The impact of neoadjuvant chemoimmunotherapy on pulmonary function in non-small cell lung cancer patients

Introduction

Non-small cell lung cancer (NSCLC) accounts for 80–85% of all newly diagnosed lung cancers each year (1,2). In recent years, immunotherapy has rapidly advanced from the treatment of advanced-stage NSCLC to earlier stages of the disease. For resectable NSCLC, neoadjuvant chemoimmunotherapy is a promising therapeutic strategy (3,4). However, there is limited research regarding the impact of neoadjuvant chemoimmunotherapy on pulmonary function (PF), particularly in the unique population with underlying pulmonary comorbidities.

It is worth noting that NSCLC is often accompanied by chronic obstructive pulmonary disease (COPD), and it is usually diagnosed at a moderate to late stage in the clinical practice (5). Some patients lose the opportunity for surgical treatment due to inadequate PF or a predicted high risk of postoperative complications (6). However, current studies have found that NSCLC patients with COPD can benefit from immunotherapy, with a higher rate of pathologic complete response (pCR), longer progression-free or overall survival (7-9).

Therefore, this study aims to investigate efficacy, safety profiles, and the changes in PF in NSCLC patients receiving neoadjuvant chemoimmunotherapy, with a particular focus on those with concomitant pulmonary diseases such as COPD. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0244/rc).

Methods

Patient selection

A total of 478 patients with NSCLC received neoadjuvant chemoimmunotherapy and operation at Shanghai Pulmonary Hospital from May 2019 to January 2023. The inclusion criteria were: (I) patients with available pre- and post-neoadjuvant chemoimmunotherapy images and PF examinations; (II) clinical TNM (cTNM) stage between IB and IIIC. The exclusion criteria consisted of the followings: (I) incomplete therapy information; (II) a history of other malignancies; (III) patients who received pulmonary rehabilitation or had airway medication changes during neoadjuvant therapy (Figure 1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Shanghai Pulmonary Hospital (No. K23-228) and individual informed consent was waived in this retrospective study.

Figure 1 Study flow diagram. COPD, chronic obstructive pulmonary disease; cTNM, clinical TNM; NSCLC, non-small cell lung cancer; TNM, tumor, node, metastasis.

PF testing

PF data was recorded before neoadjuvant therapy and again approximately 1–2 days before surgery. The indicators for PF testing included forced expiratory volume in one second (FEV1), the ratio of FEV1 to the predicted value (FEV1%pred), FEV1/forced vital capacity (FVC), carbon monoxide diffusion capacity (DLCO), the ratio of DLCO to the predicted value (DLCO%pred), residual volume (RV) to total lung capacity (TLC), maximal expiratory flow 25/50 (MEF25/50), and the ratio of MEF25/50 to the predicted value (MEF25/50%pred). According to the 2021 Global Initiative for Chronic Obstructive Lung Disease diagnostic criteria, COPD was defined as FEV1/FVC <0.70 before neoadjuvant treatment. The diagnosis of obstructive pneumonia/atelectasis was confirmed through chest computed tomography. In addition, high risk for surgical resection was defined as either predicted postoperative (ppo) FEV1%pred or ppoDLCO%pred <30% (i.e., poor pulmonary reserve), low risk (i.e., good pulmonary reserve) referred to both ppoFEV1%pred and ppoDLCO%pred >60%, and the remaining (i.e., either ppoFEV1%pred or ppoDLCO%pred <60% but both >30%) was considered moderate risk (i.e., moderate pulmonary reserve).

The effectiveness and safety assessment

The neoadjuvant chemoimmunotherapy duration mainly ranged from two to four cycles depending on a multidisciplinary team. Surgery was usually performed 4–6 weeks after the last treatment cycle. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Postoperative complications were monitored within one month postoperatively. By systematically reviewing electronic medical records, clinical nursing notes, laboratory findings, and imaging studies, postoperative complications—including but not limited to chylothorax, arrhythmia, pulmonary embolism, bronchopleural fistula, etc.—were assessed. Radiologic response was assessed before operation according to the Response Evaluation Criteria in Solid Tumors (RECIST). Major pathologic response (MPR) was defined as the proportion of surviving tumor cells being ≤10%, and pCR was described as the proportion of surviving tumor cells being 0% without lymph node invasion.

Statistical analysis

Categorical variables were compared by either the Chi-squared test or Fisher’s exact test. Normally distributed continuous variables were analyzed using Student’s t-test. The PF before and after neoadjuvant chemoimmunotherapy were compared by paired t-test. Covariance analysis was performed to identify the differences in PF parameters (before and after neoadjuvant therapy) between patients with and without COPD. Subgroup analysis was applied to account for the confounding effect of obstructive pneumonia/atelectasis. Logistic regression analyses were performed to evaluate factors associated with improvement in pulmonary ventilation function. Variables including gender, age, histopathologic types, and others were first assessed in univariate analysis, and those with P<0.05 were then entered into multivariate analysis. The variable “improvement in FEV1” in the logistic regression was defined as ΔFEV1 >0. “Δ” represents the difference between the post-neoadjuvant chemoimmunotherapy values and the pre-neoadjuvant treatment values. All analyses were exploratory and should be interpreted with caution. Statistical significance was defined as a two-sided P value <0.05. Statistical analyses were performed by R software and GraphPad Prism 9.

Results

Patient characteristics

A total of 253 patients were included. The median age was 64 [interquartile range (IQR), 58–68] years, with the majority being male (90.9%), and having a history of smoking (75.1%). Seventy-one cases (28.1%) were accompanied by COPD, all of whom did not receive any respiratory therapy. Additionally, 41.1% of the patients had obstructive pneumonia/atelectasis. Squamous cell carcinoma was the predominant pathological type (60.8%). Video-assisted thoracoscopic surgery (VATS) (98.4%) was the most frequently surgical approach, and lobectomy (74.7%) was the predominant type of resection (Table 1).

Treatment response

The objective response rate (ORR) was 64.8%, including 2 cases of complete response (CR) and 162 cases of partial response (PR). The rates of MPR and pCR were 53.4% and 28.5%, respectively (Table 1). Patients with COPD exhibited a significantly higher MPR rate (64.8% vs. 48.9%, P=0.02), and a better pCR rate (39.4% vs. 24.2%, P=0.01) compared to those without COPD (Figure 2A).

Figure 2 Neoadjuvant therapy efficacy and paired changes in FEV1/FEV1%pred in NSCLC patients with and without COPD. (A) Comparison of neoadjuvant therapy efficacy in NSCLC patients with and without COPD. (B) Paired comparison of FEV1 or FEV1%pred before and after neoadjuvant chemoimmunotherapy in NSCLC patients with COPD (with or without obstructive pneumonia/atelectasis). From left to right, the mean differences (95% CIs) are: 0.256 (0.139, 0.370); 8.012 (4.147, 11.880); 0.130 (0.054, 0.205); 4.405 (1.276, 7.535). (C) Paired comparison of FEV1 or FEV1%pred before and after neoadjuvant chemoimmunotherapy in NSCLC patients without COPD (with or without obstructive pneumonia/atelectasis). From left to right, the mean differences (95% CIs) are: 0.139 (0.062, 0.215); 4.203 (1.200, 7.207); 0.036 (−0.002, 0.074); 1.169 (−0.365, 2.703). *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CR, complete response; FEV1, forced expiratory volume in one second; FEV1%pred, the ratio of FEV1 to the predicted value; MPR, major pathologic response; ns, not significant; NSCLC, non-small cell lung cancer; pCR, pathologic complete response; PD, progressive disease; PR, partial response; SD, stable disease.

PF changes

The pulmonary ventilation function indicators, including FEV1 (2.34 vs. 2.45 L, P<0.001) and FEV1%pred (86.10% vs. 89.50%, P<0.001), showed a significant increase after neoadjuvant treatment. Among the small airway function indicators, only MEF50%pred (71.50% vs. 74.50%, P=0.02) showed significant improvement. However, the pulmonary diffusion function indicators, including DLCO (19.18 vs. 17.20 mL/min/mmHg, P<0.001) and DLCO%pred (103.20% vs. 91.74%, P<0.001), decreased after neoadjuvant treatment (Table 2).

To further investigate the impact of neoadjuvant treatment on patients with poor baseline PF, subgroup analysis revealed that FEV1 (1.88 vs. 2.07 L, P<0.001) and FEV1%pred (69.30% vs. 75.50%, P<0.001) showed a significant increase after neoadjuvant treatment, while DLCO and DLCO%pred decreased in patients with COPD. Covariance analysis showed that improvement of FEV1 (0.189 vs. 0.075 L, P=0.049) was more significant in patients with COPD compared to patients without COPD (Table 3). In addition, small airway function parameters, including MEF25, MEF50, MEF25%pred, and MEF50%pred, showed an improvement in patients with COPD. However, no significant improvement was observed in those without COPD (Table 3).

It should be noted that the presence of obstructive pneumonia/atelectasis may confound the assessment of PF changes following neoadjuvant treatment. Subgroup analyses revealed that FEV1 and FEV1%pred showed significant improvement after neoadjuvant treatment in patients with COPD, regardless of the presence of obstructive pneumonia/atelectasis (Figure 2B). However, among patients without COPD, FEV1 and FEV1% improvement was only observed in the subgroup with obstructive pneumonia/atelectasis (Figure 2C). In addition, significant improvement in FEV1 and FEV1%pred was observed in patients with centrally located NSCLC or those achieving radiologic PR/CR, but not in patients with peripherally located NSCLC or those with radiologic stable disease (SD)/progressive disease (PD) (Figure S1).

A total of 109 patients with available data on both ppoFEV1%pred and ppoDLCO%pred underwent an assessment of surgical risk. Among 33 patients with COPD, 4 patients experienced an amelioration in surgical risk from moderate to low after neoadjuvant therapy. However, among 76 patients without COPD, only 2 patients experienced this trend, but 12 patients showed an increase in surgical risk from low to moderate (Figure S2). In addition, among the 109 patients, there were 62 patients with improved FEV1. Of these, 33 patients were at moderate risk before neoadjuvant therapy (6 cases improved to low risk), and 29 patients were at low risk before neoadjuvant therapy (4 cases deteriorated to moderate risk).

Univariate analysis revealed that COPD, obstructive pneumonia/atelectasis, tumor location, pathology, and cTNM stage were factors associated with the increase of FEV1. Multivariate analysis showed that COPD [odds ratio (OR), 2.273; 95% confidence interval (CI): 1.211–4.405] remained an independent factor for the improvement in FEV1 after neoadjuvant therapy (Table 4).

Adverse events

A total of 220 NSCLC patients (87.0%) experienced grade I–II adverse events, while 29 cases (11.5%) had grade III–IV adverse events. The most common grade I–II adverse events included myelosuppression (76.7%), impaired liver function (56.9%), and impaired renal function (42.3%). Grade III–IV adverse events mainly consisted of myelosuppression (5.9%), fever (2.0%) and rash (2.0%). Patients with COPD exhibited similar safety profiles (grade I/II: 83.1% vs. 88.5%; grade III/IV: 15.5% vs. 9.9%; P=0.41) compared to those without COPD (Figure 3A).

Figure 3 Adverse events and postoperative complications in NSCLC patients. (A) The adverse events in NSCLC patients with and without COPD received neoadjuvant chemoimmunotherapy. (B) The postoperative complications in NSCLC patients with and without COPD received neoadjuvant chemoimmunotherapy. (C) The postoperative complications between patients with improved pulmonary ventilation function and those without improvement. COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; FEV1%pred, the ratio of FEV1 to the predicted value; ns, not significant; NSCLC, non-small cell lung cancer.

Postoperative complications

The median postoperative drainage time was 7 days. Additionally, 19 patients (7.6%) experienced postoperative complications, including 10 cases (4.0%) of chylothorax and 6 patients of arrhythmia (2.4%) (Table 5), with no significant difference between patients with and without COPD (4.2% vs. 8.8%, P=0.26) (Figure 3B). It was worth noting that no significant difference in postoperative complications was found between patients with improved FEV1 and those without improvement (Figure 3C).

Discussion

In our study, patients with NSCLC were observed to have a high rate of response to neoadjuvant chemoimmunotherapy, accompanied by an improvement in pulmonary ventilation function. Notably, among patients with comorbid COPD, improvement in FEV1 and FEV1%pred was observed after neoadjuvant chemoimmunotherapy, regardless of the presence of comorbid obstructive pneumonia/atelectasis. Additionally, this patient population was associated with better pathologic response to neoadjuvant chemoimmunotherapy, with acceptable safety profiles.

Previous studies showed that FEV1 and FEV1%pred improved after neoadjuvant chemoimmunotherapy in patients with NSCLC or esophageal cancer (10-12). Similarly, in our study, an improvement in pulmonary ventilation function was observed. A possible explanation was that central tumor could cause local bronchial obstruction, leading to an obstructive pneumonia/atelectasis. Anticancer treatment decreased tumor size and restored luminal patency, thus improving pulmonary ventilation function (11,12). In the study, it was observed that the improvement in pulmonary ventilation function was more pronounced in patients with COPD (independent of the presence of obstructive pneumonia/atelectasis), which may be also associated with the immunotherapy-induced amelioration of underlying chronic inflammation in the small airway (13-16). The observed decline of 11.4% in DLCO%pred, aligning with findings from Zhu et al. (11), may increase postoperative risk, as reduced diffusing capacity has been associated with major morbidity after lung resection, including bronchopleural fistula, adult respiratory distress, etc. (17). It was speculated that although chemotherapy killed tumor cells, they may also damage alveolar epithelial cells, which could affect gas exchange and lead to a decrease in DLCO. Moreover, immunotherapy may excessively activate the immune system, causing inflammatory side effects in the lungs, further affecting the integrity and function of the alveolar capillary membrane (11,18-20). This decline contrasts with the modest improvement in FEV1 and suggests that clinicians should evaluate both ventilatory and diffusing capacity when reassessing surgical candidacy after neoadjuvant therapy.

In addition, patients showed a significantly high MPR and pCR rate after neoadjuvant chemoimmunotherapy, especially for those with COPD. The possible reason could be that the long-term chronic inflammation and the remodeling of the pulmonary immune microenvironment inherent to COPD, such as the higher exhaustion of CD8 tumor-infiltrating lymphocytes, were conducive to improving the effectiveness of immunotherapy (21-23). Consistently, Dong et al. reported a study of 74 patients with NSCLC, finding that the presence of COPD was associated with significantly longer progression-free survival and a higher pCR rate after neoadjuvant chemoimmunotherapy (9). Similarly, the presence of COPD/emphysema was significantly associated with a longer survival in patients with advanced NSCLC who received immune checkpoint inhibitors (24).

The study found that the rate of grade III/IV adverse events discovered during neoadjuvant therapy in NSCLC patients was 11.5%. Even among patients with COPD, no significant increase of the rate existed compared to those without COPD. Previous studies also reported that NSCLC patients with COPD had a similar treatment-related adverse events after neoadjuvant chemoimmunotherapy compared to those without COPD (9), but those with Global Initiative for Chronic Obstructive Lung Disease (GOLD) III COPD may have a higher risk (25). Additionally, no significant differences in postoperative complications were observed between these two groups after neoadjuvant immunotherapy in the study, despite prior studies have reported that patients with COPD undergoing routine lung cancer resection were at a higher risk of postoperative complications (26-28). In addition, the absence of a significant association between improvements in FEV1 and postoperative complications suggests that the observed spirometric gains may lack clinical relevance for perioperative risk. Further confirmation in larger cohorts is warranted.

Our study has several limitations. First, as a retrospective study, the population consisted largely of males, smokers, and patients with squamous cell carcinoma, potentially leading to selection bias. Second, COPD was defined using a pre-bronchodilator FEV1/FVC ratio <0.70 (7,8). This definition was primarily driven by the lack of available post-bronchodilator spirometry in this retrospective cohort. Consequently, it may have included a minority of patients with reversible airflow limitation. Third, this study only included patients undergoing surgical resection, and patients without surgery due to disease progression, severe toxicity, and/or functional deterioration were excluded, which likely overestimated the observed improvement in FEV1. Therefore, it is unknown whether the improvement of FEV1 could convert initially inoperable patients into surgical candidates. Finally, this study focused on the clinical association; further research is needed to explore the underlying mechanisms, including whether the observed improvements in pulmonary ventilation function are attributable to the treatment itself or to tumor response‑related relief of airway obstruction.

Conclusions

Following neoadjuvant chemoimmunotherapy, improvement in pulmonary ventilation function was observed in patients with NSCLC, along with a high response rate and an acceptable safety profile. Moreover, for patients with comorbid COPD, neoadjuvant chemoimmunotherapy was associated with superior efficacy and an observed improvement in pulmonary ventilation function that may be linked to increased operability. Nonetheless, reassessment of PF after neoadjuvant treatment is warranted.

Acknowledgments

This abstract has been accepted as a poster presentation at the 106th Annual Meeting of the American Association for Thoracic Surgery.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0244/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0244/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0244/prf

Funding: This study was supported by the National Natural Science Foundation of China (grant Nos. 82172848 and 82473466) and Shanghai Municipal Health Commission Special Clinical Research Project for the Hygiene Industry (No. 20234Y0248).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0244/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 and its subsequent amendments. This study was approved by the Institutional Review Board of Shanghai Pulmonary Hospital (No. K23-228) and individual informed consent was waived in this retrospective 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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