Impact of bilateral mediastinal lymph node dissection on pulmonary function during the early postoperative period after curative-intent lung surgery for cancer: a randomized study
Highlight box
Key findings
• Vital capacity (VC) and forced expiratory volumes in 1st second (FEV1) significantly decreased on 1 postoperative day from the baseline measurements and subsequently increased within the first week. The patterns of change in the VC and FEV1 were similar for both groups, and there were no significant differences between them on postoperative days 1, 3–5, 7–9, and 30–32.
What is known and what is new?
• Bilateral lymph node dissection (BML) is not the standard surgical treatment for non-small cell lung cancer. However, data from anatomical studies showing lymph flow to the contralateral mediastinal lymph nodes have prompted attempts to extend lymph node dissection to the contralateral mediastinum. Promising results have been reported by several small nonrandomized studies, but little is known about the effects of extended lymphadenectomy on pulmonary function.
• Our study provides original data showing the comparable patterns of changes in the VC and FEV1 after BML and standard lymphadenectomy, with no significant differences on postoperative days 1, 3–5, 7–9, and 30–32. Evidence on this has not yet been published.
What is the implication, and what should change now?
• The knowledge that BML does not lead to more severe deterioration of respiratory function than standard lymph node dissection is important for clinical decision-making and assessment of the surgical risk associated with cancer surgery. Large, preferably multi-center, prospective trials are needed to confirm our results and provide data to enable the analysis of complication risks associated with BML.
Introduction
Background
Bilateral lymph node dissection is not considered the standard surgical treatment for non-small cell lung cancer (NSCLC) (1). However, an anatomical study of lymph flow from different segments of the lung by Hata et al. showed that lymph flow to contralateral mediastinal lymph nodes is common, especially from the left lower lobe (2). Metastatic deposits left in the lymph nodes on the other side of the mediastinum may lead to cancer recurrence. This finding has prompted attempts to extend lymph node dissection to the contralateral mediastinum, and promising results have been published by several non-randomized studies (2-5). The pilot BML-1 study was the first randomized trial to compare bilateral mediastinal lymphadenectomy (BML) with standard systematic lymph node dissection (SLND) (1). Its results on the effects of BML on survival have been previously reported (1).
Rationale and knowledge gap
Knowledge of the potential deterioration of pulmonary function after surgery for lung cancer is important in clinical decision-making. However, the postoperative effect of BML on pulmonary function has not yet been established. BML may affect the respiratory function in two ways: (I) pain intensity associated with additional incision and dissection may contribute to more profound limitation of respiratory movements; (II) bilateral dissection of the mediastinal lymphatic system may affect lymph drainage from the lungs, resulting in interstitial edema worsening lung compliance. In this study, we report effect of BML on the respiratory function during the early postoperative period after curative-intent lung resection of NSCLC.
Objective
This study aimed to assess whether BML performed as part of lung cancer surgery leads to more severe impairment of respiratory function than SLND. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/rc).
Methods
This study was approved by the Bioethical Committee of Jagiellonian University in Cracow (K/ZDS/002337). All patients received detailed information regarding the procedures and their potential risks and benefits were discussed. Informed consent was obtained from all patients. There were no changes to the protocol during the trial.
Clinical question
Does BML result in more severe deterioration of respiratory function than SLND?
Study design
This was a prospective, randomized, parallel study. The BML-1 trial was designed as a pilot study and aimed to provide preliminary data on the different aspects of bilateral mediastinal lymph node dissection.
Setting
Department of Thoracic Surgery, Jagiellonian University Medical College, John Paul II Hospital, Cracow, Poland.
Patients
The inclusion criteria were as follows: (I) adult patients with confirmed or suspected NSCLC stage I–IIIA; accepted stage IIIA included only single-station, non-bulky N2 disease; (II) preoperative staging was routinely performed using chest radiography, computed tomography, positron-emission tomography-computed tomography (PET-CT), abdominal ultrasonography, bronchoscopy, endobronchial ultrasonography (EBUS), and endoscopic ultrasonography (EUS); and (III) general fitness enabling appropriate lung resection, assessed according to the European Respiratory Society and European Society of Thoracic Surgery Guidelines (6). The exclusion criteria were as follows: (I) history of malignancies other than non-melanoma skin cancer; (II) induction chemotherapy or chemoradiotherapy; (III) pathological confirmation of tumors other than NSCLC; (IV) ground-glass opacity lesions; and (V) lack of informed consent (1).
Intervention
Randomization was performed by the study coordinator (J.K.) using a computer-based random-digit generator (LUCASC, version 1.0, Morawski, Poland) with a 1:1 allocation ratio.
The technique of lymph node dissection was described in detail elsewhere (1). In brief, in patients, in whom diagnosis of cancer was not confirmed preoperatively, wedge resection of the lesion and frozen-section examination was initially performed. In patients with confirmed NSCLC appropriate anatomical lung resection was continued. After completion of the lung resection, standard lymph node dissection was performed in all patients, according to the European Society of Thoracic Surgeons guidelines, including the following nodal stations: 2R, 4R, 3A, 7, 8, and 9 (right side) or 5, 6, 7, 8, and 9 (left side) (7). In the SLND group mediastinal dissection was finished at this stage. In the BML group the chest was closed, patients were next placed in a supine position, and an additional, ~5 cm cervical incision was performed. The transcervical dissection included nodal stations not accessible during the standard lung resection: station 2L and 4L for right lung tumours and 2R, 4R, 2L, and 4L for left lung tumours.
The strap muscles were divided in the median line and then dissected from the thyroid gland. Middle thyroid veins were divided and the both carotid arteries and brachiocephalic artery were dissected free. The right laryngeal recurrent nerve was visualized first. Next, the left carotid artery was retracted laterally, and the left laryngeal recurrent nerve was visualized. At this stage of the procedure a sternal retractor (Munster Frame, Aesculap GmbH, Tuttlingen, Germany) was placed under the manubrium of the sternum. The sternum was elevated, allowing better exposure of the mediastinum. The upper poles of the thymus were divided from the thyroid gland and retracted upwards and the superior surface of the innominate vein was dissected free. Having both laryngeal recurrent nerves visualized, the whole tissue lying in front of the trachea, behind the upper poles of the thymus was removed en bloc; the laryngeal recurrent nerves are the lateral margins of dissection. Dissection of the left paratracheal space was performed while retracting the trachea to the right side and the left common carotid artery to the left and upwards, which enables visualization of the whole left paratracheal space to the level of the proximal 1/3 of the left main bronchus. Carefully preserving the left laryngeal recurrent nerve, the lymph nodes 2L and 4L were dissected. In patients with right lung tumors, the transcervical dissection ends at this point, as the remaining nodal stations have already been dissected via thoracic approach. Although dissection of the stations 5, 6 and 8 (both sides) is feasible using the transcervical approach, as described elsewhere (8), it was not performed in this study, because metastases in these nodes are extremely rare in patients with the right lung tumor and the mediastinum negative on PET, EBUS and EUS. Transcervical dissection of the contralateral station 9 nodes is not feasible, but again, metastases in this location are unlikely in patients with clinical N0–1 stage. In patients with left lung tumors, the right paratracheal space was dissected next. The confluence of the innominate veins was elevated using the retractor, the trachea was retracted to the left side and the right paratracheal space was opened by blunt dissection under the brachiocephalic artery and above it, along the course of the vagus nerve. The access above the artery is more convenient for dissection of the 2R nodes, whereas the access between the artery and the tracheal wall is better suited for removing of 4R nodes. All of the tissue from the right paratracheal space was removed to the level below the azygos vein. The borders of dissection are: the innominate vein and vena cava superiorly, vertebral column inferiorly, mediastinal pleura laterally and the trachea, ascending aorta and right main bronchus medially.
Variables measured
The variables recorded were: (I) preoperative vital capacity (VC) and forced expiratory volumes in 1st second (FEV1) expressed as absolute and percentage values; (II) VC measured on postoperative days 1, 3–5, 7–9, and 30–32; and (III) FEV1 measured on postoperative postoperative days 1, 3–5, 7–9, and 30–32. All spirometric measurements were performed using a LungTest 250 compact spirometer (MES; Cracow, Poland). There were no changes in the trial outcomes after commencement.
Statistical analysis
The BML-1 study is the first randomized trial comparing BML with SLND, and there were insufficient data to enable sample size calculation before the trial commenced.
Repeated-measures analysis of variance (ANOVA) was used to reveal the differences in the VC and FEV1 measures over time across groups, and pairwise comparisons of the predictive margins were used to assess the difference between simple effects, meaning the differences in VC and FEV1 within groups over time. To assess the inter-group differences in the measured parameters, the contrasts of the marginal linear predictions at each time point were analyzed. Growth mixed models with linear predictions of changes in VC or FEV1 over time after the intervention were used to determine whether the curves representing the changes in the measures over time differed for the groups; the time-point measures were considered. If a linear prediction was not observed, the quadratic prediction was also tested, assuming that the nature of the change may not be clearly linear but may also be quadratic. Statistical significance was set at P<0.05.
Results
Comparison of baseline characteristics
A total of 102 patients were included in the BML-1 study between 2010 and 2013; 50 and 52 were randomly allocated to the BML and SLND groups, respectively. After randomization, 13 patients met the exclusion criteria: 10 in the BML group and 3 in the SLND group. Data from 89 patients were available for the final analysis. Complete respiratory function test data were available for 35 patients (Figure 1). The age, sex, Thoracoscore, revised cardiac risk index, dyspnea score, lobar tumor location, histology, lung resection type, baseline VC, and FEV1 of both groups were comparable (Table 1).
Table 1
| Parameters for lung ventilation | SLND (n=20) | BML (n=15) | P value |
|---|---|---|---|
| VC | |||
| Baseline VC | 0.82 | ||
| Mean (SD) | 3.69 (0.88) | 3.64 (0.87) | |
| Median (IQR) | 3.87 (1.53) | 4.00 (1.10) | |
| Day 1 VC | 0.49 | ||
| Mean (SD) | 1.78 (0.62) | 1.62 (0.51) | |
| Median (IQR) | 1.60 (0.81) | 1.60 (0.72) | |
| Days 3–5 VC | 0.66 | ||
| Mean (SD) | 2.10 (0.54) | 2.00 (0.63) | |
| Median (IQR) | 1.98 (0.97) | 2.07 (1.05) | |
| Days 7–9 VC | 0.18 | ||
| Mean (SD) | 2.44 (0.52) | 2.14 (0.70) | |
| Median (IQR) | 2.45 (0.81) | 2.13 (1.38) | |
| Days 30–32 VC | 0.16 | ||
| Mean (SD) | 2.75 (0.57) | 2.35 (0.69) | |
| Median (IQR) | 2.80 (1.01) | 2.23 (1.21) | |
| FEV1 | |||
| Baseline FEV1 | 0.96 | ||
| Mean (SD) | 2.74 (0.65) | 2.73 (0.79) | |
| Median (IQR) | 2.78 (1.27) | 3.01 (1.56) | |
| Day 1 FEV1 | 0.40 | ||
| Mean (SD) | 1.38 (0.45) | 1.23 (0.37) | |
| Median (IQR) | 1.25 (0.73) | 1.20 (0.58) | |
| Days 3–5 FEV1 | 0.72 | ||
| Mean (SD) | 1.62 (0.43) | 1.55 (0.53) | |
| Median (IQR) | 1.50 (0.48) | 1.60 (0.67) | |
| Days 7–9 FEV1 | 0.81 | ||
| Mean (SD) | 1.79 (0.42) | 1.75 (0.56) | |
| Median (IQR) | 1.83 (0.67) | 1.60 (0.93) | |
| Days 30–32 FEV1 | (n=16) | (n=8) | 0.32 |
| Mean (SD) | 1.99 (0.45) | 1.77 (0.54) | |
| Median (IQR) | 1.99 (0.77) | 1.55 (0.96) |
SLND, systematic lymph node dissection; BML, bilateral mediastinal lymphadenectomy; VC, vital capacity; SD, standard deviation; IQR, interquartile range; FEV1, forced expiratory volumes in 1st second.
Comparison of pulmonary ventilation
Significant reductions in the VC and FEV1 were observed on the first postoperative day for both groups (P<0.001), followed by a gradual increase within the first week. After the first week, minimal improvements in the VC and FEV1 were observed in the BML group, with no significant differences between postoperative days 7–9 and 30–32 (P=0.10 and 0.22, respectively). In the SLND group, significant improvements in the VC and FEV1 were observed between postoperative days 7–9 and 30–32 (P=0.05 and P=0.04, respectively) (Figure 2A,2B). There were no differences between the VCs of the groups on postoperative days 1, 3–5, 7–9, and 30–32 (P=0.49, 0.66, 0.18, and 0.16, respectively). There were also no inter-group differences in FEV1 at the same time points (P=0.40, 0.72, 0.81, and 0.32, respectively). Growth mixed models with linear predictions of the changes in VC or FEV1 over time after surgery did not show significant differences between the BML and SLND groups (P=0.58 and 0.94, respectively) (Figure 3A,3B).
Comparison of respiratory complications
No postoperative death or respiratory failure occurred in either group. No significant differences in complications were observed between the two groups. Of the patients in the BML and SLND groups, 34.7% and 37.5% developed complications [odds ratio (OR) 1.13, 95% confidence interval (CI): 0.47–2.69, P=0.82] (1). The respiratory complications included atelectasis in 4 patients (3 patients in the BML group and 1 patient in the SLND group) and pneumonia in 2 patients (both in the BML group).
Discussion
Key findings
Our study provides original data showing comparable patterns of changes in the VC and FEV1 after BML and standard lymphadenectomy, with no significant differences on postoperative days 1, 3–5, 7–9, and 30–32. Evidence on this has not yet been published. We showed a significant decrease in VC and FEV1 on postoperative day 1 from the baseline and a subsequent increase within the first week.
Strengths and limitations
To our knowledge, this is the first study to analyze the impact of bilateral mediastinal lymph node dissection on respiratory function in patients who have undergone surgery for lung cancer. The strength of this study is its design. The analyzed data were obtained from a randomized study. One drawback is the small sample of patients included, which is associated with the pilot characteristics of the BML-1 study. Nevertheless, our findings can be used in predicting the postoperative course in patients, in whom BML is considered.
Comparison with similar research
Published evidence on bilateral mediastinal lymph node dissection during anatomical lung resection for cancer is limited. Data on the effect of lymphadenectomy on respiratory function have not been included in most analyses.
Th only detailed data on the changes in respiratory function associated with bilateral mediastinal lymph node dissection come from a small randomized study comparing transcervical extended mediastinal lymphadenectomy (TEMLA) and standard cervical mediastinoscopy for lung cancer staging. Unlike our study, pulmonary resection was not performed in that trial (9). However, similar to the present study, significant reductions in the VC and FEV1 were observed on postoperative day 1, with subsequent increments on the following days. In addition, the differences between the VC and FEV1 in the TEMLA and mediastinoscopy groups on postoperative days 1, 3, and 5 were not significant, which is consistent with our results. Noteworthy, this was the only study to analyze the lung compliance after bilateral mediastinal dissection. Because patients in this study did not underwent lung resection, the question if BML is associated with impairment of lymphatic drainage of the lungs causing clinically important interstitial edema and worsening of lung compliance, remains to be addressed in future studies.
In our study, respiratory complications were observed in 6 patients: atelectasis in four patients (3 patients in the BML group and 1 in the SLND group) and pneumonia in 2 patients (both in the BML group).
Witte et al. compared minimally invasive lung resection with SLND and bilateral mediastinal dissection using the video-assisted mediastinoscopic lymphadenectomy (VAMLA) technique. The main objective of this study was to assess the feasibility and radicality of a combined thoracoscopic and mediastinoscopic approach to mediastinal lymphadenectomy compared with thoracoscopy (10). Respiratory function was not analyzed, but the authors observed fewer cases of respiratory tract infections: 3 of 18 patients who underwent VAMLA and 2 of 14 patients who underwent SLND. The differences were not significant. In a study by Turna et al. that compared SLND with VAMLA, data on the rate of respiratory complications were not reported (11).
Three studies performing bilateral mediastinal dissection for lung cancer staging without pulmonary resection have been published. In a small observational study of 25 patients who underwent VAMLA for lung cancer staging, no respiratory complications were found (12). A randomized study compared 21 patients who underwent TEMLA with 20 who underwent standard cervical mediastinoscopy. The pulmonary complications in both groups were as follows: atelectasis, 0 vs. 1; pleural effusion, 4 vs. 1; and respiratory failure, 1 vs. 0. The differences were not significant (13).
Explanations of findings
The significant decrease in VC and FEV1 on postoperative day 1 from the baseline can be explained by the loss of lung volume and impairment of ventilation, which is typical for early postoperative period after thoracic surgery. The respiratory parameters did not reach the preoperative levels, which was attributable to the permanent loss of the resected lung parenchyma.
Implications and actions needed
The knowledge that BML does not lead to a more pronounced deterioration of respiratory function than standard lymph node dissection is important for clinical decision-making and assessment of the surgical risk associated with cancer surgery. Large, preferably multi-center, prospective trials are needed to confirm our results and provide data to enable the analysis of the complication risks associated with BML.
Conclusions
BML was not associated with a more severe deterioration of respiratory function than standard (unilateral) lymph node dissection. We did not find significant differences in the respiratory complication rates of the groups, but the small sample of patients analyzed did not allow for concrete conclusions.
Acknowledgments
Funding: The BML-1 study was financially supported by
Footnote
Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/rc
Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/tp
Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/dss
Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/coif). J.K. reports Jagiellonian University Statutory Grant. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the principles of the Declaration of Helsinki (as revised in 2013). This study was approved by the Bioethical Committee of Jagiellonian University in Cracow (K/ZDS/002337), and informed consent was obtained from all participants.
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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