the propensity score–matched cohort
With a median follow-up period of 4.3 years (range, 0.2 to 13.4 years), deaths and recurrences were reported in 98 (49.5%) and 124 (62.6%) patients, respectively. Among those with recurrences, 62 patients (31.3%) showed LRR and 116 patients (58.6%) showed DM. The estimated 5-year OS rates were 68.3% in the PORT group and 60.5% in the no PORT group (p=0.112). Similarly, the estimated 5-year DFS rates were 32.3% with PORT and 31.8% without PORT (p=0.286). However, PORT treatment was associated with a significant improvement in the LRR-free rate, with 74.8% in the PORT group compared to 66.4% in the no PORT group at 5 years (p=0.011). The isolated LRR-free rate was significantly higher in the PORT group compared to the no PORT group (89.5% vs. 79.0% at 5 years, p=0.041). However, no significant difference in the 5-year DM-free rate was observed between the two groups (41.2% vs. 41.4% at 5 years, p=0.646). These comparisons between the PORT and no PORT groups are illustrated in Fig. 1.
3. Pattern of failures for the propensity score–matched cohort
An analysis of the pattern of failures in patients with or without PORT was performed. Among patients who did not undergo PORT, LRR and DM were detected in 40 (40.4%) and 59 (59.6%) patients, respectively. LRR plus DM were detected in 34 patients (34.3%). Isolated LRR was detected in 15 patients (15.2%). Meanwhile, among patients who underwent PORT, LRR, DM, and LRR plus DM were detected in 22 (22.2%), 57 (57.6%), and 19 patients (19.2%), respectively. Isolated LRR was detected in seven patients (7.1%).
Since PORT was delivered primarily to the ipsilateral side of mediastinum and subcarinal regions, we further analyzed LRR by categorizing it as failure occurring in either the ipsilateral mediastinum and subcarina or in the contralateral mediastinum and supraclavicular nodal area. Among patients without and with PORT, LRR at the ipsilateral mediastinum and subcarinal was observed in 38 (38.4%) and 14 (14.1%) patients, respectively (p < 0.001). In contrast, LRR at the contralateral mediastinum and supraclavicular area occurred in 22 (22.2%) and 19 (19.2%) patients, respectively (p=0.731).
4. Subgroups that benefit from PORT
Subgroup analyses were conducted to identify patient groups that derived significant benefit from PORT. OS was significantly improved in patients with 1-3 positive N2 lymph nodes following PORT (HR, 0.54; 95% CI, 0.33 to 0.88; p=0.013), whereas no significant OS improvement was observed in those with ≥ 4 positive N2 lymph nodes (HR, 1.55; 95% CI, 0.68 to 3.53; p=0.294). A marginal association with improved OS was also noted in patients with involvement of a single N2 station (HR, 0.64; 95% CI, 0.40 to 1.04; p=0.074), absence of ENE (HR, 0.63; 95% CI, 0.38 to 1.05; p=0.075), absence of lymphatic invasion (HR, 0.48; 95% CI, 0.23 to 1.00; p=0.051), and male sex (HR, 0.60; 95% CI, 0.35 to 1.02; p=0.060). In contrast, no significant improvement in OS with PORT was observed in subgroups stratified by age, histologic type, pathologic T category, number of positive N1 lymph nodes, perineural invasion, or vascular invasion (Fig. 2). Similarly, PORT was associated with improved DFS in patients with 1-3 positive N2 lymph nodes (HR, 0.70; 95% CI, 0.48 to 1.03; p=0.074), no ENE (HR, 0.65; 95% CI, 0.43 to 0.99; p=0.046), and no lymphatic invasion (HR, 0.50; 95% CI, 0.27 to 0.94; p=0.032). In contrast, stratified analyses revealed no significant DFS benefit from PORT in subgroups defined by age, sex, histologic type, pathologic T category, number of positive N1 lymph nodes, single involvement of N2 station, perineural invasion, or vascular invasion (Fig. 3). PORT improved the LRR-free rate in most subgroups, except for those with squamous cell histology, male sex, pathologic T1-2 disease, < 3 positive N1 lymph nodes, ≥ 4 positive N2 lymph nodes, multistation N2 involvement, or the presence of ENE, lymphatic invasion, vascular invasion, or perineural invasion. Significant benefits of PORT were observed in patients with 1-3 positive N2 lymph nodes (HR, 0.49; 95% CI, 0.26 to 0.92; p=0.025), single station N2 involvement (HR, 0.48; 95% CI, 0.26 to 0.89; p=0.020), absence of ENE (HR, 0.48; 95% CI, 0.24 to 0.93; p=0.029), absence of lymphatic invasion (HR, 0.27; 95% CI, 0.08 to 0.95; p=0.042), absence of vascular invasion (HR, 0.46; 95% CI, 0.21 to 1.00; p=0.051), absence of perineural invasion (HR, 0.46; 95% CI, 0.26 to 0.81; p=0.007), female sex (HR, 0.43; 95% CI, 0.20 to 0.96; p=0.038), adenocarcinoma histology (HR, 0.44; 95% CI, 0.24 to 0.81; p=0.009), pathologic T3-4 category (HR, 0.17; 95% CI, 0.05 to 0.60; p=0.006), and ≥ 3 positive N1 lymph nodes (HR, 0.42; 95% CI, 0.20 to 0.89; p=0.023) (Fig. 4). In contrast, PORT did not result in an improvement in the DM-free rate in any subgroups (Fig. 5).
5. Pattern of failures in patients who did not receive PORT
To better understand the natural course of disease progression in the absence of PORT, we analyzed recurrence patterns among patients who did not receive PORT. As shown in Table 2, this analysis aimed to delineate the predominant patterns of failure in subgroups defined by the number of positive N2 lymph nodes, presence of ENE, and lymphatic invasion. These findings provide important context for interpreting the treatment effect of PORT. DM was the predominant mode of failure across all subgroups. Among patients with 1-3 positive N2 nodes, isolated LRR accounted for 17.2% of all LRR cases and 10.0% of total recurrences, whereas in those with four or more nodes, these proportions were lower at 9.1% and 6.7%, respectively. In the absence of ENE, isolated LRR comprised 19.2% of all LRR cases and 11.1% of total recurrences, compared to 7.1% and 5.0% in patients with ENE. Similarly, patients without lymphatic invasion showed higher proportions of isolated LRR (25.0% of all LRR cases and 13.6% of total recurrences) compared to those with lymphatic invasion (10.7% and 7.0%, respectively). Conversely, the proportion of DM among total recurrences was consistently high, ranging from 86.4% to 95.0% across all subgroups. These findings indicate that while isolated LRR occurs less frequently, it is relatively more common in patients with limited N2 involvement, absence of ENE, or no lymphatic invasion.
6. Toxicities of PORT
No PORT-related grade 4 or 5 adverse events were observed during follow-up. Grade 1 and 2 esophagitis was recorded in 45 (45.5%) and 13 (13.1%) patients, respectively; grade 3 esophagitis was not detected in any of the patients. In addition, grade 3 pneumonitis was detected in two patients (2.0%), while grade 1 and 2 pneumonitis were reported in 30 (30.3%) and three (3.0%) patients, respectively.
Discussion
Although several retrospective studies have reported on the benefit of PORT in completely resected pN2 NSCLC, the results of prospective randomized trials have demonstrated that survival outcomes are not achieved in all patients treated with PORT. In this study, our findings demonstrated that the role of PORT in decreasing the LRR did not translate to a survival benefit in the general population of patients with pN2 NSCLC, consistent with the randomized study. Nonetheless, our findings indicated that addition of PORT following complete dissection of mediastinal lymph nodes and adjuvant chemotherapy resulted in significantly improved survival outcomes for patients without risk factors, including ENE, lymphatic invasion, and high N2 nodal burden.
Based on the lack of a survival benefit from treatment with PORT in the PORT-C and Lung ART trials [9,10], routine use of PORT after complete resection of pN2 NSCLC cannot be recommended. However, many experts still believe that PORT can improve survival outcomes in certain subgroups of patients [11]. Indeed, the findings of the PORT-C and Lung ART trials demonstrated a significant reduction in LRR by approximately 50%, a result that has been consistently reported in multiple retrospective studies. Our analysis also confirmed that PORT significantly improves LRR-free survival in most subgroups. However, we did not observe an improvement in OS or DFS following the administration of PORT in the overall population. This is likely due to the predominance of DM as the primary pattern of failure in pN2 NSCLC, which cannot be effectively reduced by PORT alone. Given its significant effect in reducing the rate of LRR, PORT should be considered for patients with identifiable risk factors for LRR. Counterintuitively, in our current study, PORT was associated with improved DFS in patients without ENE, but not in those with ENE. Indeed, several previous studies have also suggested that the absence of certain risk factors is associated with greater benefit from PORT [13,23,24]. For example, Moretti et al. [23] reported that PORT prolonged OS in patients without ENE, but not in those with ENE. Similarly, Yuan et al. [13] found improved OS following PORT in patients with involvement of a single N2 station, but not in those with multiple N2 stations. A secondary analysis of the PORT-C trial by Ma et al. [24] also demonstrated that PORT was beneficial for patients with an intermediate risk of DM. In the present study, we observed that isolated LRR was relatively more common in patients with limited N2 involvement, absence of ENE, or no lymphatic invasion. Furthermore, recurrence was less frequent in regions that received radiation therapy. Based on these findings, we suggest that patients with a relatively high risk of isolated LRR may be appropriate candidates for PORT following complete surgical resection and adjuvant chemotherapy.
The number of involved N2 stations is now recognized as a prognostic factor in NSCLC, and the N2 category is further subdivided into single-station (N2a) and multi-station (N2b) involvement in the 9th edition of the AJCC classification. Matsuguma et al. [11], who analyzed 91 patients with pN2 disease, reported that DFS showed significant improvement by treatment with PORT in multiple N2 stations; however, PORT without CT planning was administered to approximately half of the patients and systemic treatment was not administered in the majority of patients, with a 5-year DFS rate of only 6% for patients who did not undergo PORT. Kim et al. [12], who also supported the use of PORT following adjuvant chemotherapy for pN2 diseases involving multiple N2 stations, reported 5-year DFS rates of 43% in the PORT group and 17% in the group without radiotherapy. In addition, a recent study by Tian et al. [18] reported that the OS rate was significantly increased in patients with involvement of multiple N2 stations. In contrast, an analysis by Yuan et al. [13] reported an association of PORT with improved OS in a single-station N2 disease, but not in multiple N2 station disease. Our results also demonstrated higher OS and lower LRR rates in patients with single station N2 disease who received PORT compared to those in control.
The prognostic impact of ENE remains unclear, as does its interplay with PORT [20]. Luchini et al. [21] identified ENE as an independent poor prognostic factor for both recurrence and survival in NSCLC by using meta-analysis. The International Association for the Study of Lung Cancer (IASLC) staging committee proposed a definition of complete resection, which includes microscopically negative resection margins, systematic or lobe-specific nodal dissection, absence of ENE, and a negative highest mediastinal node. Based on this knowledge, some experts argue that the presence of ENE should be regarded as indicative of incomplete resection, thereby justifying the use of PORT [19]. However, a recent analysis of resection margins using the IASLC database was unable to determine the precise impact of ENE [20]. Notably, Lung ART trial did not include patients with ENE [9]. To date, only one retrospective study has directly examined the association between ENE and the efficacy of PORT in NSCLC, reporting an OS benefit in patients without ENE, but not in those with ENE [23].
We also observed an association between lymphatic invasion and the absence of a survival benefit from PORT. Improvement in the LRR-free rate was noted following PORT in patients without lymphatic invasion (HR, 0.27; 95% CI, 0.08 to 0.95; p=0.042), but not in those with lymphatic invasion (HR, 0.63; 95% CI, 0.35 to 1.13; p=0.123). To our knowledge, no studies have specifically investigated the relationship between lymphatic invasion and the efficacy of PORT. However, a retrospective study demonstrated that lymphovascular invasion was significantly associated with a higher risk of distant metastases and mortality in adenocarcinoma patients, as shown by multivariate analysis (HR, 1.75; p=0.006 and HR, 1.53; p=0.003), but this association was not observed in squamous cell carcinoma [25]. Despite this, most experts do not consider lymphatic invasion to be a risk factor when selecting patients for PORT in pN2 NSCLC [19]. Interestingly, subgroup analyses showed that patients without adverse pathologic features (i.e., limited nodal burden, absence of ENE, or no lymphatic invasion) appeared to benefit more from PORT. Conversely, patients with these high-risk characteristics did not demonstrate a clear advantage. This paradox may be explained by the predominance of distant metastases as the failure pattern in biologically aggressive tumors, suggesting that PORT alone may not adequately address systemic disease. These findings imply that patients with high-risk features might benefit more from intensified systemic therapy rather than the application of PORT, and this warrants further investigation.
The benefit of PORT should be carefully weighed against its potential toxicities. Esophagitis and pneumonitis are the most significant adverse effects associated with thoracic radiotherapy. In our cohort, only two patients experienced grade 3 pneumonitis, and no cases of grade 3 or higher esophagitis were observed; the toxicity profile of our cohort is comparable to that of the PORT-C and Lung ART trials, which reported 0.7% and 4% risk of grade 3+ pneumonitis and 0% and < 1% risk of grade 3+ esophagitis, respectively. Therefore, PORT administered with a median total dose of 50 Gy does not appear to cause severe morbidities following lung cancer surgery and adjuvant chemotherapy.
Recent advancements in systemic therapy have led to substantial changes in the management of locally advanced NSCLC, even after complete resection. Treatment with osimertinib has been shown to significantly improve survival outcomes in patients with resected epidermal growth factor receptor (EGFR)-mutated NSCLC [26]. Similarly, the addition of immune checkpoint inhibitors to adjuvant chemotherapy has resulted in significantly improved clinical outcomes in resected NSCLC [27,28]. These novel agents are thought to contribute to a reduced incidence of both locoregional and distant failures. A key limitation of the present study is the absence of molecular profiling, including EGFR mutation status and programmed cell death-ligand 1 expression, which may affect not only systemic treatment selection but also potentially the effectiveness of PORT. Furthermore, the study period (2010-2020) predates the widespread clinical adoption of targeted therapies and immune checkpoint inhibitors. Consequently, our findings may not fully reflect current treatment paradigms, and future studies incorporating molecular characteristics are warranted to enhance the applicability of these results to contemporary clinical practice.
This study is also subject to limitations inherent to its retrospective design, which may have led to selection bias despite the use of propensity score matching to minimize this risk. Decisions regarding PORT were primarily made by the attending thoracic surgeons, with input from radiation oncologists and medical oncologists in selected cases. At that time, available evidence consisted of conflicting non-randomized reports regarding the benefit of PORT in patients with pN2 disease. Although presence of pN2 status was the primary guideline-based indication, physicians often considered additional clinical factors including the absolute number or proportion of positive lymph nodes and the presence of clinically bulky N2 disease. Moreover, multidisciplinary tumor board review was not routinely performed for all patients during the study period. These institutional patterns may have introduced treatment heterogeneity and represent a potential source of confounding.
Patients who received neoadjuvant chemotherapy were not included in this study, resulting in a relatively low proportion of clinical N2 disease (19% in the no PORT group and 29% in the PORT group) (Table 1), which represents a more favorable subset of N2 disease. This may limit the generalizability of our findings, particularly in the current era when neoadjuvant immunochemotherapy is increasingly used for resectable clinical N2 disease. The role of PORT in this setting warrants further evaluation.
In summary, PORT significantly reduced the risk of LRR in patients with pN2 NSCLC after complete surgical resection and adjuvant chemotherapy. A survival benefit was suggested among patients with a relatively low risk of DM, such as those with limited N2 involvement, absence of ENE, or no lymphatic invasion. These findings indicate that PORT may be particularly beneficial for patients with pN2 NSCLC who have a lower likelihood of distant failure. However, as OS and DFS were not improved in the overall matched cohort and subgroup analyses were limited by small sample sizes and retrospective methodology, these results should be interpreted with caution. Future prospective studies with larger patient populations are required to validate these conclusions and more clearly define optimal candidates for PORT.
NOTES
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Ethical Statement
All procedures in this study involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee as well as the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2308-847-101). The requirement for informed consent was waived due to its retrospective design.
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Author Contributions
Conceived and designed the analysis: Song C, Jeon JH, Jeon SH.
Collected the data: Jeon JH, Jeon SH, Song C.
Contributed data or analysis tools: Jeon SH, Song C, Jeon JH, Chung JH, Cho S, Kim K, Jheon S, Kim SH, Kim YJ, Kim JS.
Performed the analysis: Jeon SH, Song C, Jeon JH.
Wrote the paper: Jeon SH, Song C, Jeon JH.
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Conflicts of Interest
Conflict of interest relevant to this article was not reported.
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Funding
This study was supported by Seoul National University Bundang Hospital Research Fund (02-2016-0038) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00252620).
Fig. 1.Treatment outcomes according to administration of postoperative radiotherapy (PORT). Kaplan-Meier curves for overall survival (A), disease-free survival (B), locoregional recurrence–free rate (C), isolated locoregional recurrence–free rate (D), and distant metastasis-free rate (E) according to administration of PORT.
Fig. 2.Forest plot of overall survival comparing postoperative radiotherapy (PORT) with observation across predefined subgroups, with hazard ratios (HRs) and 95% confidence intervals (CIs) shown for each subgroup. ADC, adenocarcinoma; SqCC, squamous cell carcinoma.
Fig. 3.Forest plot of disease-free survival comparing postoperative radiotherapy (PORT) with observation across predefined subgroups, with hazard ratios (HRs) and 95% confidence intervals (CIs) shown for each subgroup. ADC, adenocarcinoma; SqCC, squamous cell carcinoma.
Fig. 4.Forest plot of locoregional recurrence–free rate comparing postoperative radiotherapy (PORT) with observation across predefined subgroups, with hazard ratios (HRs) and 95% confidence intervals (CIs) shown for each subgroup. ADC, adenocarcinoma; SqCC, squamous cell carcinoma.
Fig. 5.Forest plot of distant metastasis–free rate comparing postoperative radiotherapy (PORT) with observation across predefined subgroups, with hazard ratios (HRs) and 95% confidence intervals (CIs) shown for each subgroup. ADC, adenocarcinoma; SqCC, squamous cell carcinoma.
Table 1.Patient characteristics before and after propensity score matching
|
Variable |
Before matching
|
After matching
|
|
No PORT (n=100) |
PORT (n=131) |
p-value |
No PORT (n=99) |
PORT (n=99) |
p-value |
|
Age (yr)
|
64.5±9.6 |
61.5±9.7 |
0.020 |
64.4±9.6 |
62.2±9.3 |
0.108 |
|
ECOG PS
|
|
|
0.814 |
|
|
0.746 |
|
0 |
65 (65.0) |
80 (61.1) |
|
64 (64.6) |
61 (61.6) |
|
|
1 |
32 (32.0) |
46 (35.1) |
|
32 (32.3) |
33 (33.3) |
|
|
2 |
3 (3.0) |
5 (3.8) |
|
3 (3.0) |
5 (5.1) |
|
|
Sex
|
|
|
0.589 |
|
|
0.886 |
|
Male |
56 (56.0) |
78 (59.5) |
|
55 (55.6) |
56 (56.6) |
|
|
Female |
44 (44.0) |
53 (40.5) |
|
44 (44.4) |
43 (43.4) |
|
|
Histology
|
|
|
0.801 |
|
|
0.321 |
|
SqCC |
23 (23.0) |
32 (24.4) |
|
23 (23.2) |
26 (26.3) |
|
|
ADC |
77 (77.0) |
99 (75.6) |
|
76 (76.8) |
73 (73.7) |
|
|
pT category
|
|
|
0.912 |
|
|
0.950 |
|
pT1 |
18 (18.0) |
23 (17.6) |
|
18 (18.2) |
17 (17.2) |
|
|
pT2 |
54 (54.0) |
76 (58.0) |
|
53 (53.5) |
57 (57.6) |
|
|
pT3 |
21 (21.0) |
25 (19.1) |
|
21 (21.2) |
19 (19.2) |
|
|
pT4 |
7 (7.0) |
7 (5.3) |
|
7 (7.1) |
6 (6.1) |
|
|
cN category
|
|
|
0.046 |
|
|
0.183 |
|
cN0 |
70 (70.0) |
71 (54.2) |
|
69 (69.7) |
57 (57.6) |
|
|
cN1 |
11 (11.0) |
19 (14.5) |
|
11 (11.1) |
13 (13.1) |
|
|
cN2 |
19 (19.0) |
41 (31.3) |
|
19 (19.2) |
29 (29.3) |
|
|
Positive N1 LNs
|
2.2±2.5 |
2.6±2.8 |
0.320 |
2.2±2.6 |
2.6±2.9 |
0.403 |
|
Positive N2 LNs
|
2.5±4.0 |
3.1±3.1 |
0.258 |
2.5±4.0 |
2.9±3.1 |
0.526 |
|
Involved N2 station
|
|
|
0.240 |
|
|
0.297 |
|
Single station |
82 (82.0) |
99 (75.6) |
|
81 (81.8) |
75 (75.8) |
|
|
Multi station |
18 (18.0) |
32 (24.4) |
|
18 (18.2) |
24 (24.2) |
|
|
Extranodal extension
|
|
|
0.074 |
|
|
0.353 |
|
Absent |
73 (73.0) |
81 (61.8) |
|
72 (72.7) |
66 (66.7) |
|
|
Present |
27 (27.0) |
50 (38.2) |
|
27 (27.3) |
33 (33.3) |
|
|
Vascular invasion
|
|
|
0.043 |
|
|
0.253 |
|
Absent |
60 (60.0) |
61 (46.6) |
|
59 (59.6) |
51 (51.5) |
|
|
Present |
40 (40.0) |
70 (53.4) |
|
40 (40.4) |
48 (48.5) |
|
|
Lymphatic invasion
|
|
|
0.059 |
|
|
0.281 |
|
Absent |
35 (35.0) |
31 (23.7) |
|
34 (34.3) |
27 (27.3) |
|
|
Present |
65 (65.0) |
100 (76.3) |
|
65 (65.7) |
72 (72.7) |
|
|
Perineural invasion
|
|
|
0.754 |
|
|
0.489 |
|
Absent |
88 (88.0) |
117 (89.3) |
|
87 (87.9) |
90 (90.9) |
|
|
Present |
12 (12.0) |
14 (10.7) |
|
12 (12.1) |
9 (9.1) |
|
Table 2.Pattern of failure in patients who did not receive postoperative radiotherapy
|
Pattern of failure |
No. of involved N2 lymph node
|
Extranodal extension
|
Lymphatic invasion
|
|
1-3 (n=83) |
4 and more (n=16) |
Absent (n=72) |
Present (n=27) |
Absent (n=34) |
Present (n=65) |
|
Total recurrences |
50 (60.2) |
15 (93.8) |
45 (62.5) |
20 (74.1) |
22 (64.7) |
43 (66.2) |
|
LRR only |
5 (6.0) |
1 (6.3) |
5 (6.9) |
1 (3.7) |
3 (8.8) |
3 (4.6) |
|
DM only |
21 (25.3) |
4 (25.0) |
19 (26.4) |
6 (22.2) |
10 (29.4) |
15 (23.1) |
|
Concurrent LRR and DM |
24 (28.9) |
10 (62.5) |
21 (29.2) |
13 (48.1) |
9 (26.5) |
25 (38.5) |
|
LRR only/Total LRR |
5/29 (17.2) |
1/11 (9.1) |
5/26 (19.2) |
1/14 (7.1) |
3/12 (25.0) |
3/28 (10.7) |
|
LRR only/Total recurrences |
5/50 (10.0) |
1/15 (6.7) |
5/45 (11.1) |
1/20 (5.0) |
3/22 (13.6) |
3/43 (7.0) |
|
DM/Total recurrences |
45/50 (90.0) |
14/15 (93.3) |
40/45 (88.9) |
19/20 (95.0) |
19/22 (86.4) |
40/43 (93.0) |
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