Prognostic value of L4 lymph node dissection during video-assisted thoracoscopic surgery in patients with left-sided non-small cell lung cancer: a single-center, retrospective cohort study

Introduction

Lung cancer is the second most frequently diagnosed malignancy worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of total cases (1,2). The cornerstone of NSCLC treatment remains surgical pulmonary resection with systemic lymphadenectomy. The rate of lymph node metastasis in patients with NSCLC is 30–40% (3), so systemic lymph node dissection (LND) during radical resection is crucial for staging and prognosis (4-6). In current guidelines, it is recommended to excise at least three mediastinal nodal stations (including subcarinal stations) as a minimum requirement, but no recommendations are detailed for the excision of left lower paratracheal (L4) lymph nodes in patients with left-sided NSCLC (7-9). However, the optimal extent of mediastinal LND using VATS in NSCLC is still under debate.

Given the narrow anatomic region demarcated by the left recurrent laryngeal nerve, pulmonary artery, aortic arch and thoracic duct, dissection of the L4 lymph node for left-side NSCLC is technically demanding with a high risk of left recurrent laryngeal nerve paralysis (10). Therefore, some thoracic surgeons choose to avoid L4 LND for left-sided NSCLC (11-13).

Recently, some studies revealed that L4 lymph node metastasis was not rare and that L4 LND might be associated with improved survival (14-16). However, these studies generally enrolled patients with the disease at various clinical stages and did not focus on cases treated using a minimally invasive approach. Video-assisted thoracoscopic surgery (VATS) is feasible and commonly performed for NSCLC (17-20). Previous studies have demonstrated that VATS is feasible for dissecting L4 lymph nodes due to the magnification of the surgical field (21,22). According to retrospective data from our center, approximately 20% of VATS left lung cancer surgeries were performed with L4 LND. There were several factors that might have contributed to this. First, our center performed LND on the basis of international guidelines, which did not demand L4 LND. Second, patients who underwent VATS were in a relatively early stage. Next, L4 LND was more difficult in VATS than in open surgery. Thus, we performed this study to evaluate the prognostic significance of video-assisted L4 LND for patients with left-sided NSCLC. We present the following article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-18/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Sun Yat-sen University Cancer Center Institutional Review Board of Clinical Research (No. B2022-051-01). The requirement for patient consent was waived due to the retrospective design of the study.

Patients

This study is a single center, retrospectively study. The surgical database of Sun Yat-sen University Cancer Center was reviewed from January 2007 to December 2016. The inclusion criteria were as follows: patients diagnosed with primary left-sided NSCLC who underwent VATS lobectomy combined with LND; patients subjected to R0 resection; and tumor pathological stage T_1-4N_0-2M0. The following patients were excluded: conversion to thoracotomy due to hemorrhage, oversized tumor/lymph node(s) or/and invasion during surgery; and patients who had no lymph node resection. Eligible patients were divided into two groups: patients with L4 LND (L4^D+) and patients without L4 LND (L4^D-). Baseline characteristics and clinical outcomes were then compared between the two groups, using statistic. The primary endpoint was overall survival (OS), and secondary endpoints included postoperative complications, lymph node metastasis rate and pathological results.

Preoperative evaluations for all patients included hematological investigations, electrocardiography, function tests, computed tomographic (CT) scans of the thorax and abdomen, bronchoscopy, and brain CT or magnetic resonance imaging scans. Cardiac ultrasound was recommender for elderly patients (over 60 years of age) and patients with a history of cardiovascular disease. Positron emission tomography (PET) was optional. Preoperative biopsy was performed when PET or CT showed suspicious lymph nodes potentially indicating metastasis. Lymph node mapping, proposed by the IASLC, was used to classify lymph node stations. The 8^th edition of the AJCC lung cancer staging system was used. The systemic LND protocol used at our institute was described previously (23). In brief, the mediastinal lymph nodes were removed en bloc at each station, whereas the intrapulmonary nodes, namely, Stations 12 to 14, were retrieved by the thoracic surgeon after specimen removal. The extent of L4 LND included all soft tissue in the paratracheal area. The borders were described as follows: medial border: trachea; lateral border: ligamentum arteriosum; superior border: aortic arch; inferior border: upper rim of the left bronchus. The origin of the left recurrent laryngeal nerve was exposed when the dissection was complete (Figure 1).

Figure 1 L4 LND by VATS. LND, lymph node dissection; VATS, video-assisted thoracoscopic surgery. L, left; N, nerve.

Follow-up

In general, patients’ follow-up examinations included computed tomography of the thorax and upper abdomen, hematological investigations, ECG, bronchoscopy, brain CT or magnetic resonance imaging scans. In addition, further examination was performed as soon as possible for a more careful evaluation if the patient had any specific symptoms. The follow-up scheme included examinations every 3 months for the first 2 years, every 6 months for 3–5 years and then once a year thereafter.

Statistical analysis

The chi-square test was used for categorical variables. For continuous variables, normally distributed variables were compared using the t-test, and rank-sum test was used for non-normally distributed variables. Postoperative complications were classified into major complications (grades III, IV, and V) and minor complications (grades I and II) according to the Clavien-Dindo classification of surgical complications. OS was calculated from the operation date to the date of death. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. For OS, patients without an event were censored at the end of the follow-up. Prespecified subgroup analysis to evaluate the prognostic value of L4 LND was conducted for patients according to the tumor location (upper lobe vs. lower lobe) and clinical T stage (T1a and T1b). Multivariate Cox proportional hazards regression analysis was used to determine independent prognostic factors impacting OS. Two-sided P<0.05 was considered statistically significant. All statistical analyses were conducted using IBM SPSS Statistics (version 24.0, IBM Corp., Armonk, NY, USA) and R 4.2.0 (The R Project for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

A total of 312 patients were included. L4 LND was performed in 119 (38.1%) patients, whereas the other 193 (61.9%) patients did not undergo this procedure (Figure 2). The baseline characteristics of the entire cohort are summarized in Table 1, and the postoperative pathological results are shown in Table 2. L4 LND was more likely to be conducted on left upper lobe (LUL) tumors than on left lower lobe (LLL) tumors (P=0.019). More LNs were dissected in the L4^D+ group than in the L4^D- group (mean: 24.21 vs. 16.30, P<0.001). Patient distributions with respect to age, sex, smoking history, clinical stage, adjuvant therapy, tumor differentiation and tumor size were well balanced between the two groups.

Figure 2 Patient flow diagram. NSCLC, non-small cell lung cancer.

Postoperative complications

The postoperative hospital stay was similar in the two groups (median: 7 vs. 7 days, P=0.995, using rank-sum test). The postoperative complication rates of the two groups were comparable (L4^D+ group: 16.8% vs. L4^D- group: 14.0%, P=0.499) (Table 3). Pneumothorax was the most common complication in the L4^D+ group (5.9%) and L4^D- group (4.1%). The major complication rates were 5.9% (L4^D+ group) and 4.7% (L4^D- group), there was no significantly difference between the two groups (P=0.635).

LN metastasis rate

As shown in Table 4, Station 11 was the most common station of metastasis. It is noteworthy that the Station L4 metastatic rate was 9.2%, which showed no significant difference between LUL and LLL tumors (8.9% vs. 10.0%, P=1.000). In contrast, the upper lobe tumor tended to metastasize to Station 5, whereas the lower lobe tumor had a higher chance of metastasizing to Stations 7 and 9.

Survival

The median follow-up was 77 months (range, 1 to 155 months). A total of 91 patients died. The log-rank test showed that the L4^D+ group had a significantly better OS than the L4^D- group (median OS: undefined vs. 130 months, HR 0.47; 95% CI: 0.31–0.72; P=0.002, Figure 3A). The OS rates at 5 and 10 years were 85.9% and 74.8% in the L4^D+ group compared with 76.1% and 53.4% in the L4^D- group, with HRs of 0.57 (95% CI: 0.34–0.97; P=0.038) at 5 years and 0.44 (95% CI: 0.29–0.68; P=0.001) at 10 years. In addition, multivariate analysis showed that L4 LND was an independent factor for OS (HR 0.41; 95% CI: 0.25–0.68) (Table 5). The L4^D+ group also showed better OS than the L4^D- group in LUL patients (HR 0.44; 95% CI: 0.25–0.78, P=0.001). However, no significant difference in OS was noted between the L4^D+ group and the L4^D- group in LLL patients (HR 0.52; 95% CI: 0.27–1.01, P=0.09) (Figure 3B,3C).

Figure 3 Survival curves for patients with or without L4 LND. (A) Kaplan-Meier curves for OS in the L4^D+ group and L4^D- group of all patients; (B) Kaplan-Meier curves for OS in the L4^D+ group and L4^D- group of subgroup LUL; (C) Kaplan-Meier curves for OS in the L4^D+ group and L4^D- group of subgroup LLL; (D) Kaplan-Meier curves for overall survival in the L4^D+ group and L4^D- group of subgroup cT1aN0-cT1bN0. L4 LND, L4 lymph node dissection; LUL, left upper lobe; LLL, left lower lobe; OS, overall survival.

In patients with tumors less than 2 cm, the OS in cT1aN0 and cT1bN0 patients was not significantly different between the L4^D+ group and the L4^D- group (OS: HR 0.44; 95% CI: 0.18–1.06; P=0.12) (Figure 3D).

Discussion

This retrospective study demonstrated that the dissection of L4 lymph nodes could improve OS in patients with left-sided NSCLC treated using the VATS approach. However, no significant difference in OS was noted between the L4^D+ group and the L4^D- group in cT1aN0 and cT1bN0 patients.

L4 LND is not routinely required as part of the radical resection procedure for early-stage left-sided NSCLC. In the ACOSOG-Z0030 study (24), cT1/cT2 and N0 or nonhilarN1 patients were recruited, and lymph node sampling did not contain Group L4 for left-sided tumors and complete L4 LND was not required in the dissection group according to the study protocol. The Z0030 study showed that mediastinal LND did not improve survival in patients with early-stage lung cancer if systematic and thorough presection sampling of the lymph nodes was negative. In addition, the prognostic value of L4 LND is unclear. Completing L4 LND is quite challenging on the left side using VATS given the complicated anatomic structures. L4 LND is not required in the CSCO guideline or the NCCN guideline (7,8). However, the results of the Z0030 study are only applicable to highly selected patients with pathologic diagnoses and are not generalizable for patients staged radiographically. Systemic mediastinal lymph node sampling is not practical in China because it is time-consuming. In a recent study (25) performed by Dezube et al., occult nodal metastases were found in 6.7% of 2,157 T1a NSCLC patients, including 1.6% with N2 disease. Therefore, accurate evaluation of nodal status is also recommended for early-stage tumors.

According to historic reports, the metastasis rate of L4 lymph nodes ranges from 10–20% (12-16). Unlike previous studies that included a variety of patients across clinical stages who underwent thoracotomy, all patients underwent VATS in this study, and among whom the majority were in the early stage. Interestingly, only 4.2% of patients had suspected N2 lymph node metastasis before surgery, but 9.2% of patients were diagnosed with L4 LNM postoperatively. L4 LNM rates were similar in LUL patients and LLL patients (8.9% vs. 10.0%, P=1.000), which is consistent with the results of previous studies (12,15). As a greater number of pN2 patients were found in the L4^D+ group (23.5% vs. 15.0%), it is reasonable that L4 dissection could provide more accurate staging for left-sided NSCLC.

Previous studies comparing the efficacy of L4 LND in patients with left-sided NSCLC have reported conflicting results. Yang et al. (15) retrospectively collected data from 1,929 patients and successfully matched 317 pairs of patients who underwent L4 LND or not. Their study showed that L4 lymph node metastasis was not rare and that L4 LND should be routinely performed. Wang et al. (12) collected data from 657 patients who underwent pulmonary resection, and the results also showed that the L4^D+ group had significantly better survival. Similar results were also obtained in the study by Zhao et al. (13). However, Gryszko et al. (16) retrospectively analyzed 659 pairs of patients matched from 5,369 patients by propensity score matching. No difference in 5-year OS was observed (L4^D+ group: 48% vs. L4^D- group: 50%, P=0.65), and multivariable analysis failed to confirm the effect of L4 nodal metastases as an independent prognostic factor. Patients enrolled in those studies mainly harbored advanced disease, and thoracotomy was mainly employed as the surgical method in those studies, with a VATS rate less than 20%. Therefore, the prognostic value of L4 LND for VATS patients is unclear. VATS lung cancer surgery has become a common option for early-stage resectable lung cancer patients. In the ESMO guidelines, stage I patients should undergo VATS as a priority. In our study cohort, all the patients had resectable lung cancer, were mostly in the early stage and underwent VATS.

Of note, L4 LND improved survival in patients with left lung cancer. In addition, among LLL patients, the survival curve suggested a better prognosis in the L4 LND group, despite the lack of statistical significance. Therefore, the value of L4 LND is important in identifying nodal metastasis and removing occult metastasis to improve survival in patients with left lung malignancies. Interestingly, in cT1aN0/cT1bN0 patients, no difference was found regarding OS. As indicated by the randomized JCOG 0802 trial (26), segmentectomy with systemic LND or selective LND was noninferior in terms of survival compared to lobectomy for NSCLCs less than 2 cm if the consolidation ratio is greater than 0.5. The extent of LND of cT1a-b tumors may be limited due to the low rate of nodal metastasis; however, further studies are warranted.

Limitations

This study has some limitations. First, our study was a single-center retrospective study. Second, cT1aN0 and cT1bN0 patients did not include enough cases, so the results in this subgroup should be considered with caution. Third, the records of recurrence and cause of death were not complete in the database, making it unqualified for assessing disease-free survival and recurrence patterns.

Conclusions

In conclusion, this study suggests that L4 LND should be mainly performed during VATS in patients with left-side NSCLC, but not cT1aN0 and cT1bN0 patients, because of the long-term survival benefit.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (Grant No. 81972614) and the Natural Science Foundation of Guangdong Province, China (Grant No. 2022A1515012217).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-18/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-18/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-18/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). This study was approved by the Sun Yat-sen University Cancer Center Institutional Review Board of Clinical Research (No. B2022-051-01). The requirement for patient consent was waived due to the retrospective design of the study.

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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