Abstract
Background
The INT0139 trial [2009] raised concerns about the safety of pneumonectomy after chemoradiation due to high perioperative mortality rates. Recent clinical trials have supported the use of neoadjuvant treatment as a viable option for stage Ib or greater lung cancer. We hypothesized that neoadjuvant treatment does not increase perioperative mortality risk in patients undergoing pneumonectomy.
Methods
Adult patients with nonmetastatic non-small cell lung cancer (NSCLC) from the 2004–2021 National Cancer Database undergoing pneumonectomy were analyzed in a retrospective cohort study. Exclusions included missing study variables, non-adenocarcinoma/squamous histology and pneumonectomy after neoadjuvant radiation alone. Multivariate logistic regression analyzed 30- and 90-day mortality and included laterality and neoadjuvant treatment interactions.
Results
Of 14,522 patients, 58.6% underwent right pneumonectomy and 41.4% underwent left pneumonectomy. Neoadjuvant treatment was received by 14.9% (systemic therapy alone: 1,008; systemic therapy + radiation: 1,156). The 90-day mortality was higher for right versus left pneumonectomy (17.2% vs. 9.8%, P<0.001). Neoadjuvant therapy was not associated with higher 90-day mortality compared to surgery alone (10.4% vs. 13%, P=0.04). Independent predictors of mortality included right-sided pneumonectomy [odds ratio (OR) =2.01, 95% confidence interval (CI): 1.78–2.28], advanced age (OR =1.05, 95% CI: 1.04–1.06), and Charlson-Deyo index ≥ 3 (OR =1.98, 95% CI: 1.53–2.57). Interaction analysis showed no increased risk with neoadjuvant therapy for either side.
Conclusions
This analysis reiterates known elevated risk associated with right pneumonectomy but disputes the dogma that neoadjuvant treatment increases the risk of pneumonectomy, suggesting that neoadjuvant treatment is not a contraindication to receipt of pneumonectomy.
Keywords: Pneumonectomy, tripple therapy, dogma
Introduction
Pneumonectomy is a highly invasive procedure reserved for patients with large or centrally located tumors where less extensive surgical options are not feasible. Concerns regarding its perioperative safety were heightened by the INT0139 trial, a phase III clinical trial conducted by Albain et al. in 2009, which reported high mortality rates following pneumonectomy after chemoradiation (1). These findings led to widespread caution regarding the use of neoadjuvant treatment in patients requiring pneumonectomy. More recently, the advent of neoadjuvant chemoimmunotherapy regimens has renewed interest in neoadjuvant approaches, introducing uncertainty in how best to manage these patients (2).
Existing literature provides mixed insights into the safety of pneumonectomy following neoadjuvant therapy (3,4). While some studies suggest that pneumonectomy can be performed with acceptable morbidity and mortality rates when conducted in experienced centers (4), others emphasize the elevated risks associated with right-sided procedures and the potential for increased postoperative complications (1). Notably, a retrospective analysis indicated a perioperative mortality rate as high as 23.9% after right pneumonectomy post-chemotherapy or chemoradiotherapy, which reiterates concerns raised by the INT0139 trial (5). Despite these findings, there remains a lack of consensus on whether neoadjuvant treatment exacerbates these risks or if it can be safely integrated into patient care pathways.
Discrepancies in the current literature highlight the need for further investigation into the relationship between neoadjuvant therapy and pneumonectomy outcomes. This study leverages data from the National Cancer Database (NCDB) to evaluate whether neoadjuvant treatment influences 90-day mortality following pneumonectomy. The specific objectives are to: (I) assess the impact of neoadjuvant therapy on 30-day and 90-day mortality after pneumonectomy; (II) evaluate differences in outcomes based on pneumonectomy laterality; and (III) identify independent risk factors associated with postoperative mortality. We hypothesize that neoadjuvant chemotherapy and radiation do not increase the risk of mortality following pneumonectomy. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1175/rc).
Methods
Data source
This was a retrospective cohort study using the NCDB Participant Use File (PUF) from 2004–2021. The NCDB is a joint program of the American College of Surgeons and the American Cancer Society and captures approximately 70% of newly diagnosed cancers in the United States from over 1,500 Commission on Cancer-accredited facilities. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The 2021 PUF was used for this analysis. Data are deidentified and include patient demographics, tumor characteristics, staging, and treatment information. The Commission on Cancer and participating hospitals have not verified the analytic methods or conclusions.
Patient selection
Adult patients (≥18 years) with non-metastatic non-small cell lung cancer (NSCLC) who underwent pneumonectomy between 2004 and 2021 were identified. Patients were stratified into three groups: pneumonectomy alone, pneumonectomy following neoadjuvant chemotherapy, and pneumonectomy following neoadjuvant chemoradiation. Patients were excluded if they underwent non-pneumonectomy resections, had metastatic disease, or had missing key variables including survival outcomes or treatment data. A complete-case analysis was performed.
Outcome measures
The primary outcomes were 30-day and 90-day mortality, defined as death occurring within 30 or 90 days from the date of surgery, respectively.
Statistical analysis
Continuous variables were compared using the Wilcoxon rank-sum test, and categorical variables using the Chi-squared test. Multivariable logistic regression models were constructed to identify factors independently associated with 30-day and 90-day mortality. Covariates were selected a priori based on clinical relevance and supplemented by univariate associations. To account for clustering at the facility level, robust standard errors were used. Interaction terms between pneumonectomy laterality and neoadjuvant treatment were included to assess effect modification. Statistical significance was defined as P<0.05. Analyses were performed using Stata MP version 17.0 (StataCorp, College Station, TX, USA), with a significance level set at P<0.05.
Results
Between 2004 and 2021, a total of 14,522 patients underwent pneumonectomy; 85.1% (n=4,522) patients underwent pneumonectomy alone, 6.94% (n=1,008) of patients underwent pneumonectomy with chemotherapy, and 7.96% (n=1,156) of patients underwent pneumonectomy with chemoradiation. Patients that underwent pneumonectomy with chemoradiation were younger than patients who underwent pneumonectomy alone and pneumonectomy with chemotherapy (59.6 vs. 60.9 vs. 63.6 years, P<0.001). A higher proportion of patients in the chemotherapy (65.7%) and chemoradiation (63.3%) groups had no comorbidities (Charlson-Deyo score of 0) compared to those in the pneumonectomy-only group (53.3%) (P<0.001) (Table 1).
Table 1. Univariable analysis across treatment group assessing differences in demographics, clinical factors, facility factors, and 90-day mortality.
| Variables | Pneumonectomy + chemo (n=1,008) | Pneumonectomy + chemoradiation (n=1,156) | P value |
|---|---|---|---|
| Age (years) | 60.94 | 59.58 | <0.001 |
| Sex | 0.75 | ||
| Male | 620 (61.5) | 725 (62.7) | |
| Female | 388 (38.5) | 431 (37.3) | |
| Race | 0.41 | ||
| NHW | 813 (80.7) | 938 (81.1) | |
| NHB | 78 (7.7) | 86 (7.4) | |
| Hispanic | 30 (3.0) | 33 (2.9) | |
| Other | 87 (8.6) | 99 (8.6) | |
| Charlson-Deyo score | <0.001 | ||
| 0 | 662 (65.7) | 732 (63.3) | |
| 1 | 238 (23.6) | 299 (25.9) | |
| 2 | 81 (8.0) | 100 (8.7) | |
| ≥3 | 27 (2.7) | 25 (2.2) | |
| Facility volume | <0.001 | ||
| Low | 134 (13.3) | 211 (18.3) | |
| Medium | 309 (30.7) | 394 (34.1) | |
| High | 565 (56.1) | 551 (47.7) | |
| Facility type | <0.001 | ||
| Community cancer program | 22 (2.2) | 32 (2.8) | |
| Comprehensive community cancer program | 279 (28.2) | 410 (36.0) | |
| Academic program | 523 (52.8) | 434 (38.1) | |
| Integrated network cancer program | 167 (16.9) | 264 (23.2) | |
| 90-day mortality | 105 (10.4) | 158 (13.7) | <0.001 |
| T stage | <0.001 | ||
| 1 | 87 (9.8) | 74 (7.0) | |
| 2 | 324 (36.3) | 396 (37.3) | |
| 3 | 286 (32.1) | 348 (32.7) | |
| 4 | 195 (21.9) | 245 (23.0) | |
| N stage | <0.001 | ||
| 0 | 337 (37.7) | 288 (26.9) | |
| 1 | 260 (29.1) | 183 (17.1) | |
| 2 | 285 (31.9) | 558 (52.2) | |
| 3 | 12 (1.3) | 40 (3.7) |
Data are presented as mean or n (%). N, node; NHB, non-Hispanic Black; NHW, non-Hispanic White; T, tumor.
Mediastinal lymph node metastasis (clinical N2 and N3) was more common in the chemoradiation group, with 52.2% having N2 disease and 3.7% having N3 disease, compared to 10.7% and 0.6% in the pneumonectomy-only group, respectively (P<0.001). Treatment at high-volume facilities was also more frequent in the chemotherapy (56.1%) and chemoradiation (47.7%) groups than in the pneumonectomy-alone group (44.3%) (P<0.001). The 90-day mortality rate was 12.9% percent after pneumonectomy and was higher in right pneumonectomy compared to left pneumonectomy (1,035/6,017, 17.2% vs. 837/8,505, 9.8%; P<0.001). Receipt of neoadjuvant therapy was not associated with inferior 90-day mortality in comparison to pneumonectomy alone (105/1,008, 10.4% vs. 1,609/12,358, 13%; P=0.04) (Table 1).
A multivariable logistic regression showed that right sided pneumonectomy was associated with increased risk of 90-day mortality [odds ratio (OR) =3.62, 95% confidence interval (CI): 2.17–6.05]. Other factors that were independently associated with increased 90-day mortality included advanced age (OR =1.05, 95% CI: 1.01–1.10) and Charlson comorbidity index ≥3 (OR =3.41, 95% CI: 1.47–7.89). Interestingly, the receipt of neoadjuvant chemotherapy had a decreased risk of 90-day mortality (OR =0.18, 95% CI: 0.03–0.99). The receipt of neoadjuvant chemoradiation was not associated with an increased risk of 90-day mortality (OR =1.21, 95% CI: 0.35–4.26) (Table 2).
Table 2. Multivariable logistic regression assessing risk of 90-day mortality.
| 90-day mortality | Odds ratio | 95% CI | P value |
|---|---|---|---|
| Laterality | |||
| Left | Reference | ||
| Right | 3.62 | 2.17–6.06 | <0.001 |
| Year of diagnosis | 0.98 | 0.75–1.28 | 0.89 |
| Age | 1.05 | 1.01–1.10 | 0.02 |
| Female sex | 0.78 | 0.43–1.39 | 0.39 |
| Charlson-Deyo comorbidity index | |||
| 0 | Reference | ||
| 1 | 1.23 | 0.70–2.18 | 0.48 |
| 2 | 1.84 | 0.88–3.84 | 0.10 |
| ≥3 | 3.41 | 1.47–7.89 | 0.004 |
| Facility type | |||
| Community cancer program | 1.38 | 0.37–5.16 | 0.64 |
| Comprehensive community cancer program | 1.00 | 0.52–1.92 | 0.99 |
| Academic/research program | Reference | ||
| Integrated network cancer program | 0.90 | 0.41–1.98 | 0.80 |
| Facility location | |||
| New England | Reference | ||
| Middle Atlantic | 0.90 | 0.26–3.08 | 0.87 |
| South Atlantic | 0.48 | 0.12–1.89 | 0.30 |
| East North Central | 0.48 | 0.15–1.57 | 0.22 |
| East South Central | 0.94 | 0.21–4.10 | 0.93 |
| West North Central | 0.67 | 0.18–2.49 | 0.55 |
| West South Central | 0.74 | 0.20–2.75 | 0.65 |
| Mountain | 1.47 | 0.30–7.27 | 0.64 |
| Pacific | 0.42 | 0.10–1.81 | 0.24 |
| Insurance status | |||
| Not insured | 0.64 | 0.151–2.71 | 0.54 |
| Private insurance | Reference | ||
| Medicaid | 1.10 | 0.45–2.73 | 0.83 |
| Medicare | 0.90 | 0.45–1.80 | 0.77 |
| Insurance status unknown | 1.60 | 0.17–15.42 | 0.68 |
| T stage | |||
| 1 | Reference | ||
| 2 | 1.15 | 0.56–2.36 | 0.71 |
| 3 | 1.18 | 0.56–2.49 | 0.66 |
| 4 | 1.89 | 0.90–3.96 | 0.09 |
| N stage | |||
| 0 | Reference | ||
| 1 | 1.31 | 0.71–2.40 | 0.39 |
| >2 | 1.34 | 0.59–3.05 | 0.48 |
| Histology | |||
| Squamous cell | Reference | ||
| Adenocarcinoma | 1.28 | 0.73–2.24 | 0.38 |
| Facility volume | |||
| Low | 0.98 | 0.45–2.14 | 0.97 |
| Medium | 1.57 | 0.86–2.87 | 0.14 |
| High | Reference | ||
| Neoadjuvant therapy | |||
| Pneumonectomy only | Reference | ||
| Neoadjuvant chemotherapy | 0.19 | 0.04–0.10 | 0.05 |
| Neoadjuvant chemoradiation | 1.21 | 0.35–4.26 | 0.76 |
CI, confidence interval; N, node; T, tumor.
To further characterize the relationship between neoadjuvant treatment and pneumonectomy laterality, we conducted an interaction analysis. This revealed significant differences in the odds of 90-day mortality based on laterality. Compared to right-sided pneumonectomy without neoadjuvant therapy, left-sided pneumonectomy consistently demonstrated lower odds of 90-day mortality across all neoadjuvant treatment categories (OR =0.52, 95% CI: 0.46–0.60). Left sided procedures with and without neoadjuvant treatment were associated with similar odds of mortality (OR =0.30, 95% CI: 0.19–0.47; OR 0.46, 95% CI: 0.31–0.68). Similarly, the odds of 90-day mortality for right-sided pneumonectomy were not significantly different between patients who received neoadjuvant treatment and those who did not (OR =0.95, 95% CI: 0.68–1.33; OR =1.00, 95% CI: 0.72–1.40) (Table 3). Factors independently associated with 90-day mortality after pneumonectomy were right sided pneumonectomy (OR =2.01, 95% CI: 1.78–2.28), advanced age (OR =1.05, 95% CI: 1.04–1.06), and Charlson-Deyo comorbidity index ≥ 3 (OR =1.98, 95% CI: 1.53–2.57). Similarly, we conducted a second multivariable logistic regression with interaction terms to assess the relationship between neoadjuvant treatment and pneumonectomy laterality on 30-day mortality and discovered identical results (Table S1).
Table 3. Multivariable logistic regression assessing risk of 90-day mortality and interaction assessing laterality of pneumonectomy and receipt of neoadjuvant chemotherapy with or without radiation therapy utilizing both left pneumonectomy without neoadjuvant treatment and right pneumonectomy without neoadjuvant chemotherapy as reference groups on two separate logistic regression analyses.
| 90-day mortality | Right pneumonectomy cohort | Left pneumonectomy cohort | ||||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | P value | Odds ratio | 95% CI | P value | |
| Left pneumonectomy − neoadjuvant chemotherapy − neoadjuvant radiation | 0.52 | 0.46–0.60 | <0.001 | Reference | ||
| Left pneumonectomy + neoadjuvant chemotherapy − neoadjuvant radiation | 0.30 | 0.19–0.47 | <0.001 | 0.57 | 0.37–0.89 | 0.01 |
| Left pneumonectomy + neoadjuvant chemotherapy + neoadjuvant radiation | 0.46 | 0.31–0.68 | <0.001 | 0.88 | 0.60–1.28 | 0.49 |
| Right pneumonectomy − neoadjuvant chemotherapy − neoadjuvant radiation | Reference | 1.91 | 1.66–2.10 | <0.001 | ||
| Right pneumonectomy, + neoadjuvant chemotherapy − neoadjuvant radiation | 0.95 | 0.68–1.33 | 0.77 | 1.81 | 1.29–2.55 | 0.001 |
| Right pneumonectomy + neoadjuvant chemotherapy + neoadjuvant radiation | 1.00 | 0.72–1.40 | 0.99 | 1.91 | 1.37–2.67 | <0.001 |
Covariates in the regression not shown include patient age, sex, Charlson-Deyo comorbidity index, facility type, facility location, insurance status, facility volume, clinical T stage, and clinical N stage. CI, confidence interval; N, node; T, tumor.
Discussion
Our study’s findings contribute to the ongoing debate surrounding the safety of pneumonectomy following neoadjuvant therapy in NSCLC patients. Our analysis of the NCDB suggests that neoadjuvant treatment does not increase the risk of 30-day or 90-day mortality following pneumonectomy, challenging previous concerns raised by studies such as the INT0139 trial as well as previous retrospective studies (1,5). Our results support the growing body of evidence suggesting that neoadjuvant therapy, including chemoradiation, can be safely integrated into treatment plans for NSCLC patients requiring pneumonectomy (6-9). This is particularly relevant as neoadjuvant treatment becomes increasingly used for stage Ib or greater lung cancer (10,11).
The overall 90-day mortality rate of 12.9% following pneumonectomy observed in our study aligns with previous literature, falling within the range of 8–15% reported in other large-scale studies (12-14). Our results reaffirm the known elevated risk associated with right pneumonectomy compared to left pneumonectomy (17.2% vs. 9.8%, P<0.001), consistent with previous findings (8). Albain et al. found that peri-operative mortality after pneumonectomy was mainly due to respiratory complications. They concluded that this diminished the benefits of surgery and suggested that trimodality treatment might be more beneficial when lobectomy, rather than pneumonectomy (1). Notably, our study demonstrates that neoadjuvant therapy was not associated with inferior 90-day mortality compared to pneumonectomy alone, contradicting earlier concerns about increased perioperative risks (1,5). Our analysis shows comparable ORs for right-sided pneumonectomy with or without neoadjuvant treatment suggest that concerns about additive risks may be overstated. The lower mortality risk consistently observed with left-sided pneumonectomy across all neoadjuvant treatment categories challenges the notion that neoadjuvant therapy uniformly increases surgical risk and suggests that tumor laterality may be a more critical factor in outcome prediction. These results are relevant in light of recent trials showing improved long-term survival with neoadjuvant chemoradiotherapy in locally advanced NSCLC (15).
Our identification of independent risk factors for 90-day mortality, including right-sided pneumonectomy, advanced age, and higher Charlson-Deyo comorbidity index, aligns with previous research (16,17). However, the lack of increased risk associated with neoadjuvant therapy contradicts some earlier studies (1,5). This discrepancy may be explained by improvements in patient selection, surgical techniques, and perioperative care over time (18-20). Our findings underscore the importance of careful patient selection and preoperative risk assessment, as emphasized in the latest guidelines for the management of NSCLC by the National Comprehensive Cancer Network (NCCN) (21). Recent clinical trials such as the Checkmate 816 trial suggested a decreased need for pneumonectomy amongst patients who received adequate neoadjuvant treatment, and thus physicians should be encouraged to pursue neoadjuvant treatment in patients that qualify (22). Clinicians can also utilize tools such as the Society of Thoracic Surgeons (STS) risk calculator to aid in making clinical decisions regarding perioperative risk in pursuing pneumonectomy (23).
There are several limitations to consider when interpreting our data. Most importantly, the NCDB does not record detailed patient comorbidities, performance status, re-operative status, smoking status, pulmonary function testing results, disease burden, access to care, cause of death, or frailty measures, which certainly may have biased the findings of this study. Additionally, this was a retrospective analysis which utilized deidentified data from a national database, which may introduce selection bias. We cannot account for incorrect or missing data in the database. The NCDB only captures patient information on 70% of newly diagnosed cancers and only receives data from Commission on Cancer-accredited hospitals, thus results may exclude patients diagnosed or receiving care at institutions outside the commission. Despite these limitations, we believe that our analysis provides valuable insights into challenging a previous dogma in pneumonectomy care. Additionally, although multivariable adjustment was performed for relevant patient, tumor, and institutional characteristics, this retrospective study remains subject to residual confounding and confounding by indication. Patients selected for neoadjuvant therapy may have differed systematically from those undergoing upfront surgery in ways that could not be fully accounted for using the variables available in the NCDB. This study was designed to evaluate perioperative mortality and was not intended to assess long-term oncologic outcomes. Future studies examining overall and disease-free survival in contemporary patients undergoing pneumonectomy after neoadjuvant therapy are warranted to complement these findings. The NCDB does not reliably distinguish patients who received neoadjuvant immunotherapy during the study period, precluding separate analysis of this increasingly common treatment strategy. As the treatment landscape for resectable NSCLC continues to evolve, future studies evaluating pneumonectomy outcomes following contemporary neoadjuvant chemoimmunotherapy are warranted.
Conclusions
This multicenter analysis of the NCDB reiterates known elevated risk associated with right pneumonectomy but disputes the dogma that neoadjuvant treatment increases the risk of right or left pneumonectomy. In this setting, we believe neoadjuvant treatment is not a contraindication to receipt of pneumonectomy. These findings underscore the importance of a multidisciplinary approach in tailoring treatment strategies to optimize surgical outcomes, particularly in high-risk populations.
Supplementary
The article’s supplementary files as
Acknowledgments
An earlier version of this work was presented as an abstract at the 61st Annual Meeting of The Society of Thoracic Surgeons, held January 24–26, 2025, in Los Angeles, California. The current manuscript represents the full-length report of that work.
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 study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1175/rc
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-2026-1175/coif). C.W.T. reports that he is a consultant for Zimmer Biomet, Arthrex, Atricure and Medtronic and is a grant recipient from The Intuitive Foundation. None of these relationships have affected this manuscript or the accuracy of the data analysis. The other authors have no conflicts of interest to declare.
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