Key risk factors for mortality after pneumonectomy for lung cancer: insights from a large single-center cohort study

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for a significant number of deaths annually (1). Among the various types of lung cancer, non-small cell lung cancer (NSCLC) constitutes approximately 85% of all cases (2). For patients diagnosed with resectable NSCLC lesions, pulmonary lobectomy is generally considered the gold standard surgical treatment (3). However, selected patients with centrally located NSCLC and extensive hilar adenopathy may require pneumonectomy (4-6). Pneumonectomy, which involves the complete removal of one lung, is usually associated with notably high rates of both mortality and morbidity (7).

Recent advances in anesthesia, surgical techniques, and perioperative care have significantly reduced the risk of complications and mortality following pneumonectomy. These improvements have also contributed to better early- and long-term quality of life for patients undergoing this procedure (8-11). Furthermore, the availability of efficient, less extensive, and safer surgical methods, such as sleeve-lobectomy, has led to a relative decrease in pneumonectomy indications (12).

The definition of post-operative mortality remains a topic of debate, with various interpretations in use (13). Typically, post-operative mortality includes any death, whether in-hospital or out-of-hospital, occurring within 30 days after surgery, regardless of the cause. The 30-day interval is generally considered adequate to capture the most severe surgical complications (14-16). Nevertheless, many authors propose taking into account longer post-operative intervals. Accordingly, in major surgeries, many complications occur after hospital discharge (17,18). Therefore, some suggestions are made to exceed this period even to 6 months after surgery if any death occurs due to a perioperative complication (19). Additionally, measuring outcomes such as 90-day mortality, hospital readmissions, and long-term survival is crucial for a comprehensive assessment of surgical success and patient recovery (14,20).

Advanced age and pre-existing comorbidities, particularly cardiovascular and pulmonary diseases, substantially increase the risk of postoperative complications and death (21). Reduced baseline lung function, often measured by forced expiratory volume in one second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), is a critical predictor of adverse outcomes (22). Additionally, poor nutritional status and low body mass index (BMI) are associated with higher mortality rates (23). Unfortunately, there is a paucity of literature addressing the predictors of mortality following discharge after pneumonectomy (24). We hypothesized that a 90-day follow-up period would provide a more accurate measure of operative mortality and address concerns related to the limitations of the 30-day interval.

This study aimed to assess the 30- and 90-day post-pneumonectomy mortality. The secondary aim was to identify predictors of early post-pneumonectomy mortality. An additional aim of our study was to examine whether discontinuing bronchial stump buttressing at the Department of Thoracic Surgery, Poznan University of Medical Sciences impacted the 30- and 90-day mortality rates. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2204/rc).

Methods

Patients and data collection

This retrospective, cohort study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Bioethics Committee of the Poznan University of Medical Sciences (No. 947/2, received on December 9, 2021). Appropriate consent for conducting this study has been obtained for analyzing and publishing anonymized data. The Bioethics Committee of Poznan University of Medical Sciences approved all methods and waived the requirement for obtaining informed consent from patients for the collection and analysis of anonymized data, as well as for the publication of results from this single-center, retrospective cohort study.

Inclusion criteria

• Histologically confirmed NSCLC;
• Patients who have undergone a pneumonectomy procedure, defined as the surgical removal of one entire lung;
• Adults aged 18 years and older;
• Preoperative evaluation: complete preoperative evaluation available, including imaging studies [computed tomography (CT), positron emission tomography (PET) scans], pulmonary function tests, and cardiovascular assessments;
• Surgery date: patients who have undergone surgery between 22 January 2006 and 20 November 2020.

Exclusion criteria

• Patients with a diagnosis of small cell lung cancer or other histological types of lung cancer apart from NSCLC;
• Patients with incomplete medical records or missing critical data points such as detailed surgical reports, postoperative complications, or follow-up information;
• Patients after video-assisted thoracoscopic surgery (VATS) pneumonectomy.

The decision to perform a pneumonectomy was based on diagnostic imaging, endoscopy, and biopsy procedures, including transbronchial biopsy and transthoracic needle aspiration biopsy. All patients underwent PET-CT scan, chest CT scan, electrocardiography, pulmonary function tests, and fiberoptic bronchoscopy. Respiratory efficiency was assessed using pulmonary function tests, DLCO, and capillary blood gas screening. Additionally, patients with lower spirometry values underwent the 6-minute walk test or stair test. Preoperative staging of mediastinal lymph nodes was performed in patients with enlarged lymph nodes (>10 mm in short-axis diameter) on CT scan, which additionally showed hypermetabolic activity on PET-CT scan. In such patients, we carried out invasive preoperative staging, utilizing endobronchial ultrasound (EBUS) and/or mediastinoscopy. The complete mediastinal lymphadenectomy followed each pneumonectomy. A bronchoscopy examination of the bronchial stump was conducted on the seventh postoperative day for all patients. After discharge from the hospital, patients were advised to have the wound checked and the drain suture removed in 10–14 days at a general surgery clinic or a family doctor’s clinic. Then, the patient visited the thoracic surgery clinic after 2–4 weeks. If there were no alarming symptoms, the next visit took place in another 2–3 months.

Clinical outcomes and histological type were classified according to the European Society of Thoracic Surgery/Society of Thoracic Surgeons definitions (25) and the World Health Organization classification (26), respectively, and the 8th edition of the 2017 tumor-node-metastasis (TNM) stage. Patients operated on before 2017 were reassessed according to these classifications. Follow-up data were based on the Polish Lung Cancer Study Group Database.

We included the following factors in the analysis of the impact on 30- and 90-day mortality: patients’ comorbidities, histopathology, final staging, surgical procedure details, and post-operative complications.

An additional aim of our study was to examine whether a radical change in surgical technique at the Department of Thoracic Surgery, Poznan University of Medical Sciences was related to 30- and 90-day mortality rates. Specifically, since 2013, we have significantly reduced the number of bronchial stump buttressing procedures. This change was prompted by an indocyanine green study (27), which identified potential ischemic sections in tissues used for buttressing. Therefore, we performed an additional analysis of perioperative mortality in two cohorts of patients: those who operated on before 2013 and those who operated on after 2013.

Statistical analysis

Data manipulation and all calculations were performed in R-programming language (version 3.6.1.; Vienna, R Project). We performed descriptive statistics. The numerical data is presented as median (25^th percentile to 75^th percentile), while categorical as number (percentage). The P value below 0.05 was considered as a significant difference. We performed the Cox proportional hazards model. The dependent variable was death 30- and 90-day after surgery. Initially, we performed univariable analysis using all variables describing the study group. We included all variables with a P value below 0.1 in the multivariable Cox proportional-hazards model. We made a manual selection based on the literature, clinical experience, and critically excluded variables that may be closely related to each other and, therefore, influence the result of the multivariable model. In the literature, factors such as the occurrence of bronchopleural fistula (BPF) (28,29), prolonged intubation (30), and chest wall infiltration (31) are significant prognostic indicators in the surgical treatment of lung cancer. We then performed stepwise variable selection procedures using the function “My.stepwise.coxph()” from R package “My.stepwise” to obtain the best-fitted model (32). We visualized overall mortality for 30- and 90-day using the Kaplan-Meier curves.

Results

Of the 551 patients who underwent pneumonectomy between 2006 and 2020, 514 meeting the eligibility criteria were included in the analysis. This retrospective cohort study included 514 patients who underwent pneumonectomy with lymphadenectomy for NSCLC by anterolateral thoracotomy at the Department of Thoracic Surgery of Poznan University of Medical Sciences between 22 January 2006 and 20 November 2020. The patient selection process is detailed in the flowchart (Figure 1).

Figure 1 Flowchart diagram presenting the successive steps of creating the group of 514 patients after pneumonectomy due to NSCLC, finally included in the analysis. NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; VATS, video-assisted thoracoscopic surgery.

The analysis included 514 patients who underwent pneumonectomy for NSCLC, comprising 377 men (73.3%) and 137 women (26.7%). The median age of the entire group was 61 [interquartile range (IQR), 56–66] years, and the median FEV1 for the entire group was 75% (IQR, 62–87%). Most patients were operated on in stages IIB—149 (29%) and IIIA—241 (46.9%). Thirty-eight (7.4%) patients received neoadjuvant therapy. The 30- and 90-day mortality for the entire group equaled 4.3% and 9.1%, respectively. The general characteristics of the group are presented in Table 1.

The variables that obtained P<0.1 for 30-day mortality in the univariable analysis were the occurrence of the BPF, partial resection of the diaphragm, the history of stroke 6 months before the operation, partial resection of the chest wall, positive bronchial resection margin, clinical stage T3, right pneumonectomy, stage IIB, prolonged intubation (>48 hours).

The variables that obtained P<0.1 for 90-day mortality in the univariable analysis were the occurrence of the BPF, partial resection of the diaphragm, partial resection of the chest wall, chest wall infiltration, parietal pleura infiltration, positive bronchial resection margin, prolonged intubation (>48 hours), acute kidney insufficiency, the history of stroke 6 months before the operation, reintubation, the procedure performed before 2013, and the stage IIB.

The results of the univariable Cox proportional hazards regression are presented in Tables 2-4.

In the multivariable Cox analysis, the following factors were significant for 30-day mortality: the occurrence of the BPF [hazard ratio (HR) =5.128; 95% confidence interval (CI): 2.009–13.087; P<0.001], positive bronchial resection margin (HR =7.917; 95% CI: 2.61–24.01; P<0.001) and the prolonged intubation (>48 hours) (HR =3.822; 95% CI: 1.06–13.785; P=0.041) (Table 5).

In the multivariable Cox proportional hazard regression the statistically significant factors for the 90-day mortality were: the occurrence of the BPF (HR =5.284; 95% CI: 2.706–10.318; P<0.001), positive bronchial resection margin (HR =3.528; 95% CI: 1.370–9.083; P=0.009), chest wall infiltration (HR =3.770; 95% CI: 1.121–12.676; P=0.03), and prolonged intubation (>48 hours) (HR =2.912; 95% CI: 1.102–7.649; P=0.03) (Table 6).

The 30-day mortality rate of patients operated on before 2013 was 4.3%, and after 2013, it was 4.2%. The 90-day mortality rate of patients operated on before 2013 was 11.4%, and after 2013, it was 6.9%.

Kaplan-Meier 90-day survival curves for the variables BPF, positive bronchial resection margin, and prolonged intubation (>48 hours) are shown in Figures 2-5. Additionally, Figure 6 includes Kaplan-Meier 90-day survival curves showing the differences in 90-day survival of patients operated on before and after 2013.

Figure 2 Kaplan-Meyer curves showing the impact of a bronchopleural fistula development on the risk of death in the first 90 days after pneumonectomy.

Figure 3 Kaplan-Meyer curves showing the impact of a prolonged intubation (>48 hours) on the risk of death in the first 30 days after pneumonectomy.

Figure 4 Kaplan-Meyer curves showing the impact of a positive bronchial resection margin on the risk of death in the first 90 days after pneumonectomy.

Figure 5 Kaplan-Meyer curves showing the impact of the chest wall infiltration on the risk of death in the first 90 days after pneumonectomy.

Figure 6 Kaplan-Meier survival curves comparing the differences in 90-day survival of patients operated on before and after 2013.

Discussion

In the multivariable analysis for both 30- and 90-day mortality, the following variables were found to be statistically significant: the occurrence of a BPF, prolonged intubation (>48 hours), and positive bronchial resection margins. Furthermore, chest wall infiltration was a significant factor for 90-day mortality.

Despite advancements in thoracic surgery, pneumonectomy still poses a considerable mortality risk compared to less extensive procedures (7). Pneumonectomy accounts for approximately 6.3% to 15% of all lung resections for primary lung cancer, with a declining trend observed over time (21,28,33). Postpneumonectomy mortality rates range from 4.6% to 7% for 30-day mortality (6) and 7% to 12% for 90-day mortality (12,34).

In-hospital death and 30-day mortality usually serve as the measure for postoperative mortality risk (7). However, the validity of the 30-day cut-off point for major pulmonary resections has been questioned regarding its ability to estimate mortality risk accurately. Patient data are typically analyzed from admission to discharge or in-hospital death without accounting for possible subsequent hospitalizations in other departments (18,25). Notably, some studies, including ours, have observed a doubling of mortality rates after 90 days (15,35,36). Therefore, relying solely on 30-day mortality in the context of major pulmonary resections may inadequately assess postoperative outcomes and potentially underestimate the risk of early postoperative mortality (18,24,35).

The higher 90-day mortality compared to 30-day mortality following pneumonectomy underscores the need for more cautious patient selection. Studies have linked early postoperative mortality to immediate surgical complications such as respiratory failure, cardiac events, and infections (37,38). Given these risks, especially within the first month post-surgery, thorough preoperative assessment is crucial to identify patients who might benefit more from non-surgical treatments. Personalized therapy, incorporating chemotherapy, radiotherapy, and immunotherapy, may offer comparable survival outcomes with a lower immediate risk of death (39). Integrating these findings into clinical practice could enhance patient outcomes by reserving pneumonectomy for those with a favorable risk profile and directing others toward systemic therapy with lower early mortality risks.

One of the larger studies on thoracic resection procedures reported that most post-pneumonectomy deaths associated with post-surgery trauma occur within 30 days after surgery or shortly after discharge (35). Accordingly, complications related to the surgery often arise between 31 and 90 days post-procedure (35). The number of studies highlights the necessity of vast postpneumonectomy mortality analysis, including all deaths within the next 90 days (18,35,40,41). Although lung cancer treatment follow-up is systematic and long-term, greater emphasis on close postoperative supervision appears warranted. Based on the available literature, it may be reasonable to extend the postoperative follow-up period after pneumonectomy to 90 days (40) or even 6 months (41) to account for various delayed postoperative causes of death. It would help to cover the variety of different types of delayed post-operative causes of death. The 90-day mortality rate is particularly relevant given the specific profile of NSCLC patients, who are often elderly and have multiple comorbidities, resulting in reduced functional reserve and higher susceptibility to complications (18).

In our study, BPF emerged as the most significant factor impacting 30- and 90-day mortality following pneumonectomy. Postpneumonectomy BPF remains the most severe complication in the early postoperative period. It occurs in 1.5% to 12.5% of pneumonectomies (10,42) and leads to life-threatening complications, such as respiratory insufficiency or sepsis. The 30-day mortality rate in patients with post-pneumonectomy BPF ranges from 13% to 67% (28,29). Notably, right-sided pneumonectomy is associated with a higher risk of mortality, primarily due to an increased incidence of BPF (5,43). In our study, the 30- and 90-day mortality rates of patients who developed BPF were 18% and 33%, respectively. The choice of surgical technique is crucial in this context. Recent discussions have focused on the potential benefits of additional tissue buttressing of the bronchial stump, highlighting the ongoing controversy in this area (27). The actual benefit of bronchial stump buttressing has not been fully elucidated (44,45); however, it appears to be particularly justified in high-risk patients. Meanwhile, new techniques for bronchial stump buttressing continue to emerge (46). Given these findings, particular attention must be directed towards patients with the highest risk factors for developing BPF (47,48). Investigating the technical aspects contributing to early BPF formation holds significant potential for reducing mortality rates post-pneumonectomy. Understanding these factors can inform surgical practices and enhance patient outcomes.

Prolonged intubation, defined as intubation extending beyond 48 hours postoperatively, contributes to increased 30- and 90-day mortality. Extended intubation periods are often indicative of underlying respiratory complications or failure to wean the patient from mechanical ventilation, both of which are associated with higher morbidity and mortality (49). Prolonged intubation can lead to ventilator-associated pneumonia and other respiratory complications, further exacerbating patient outcomes (50,51).

The presence of microscopic tumor invasion at the bronchial resection margin (R1 resection) following pneumonectomy is a critical predictor of early mortality. Studies have demonstrated that patients with positive bronchial margins have significantly worse prognoses and higher rates of early postoperative mortality compared to those with clear margins (52-54). Positive resection margins suggest residual disease, which can rapidly progress and lead to early recurrence and metastasis (52,53). Therefore, resection margin positivity should be recognized as a general risk factor, as it consistently serves as a negative prognostic indicator, regardless of the surgical procedure performed. However, it should be mentioned that although microscopically positive bronchial resection margin is indeed described in the literature as a factor reducing the chance of long-term survival, it is much less likely to appear as a predictor of 90-day death. A possible explanation is that residual bronchial tumor is a risk factor for BPF (55), which is a fatal complication with high mortality. Our study also demonstrated the association between BPF and increased 30- and 90-day mortality. This interpretation appears to be the most consistent with recent studies (54). In our study, the microscopic invasion of lung cancer into the chest wall represents a significant prognostic factor affecting post-pneumonectomy mortality rates. Studies have shown that the presence of microscopic chest wall invasion is associated with lower 5-year survival rates due to its implications for surgical resection and tumor clearance (31,56,57). Microscopic chest wall invasion is indicative of locally advanced, T3 lung cancer, posing challenges for complete tumor eradication during surgery and increasing the likelihood of residual tumor cells (58). However, chest infiltration is mentioned much less frequently in the context of compliance within 30 or 90 days of surgery. According to the authors, the impact of this invasive pattern should be further analyzed in terms of association with a potentially higher incidence of postoperative complications, such as infections and respiratory insufficiency, contributing to elevated mortality rates following pneumonectomy. Consequently, patients exhibiting microscopic chest wall invasion necessitate meticulous postoperative monitoring and may benefit from more aggressive neoadjuvant and adjuvant therapies to improve outcomes and mitigate mortality risk (59).

An interesting observation was that the 90-day mortality rate in our center decreased after 2013. This observation is challenging to justify definitively. We believe, however, that it may be associated with general improvements in patient care over the past two decades. In our center, we have successfully implemented numerous elements of the enhanced recovery after surgery (ERAS) protocol: patients receive nutritional support, undergo faster rehabilitation and mobilization, and are better prepared for the postoperative period. At the same time, 30-day mortality did not change significantly. On the other hand, the analyses showed that bronchial stump buttressing did not decrease the overall mortality. In one of our previous papers, we also observed that it has no effect on the occurrence of BPF (44). Therefore, we observed that changing the surgical technique had an impact on number of early mortality rates.

The authors acknowledge several limitations of this study. Firstly, the retrospective nature of the study may affect the accuracy and completeness of the data. Post-discharge deaths may result from incidental factors unrelated to the surgery, which might complicate the interpretation of the extended follow-up period. Nevertheless, we obtained reasonably detailed data on the cause of death for our patients within approximately 3 months post-procedure. Patients with incomplete medical records were excluded from the analysis. Additionally, most data were sourced from the national lung cancer database, supplemented by physician reports. This analysis reflects the experience of a single high-volume center. On the other hand, the study benefits from long-term observation of a large cohort of pneumonectomies, all performed at a high-volume center by an experienced team. Finally, potential confounders such as comorbidities, variations in postoperative care, and adjuvant therapies might influence outcomes and present challenges for retrospective control. However, we employed statistical methods such as multivariable regression analysis to adjust for confounding factors, ensuring that the primary outcomes are robust and reflect the actual effects of pneumonectomy on survival.

One of the clinical implications of this study is more detailed post-discharged monitoring of high-risk patients. In justified cases, this care would involve general practitioners or other medical professionals providing long-term care or periodic home visits. It could lead to earlier identification of possible complications and prevent early postoperative deaths. Patients undergoing extended resections face higher operative risks; therefore, a thorough preoperative workup of the cardiopulmonary function should be performed for adequate risk assessment (12). Additionally, patients at risk of developing BPF should receive exceptional care. Their preoperative evaluation should include strict cardiopulmonary and thorough BPF risk factors assessment. These patients require even more attention after discharge, potentially including additional home checks by their general practitioner.

Furthermore, the findings from this study suggest significant clinical implications for future patient monitoring strategies. Enhanced postoperative monitoring through telemedicine could improve patient outcomes by enabling continuous remote observation of vital signs, such as heart rate, electrocardiography, and oxygen saturation via pulse oximetry. These technologies facilitate early detection of complications, allowing for timely interventions. Furthermore, integrating remote monitoring systems with regular teleconsultations can provide patients with prompt medical support, potentially reducing readmission rates and improving long-term survival. This approach highlights the importance of incorporating advanced telehealth solutions into routine postoperative care to enhance patient safety and optimize recovery.

In conclusion, careful staging is essential in the case of pneumonectomy. The procedure is burdened with a high perioperative risk, and according to the authors, it should be limited to a small group of patients with good respiratory efficiency and physical condition. Addressing these factors is essential for improving surgical outcomes and reducing early mortality rates following pneumonectomy. Enhanced perioperative care protocols, early identification and management of complications such as BPF, timely weaning from mechanical ventilation, and ensuring complete tumor resection are vital strategies in this regard. We highly recommend that lung cancer databases collect the 90-day mortality data systematically.

Conclusions

This study highlights the importance of extending the follow-up period to 90 days when assessing mortality after pneumonectomy for NSCLC. The findings reveal that 30- and 90-day mortality rates are significant at 4.3% and 9.1%, respectively. Critical factors contributing to increased mortality within these time frames include the presence of a BPF, prolonged intubation, chest wall infiltration, and positive bronchial resection margins. These results underscore the need for careful post-operative monitoring and management of patients with these risk factors to improve outcomes following major pulmonary resections.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2204/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2204/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2204/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2204/coif). Mikołaj Kamiński reports that he has received support for conference participation from the following companies: Medac, Berlin-Chemie Menarini, Boehringer Ingelheim, and Eli Lilly. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective, cohort study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Bioethics Committee of the Poznan University of Medical Sciences (No. 947/2, received on December 9, 2021). Appropriate consent for conducting this study has been obtained for analyzing and publishing anonymized data. The Bioethics Committee of Poznan University of Medical Sciences approved all methods and waived the requirement for obtaining informed consent from patients for the collection and analysis of anonymized data, as well as for the publication of results from this single-center, retrospective cohort 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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