Short and long-term outcomes of anatomic lung resection surgery with bronchovascular reconstruction versus pneumonectomy

Introduction

Surgery for centrally located non-small cell lung cancer (NSCLC) is frequently associated with massive parenchymal resection and poor prognosis due to the highly invasive nature of the primary tumors. Traditionally, a pneumonectomy (PN) is performed, which is one of the most aggressive procedures for patients and produces a substantial decrease in lung function and quality of life. This can sometimes translate into high postoperative morbidity and mortality and delay or even hinder adjuvant treatments (1,2).

However, sometimes lung parenchyma-sparing surgeries such as sleeve bronchovascular resection or resections with bronchovascular reconstruction (BVR) can be used to avoid PN (1-5). The procedure, which involves reconstruction of the bronchus and/or pulmonary artery, has gained popularity in recent years for NSCLC, and it appears that in the short and even long term the results may be better than those of PN (1,2). As a result, the use of broncho/angioplastic procedures has increased to avoid PN in patients with centrally located NSCLC, showing an increasing proportion compared to PN (2,3).

Due to all these nuances, PN should always be the last option, with lung-sparing anatomic resection being preferable, especially in patients with comorbidities or poor lung function, but as long as they are anatomically appropriate and a margin-negative resection can be achieved.

Our main objective in the present study is to perform a detailed analysis of the technical aspects, clinicopathological characteristics and surgical outcomes after BVR in modern times, as well as evaluating the long-term survival of BVR patients compared to PN. We present this article in accordance with the STROBE reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-24-8/rc).

Methods

In 2015, the Spanish Society of Thoracic Surgery (SECT) created a multicenter working group (GE-VATS) to carry out a prospective registry of patients undergoing anatomical lung resection (6). The patients were included during a period of 15 months (from December 20, 2016 to March 20, 2018). Thirty-three national departments participated in this registry, patients undergoing bilateral surgery in the same procedure and those under 18 years of age were excluded. The project was approved by the ethical committees of the participating centers and all patients gave written consent to use their clinical data for scientific purposes. As it was a multicenter study, the researchers asked permission from the clinical research committees of all the hospitals belonging to the study. The original project, which was the creation of the database, was initially granted by the Clinical Research Ethics Committee of Aragon (CEICA) (No. PI15/0072) (information of the other centers will be provided upon request).

Given that the original registry included patients with benign pathology, primary neoplasms and secondary neoplasms, only those patients with a confirmed histological diagnosis of NSCLC were taken into account for this study. The clinical staging of the patients was performed based on the findings of the computed axial tomography and positron emission tomography according to the eighth edition of the Tumor Nodes Metastasis (TNM) classification of lung cancer. The presence of cerebral dissemination was ruled out by magnetic resonance imaging (preferable) or computed axial tomography with contrast. Invasive staging of the mediastinum was not performed systematically in all participating centers, using mediastinoscopy or puncture guided by echobronchoscopy in the centers that did perform it. The indication for neoadjuvant treatment, as well as the type of treatment administered, was determined by the multidisciplinary committees of each center, mainly in cases with ipsilateral mediastinal lymph node involvement, tumors of the superior sulcus, and central tumors with invasion of mediastinal structures. The induction treatments applied included chemotherapy, chemoradiotherapy, targeted therapies (tyrosine kinase inhibitors, immunotherapy) and their combinations. The adjuvant treatments applied were the same as those used for neoadjuvant treatment, and their indication was based on the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines (7).

Patients were classified based on having received PN or BVR. Regarding the surgical technique, the approach was open or minimally invasive depending on the criteria of each surgeon, including video-assisted thoracic surgery (VATS), robotic-assisted thoracic surgery (RATS) and subxiphoid single-incision VATS. In the VATS group, the approach included uniportal, biportal, and three or more ports. All surgeries were anatomical resections (PN, lobectomy or segmentectomy), and were accompanied by sampling or mediastinal lymph node dissection. Extended resections were those in which the lung tumor was resected en bloc along with the chest wall, vertebral body, diaphragm, vena cava, aorta, left atrium, esophagus and/or pericardium. To define postoperative complications, the consensus document signed by the European Society of Thoracic Surgeons (ESTS) and the Society of Thoracic Surgeons (STS) (8) was used. Mortality was assessed at discharge and 90 days after surgery. Readmissions were assessed in the first month after discharge.

The BVR group included patients who underwent arterial resection/reconstruction (conduit type prothesis, patch, sleeve) and/or bronchial resection (sleeve, wedge). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Statistical analysis

A descriptive analysis of demographic, epidemiological, clinical, oncological, surgical variables, complications and mortality was carried out.

For descriptive analysis, continuous variables were tested for normal distribution (Shapiro-Wilk test) and homoscedasticity (Levene’s test). Normally distributed variables were reported as mean and standard deviation, while non-normal were reported as median and interquartile range (IQR). Mean differences were assessed with a Student’s t/Mann Whitney U test. Categorical variables were reported as absolute (count) and relative (percentage) frequencies and compared with a Chi-squared/Fisher test. Some variables had missing data, as noted in Tables 1-3. For hypothesis testing, P<0.05 was used as the statistical significance value. A survival analysis was performed using Kaplan-Meier (log-rank) and Multivariate Cox. Statistical analysis was performed using SPSS, version 19.0.

Results

Table 1 shows the clinical characteristics of the patients, with no statistically significant differences between both groups, except for better albumin figures in the PN group (3.93 vs. 3.63 g/dL, P=0.007), more patients with depression in the PN group (5.1% vs. 0%, P=0.03), and better postoperative lung capacity values in the BVR group.

Regarding tumor characteristics (Table 2), the PN group stands out for having larger tumors (49.73 vs. 34.69 mm, P<0.001), more invasive (pT3–4 55.7% vs. 29.6%, P<0.001) and located in the left upper lobe (32.7%) while the BVR group was mostly in the right upper lobe (49.3%). Regarding tumor histology, the most frequent tumors were squamous cell carcinoma and adenocarcinoma, with a predominance of carcinoid tumors in the BVR group.

The main characteristics of the surgery are shown in Table 3. Surgical time was longer in BVR compared to PN (264.81 vs. 205.49 min, P<0.001). Most PN were left (62.1%) while BVR were mostly upper lobectomies (52.1% right and 28.8% left). Surgery was R0 in 85% of PN versus 78% of BVR. The most common approach was thoracotomy and extended resections were performed in a greater proportion in PN than in BVR. The different types of BVR are listed in Table 4.

Regarding the postoperative results (Table 5), there was a higher frequency of respiratory complications in the BVR group (31.5% vs. 15.4%, P=0.003), but when studied separately, only reintubation, persistent air leak and atelectasis were significant. In the rest of complications, no statistically significant differences were found nor in the number of readmissions or deaths at 90 days. No statistically significant differences were found when analyzing relapses, either as a whole or separately. In the long term, a higher frequency of death from cancer (35% vs. 20.5%, P=0.01) and from other causes was found in the PN group (6.5% vs. 4.1%, P=0.04). In the analysis of 5-year overall survival, BVR had better results than PN (log-rank test P=0.01) (Figure 1).

Figure 1 Survival analysis. BVR, bronchovascular reconstruction; PN, pneumonectomy.

In the multivariate study for overall mortality, the type of surgery continued to be significant, as well as age, sex and pathologic TNM (pTNM) (Table 6).

Discussion

For decades, PN was the treatment of choice for central NSCLC. But it is well known that they can lead to higher morbidity and mortality than lobectomies, with rates of major complications [Clavien-Dindo grade >3 (9)] that can reach 30% and mortality around 10% in the first month (10). These figures increase if we evaluate 90-day mortality (11) and if we apply neoadjuvant therapies (12). In our study, PN had fewer postsurgical complications, but they had more mortality at 90 days (8.8% vs. 6.8%; P=0.39) and more readmissions in the first month (12.1% vs. 5.4%; P=0.07), with 17.7% of the cases operated after induction therapies.

Same with other pathologies and other surgeries, it seems that a larger resection does not ensure better results. Several studies have shown that PN, a surgical procedure performed with curative intent, can behave like a disease in itself and lead to a decrease in long-term survival for reasons unrelated to the disease that caused it (13-15). Our results confirm these data, observing that long-term mortality is higher in the PN group, both due to cancer (35% vs. 20.5%; P=0.04) and other intercurrent diseases (6.5% vs. 4.1%; P=0.04).

Bronchial sleeve resection was introduced by Price-Thomas in 1947 as a means of conserving lung parenchyma in patients with compromised pulmonary function, and the first sleeve lobectomy was reported by Allison in 1954 (16). Although BVR was initially proposed for patients who did not tolerate PN and it was feared that BVR was not appropriate for oncological surgeries, over time it has been seen that this is not the case. There are several reviews and meta-analyses that have shown that BVR is preferable to PN, both in short-term and long-term results, including analysis of quality of life and cost-effectiveness (16-20).

In a review of the 2021 ESTS database, Gonzalez et al. published postoperative complication rates of 40.6% and 30-day mortality of 2.2%, with a 21.1% conversion rate to open surgery (21). Our report includes a similar number of conversions (20.5%). Regarding morbidity and mortality, our complications are broken down into two categories: respiratory (31.5%), most frequently pneumonia (10.9%); and cardiovascular (15%), most frequently atrial fibrillation (9.5%). Our data are similar to theirs; with a death rate at 90 days of 6.8%.

The drawback of BVR is that they are technically more demanding than PN, so they tend to be an indicator of quality and are carried out in high-volume centers with extensive experience. In our series, surgical time was longer in BVR compared to PN (264.81 vs. 205.49 min, P<0.001). Regarding local control, although R0 surgery was achieved in only 78% of BVR cases, the majority of long-term relapses that these patients presented were systemic (20.5%). This may be due to the fact that there was a greater proportion of BVR patients who received adjuvant radiotherapy versus PN (15.4% vs. 23.2%; P=0.10) and there was greater proportion of large, aggressive and locally advanced tumors in the PN group.

During the first years of its use, BVR was performed through open surgery in very selected patients. Currently, its performance has improved and today it can be carried out safely even after induction treatments (22,23), using minimally invasive techniques (MIS) (22-25). In fact, regarding MIS (VATS or RATS), few studies support their use in locally advanced stages, despite their clear benefits for patients: less postoperative pain, less deterioration respiratory function deterioration, less inflammatory response, shorter hospitalization and the possibility of administering prior adjuvant therapies sooner than with open surgery (26). Likewise, since the 1990s, when induction therapies were first used, there has also been concern about the possibility of subsequent technical difficulties (27). However, although there are no randomized studies in this regard, it seems that MIS will also be the standard approach for the locally advanced stages of NSCLC after neoadjuvant therapies and, with the acquisition of the necessary experience, the long-term results are similar to those obtained with open surgery (23,27-29).

Our study supports previously published results, and since it seems complicated that a randomized study could be carried out, we should try to avoid PN as much as possible given their long-term deleterious effects on the quality of life and survival of patients, and try BVR as the first surgical option in central NSCLC.

Limitations

This study has several limitations. Although its design was prospective, the decision regarding the surgical management of patients was not randomized or subject to a common protocol, so it was subject to the clinical judgment of each professional, which may have translated into selection bias. Surely some or many of the patients undergoing PN could have been operated on by BVR if a surgeon with more expertise in this technique had treated the patient. Likewise, the decision to cover the bronchial stump of PN or bronchoplasty sutures was subject to the decision of each surgeon and such information is not available in the database.

Although carcinoid tumors represent a minority of the patients operated on (2.5% PN patients and 14.1% BVR patients), the World Health Organization (WHO) includes them as histological subtypes within the spectrum of lung neuroendocrine tumors and that is why they have been included (30). However, its prognosis is better than the most common histologies of lung cancer and this may have influenced survival.

The database was designed as a prospective registry of anatomical lung resections, and lacks specific information related to complications of bronchovascular anatomoses and their management.

There was no control over the drugs, doses and number of cycles received by patients who received neoadjuvant treatments, complications related to their administration, as well as to adjuvant therapies. The majority of patients received treatments with chemotherapy and chemoradiotherapy, with cases treated with tyrosine kinase inhibitors and/or immunotherapy being a minority and commonly included in the database as targeted therapies.

Given that there was greater long-term mortality in patients undergoing PN without cancer, it would have been interesting to know these causes of mortality, but this information was not collected in the database.

However, we believe that the number of patients and the evaluation of 90-day mortality partially mitigate these problems and make this study a good contribution to the current literature.

Conclusions

BVR had a higher incidence of respiratory complications in the immediate postoperative period, with no differences regarding postoperative mortality. However, in the long-term, it represents an advantage in terms of survival and should be preferred to PN whenever possible.

Acknowledgments

We would like to thank all the members of GE-VATS group, and the Spanish Society of Thoracic Surgery (SECT) for supporting this project.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-24-8/rc

Data Sharing Statement: Available at https://vats.amegroups.com/article/view/10.21037/vats-24-8/dss

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-24-8/prf

Funding: All costs related to the start-up and maintenance of the GE-VATS database were covered by Ethicon and Johnson & Johnson. The authors had freedom of investigation and full control of the design of the study, methods used, outcome parameters and results, data analysis, and production of the written report. The GE-VATS was awarded a grant from the SECT as the best national research project of 2015.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-24-8/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). The project was approved by the ethical committees of the participating centers and all patients gave written consent to use their clinical data for scientific purposes. The original project, which was the creation of the database, was initially granted by the Clinical Research Ethics Committee of Aragon (CEICA) (No. PI15/0072) (information of the other centers will be provided upon request).

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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