Impact of chronic obstructive pulmonary disease on the prognosis of patients with extensive-stage small-cell lung cancer treated with chemoimmunotherapy

Introduction

Lung cancer is a malignancy with high mortality and morbidity, and among its subtypes, small-cell lung cancer (SCLC) is particularly lethal—with a strong tendency for metastasis and invasion—and accounts for approximately 15–20% of all cases (1). Although the survival rate of patients with treatment-naïve extensive-stage SCLC (ES-SCLC) has improved dramatically after immunotherapy was introduced into the first-line setting (2), a sizable portion of patients experience transient responses. Therefore, there is an urgent need to identify reliable biomarkers that can guide the selection of the appropriate population to receive immunotherapy.

SCLC is also characterized by the inactivation of the RB1 and TP53 genes and heavy tobacco exposure (1), which is closely associated with the incidence of a systemic comorbidity, chronic obstructive pulmonary disease (COPD). Therefore, patients with SCLC are more vulnerable to COPD. COPD is a prevalent and curable condition typified by airflow restriction and enduring respiratory symptoms, which is currently the third cause of death globally (3). According to previous research, COPD increases the likelihood that SCLC will develop (4), which is not only attributable to age and smoking but also the overexpression of STAT3 and tumorigenesis-related genes (5). However, the effect of COPD on the prognosis of patients with SCLC remains unclear. In the study by Liao et al., COPD was associated with lower 1-year mortality in patients with SCLC (6), while Kahnert et al. reported no significant differences in overall survival (OS) between patients with and without COPD (7). Moreover, although a higher ratio of residual volume to total lung capacity ratio, along with a lower diffusing capacity of the lung for carbon monoxide and forced expiratory volume in 1 second percent predicted (FEV₁%), has been linked with unfavorable survival (7,8), no pulmonary function parameter has been established as a reliable survival predictor for patients with SCLC and comorbid COPD. Moreover, although COPD has been demonstrated to adversely affect the survival of patients with non-small cell lung cancer (NSCLC) receiving chemotherapy or surgical resection, it has also been shown to be a protective factor for patients with NSCLC receiving immunotherapy (9,10). However, no studies have examined the effect of COPD on the prognosis of patients with SCLC in the setting of immunotherapy. This may be because SCLC constitutes only 15–20% of all lung cancer cases, and any underlying COPD may be missed or underdiagnosed in such cases.

In this study, we assessed influence of comorbid COPD on the prognosis of patients with ES-SCLC receiving first-line chemoimmunotherapy and sought to identify candidate predictors for survival in this population. Our findings may help inform the selection of patients with SCLC and comorbid COPD suited for immunotherapy and improve the clinical management of these patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0496/rc).

Methods

Study design

This retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of Jinling Hospital (registration ID 2024NZKY-050-01). The requirement for written informed consent was waived due to the retrospective nature of the study. From April 2019 to May 2024, patients with histologically confirmed ES-SCLC receiving first-line chemoimmunotherapy in Jinling Hospital were retrospectively recruited. Eligible patients were required to meet the following criteria: (I) histologically proven ES-SCLC; (II) pulmonary function test completed at the onset; and (III) administration of first-line immunotherapy combined with platinum-based chemotherapy. Patients were excluded from the study for the following reasons: (I) death due to noncancer causes such as cardiovascular diseases or infectious diseases; (II) a history of systemic treatment; (III) loss to follow-up within 1 month; and (IV) Eastern Cooperative Oncology Group performance status ≥4 and unable to receive immunotherapy. Follow-up concluded in August 2024.

Collection of clinical parameters

Baseline information including age, gender, smoking status, immunotherapy regimen, chemotherapy regimen, liver metastases, bone metastases, brain metastases, and contralateral lung metastases was collected from electronic records. Pulmonary function parameters were measured via spirometry at diagnosis and included vital capacity percent predicted (VC%), maximum VC% (VC_MAX%); forced VC% (FVC%), FEV₁%, ratio of FEV₁ to FVC (FEV₁/FVC), peak expiratory flow percent predicted (PEF%), maximal expiratory flow percent predicted (MEF%), maximal mid-expiratory flow curve percent predicted (MMEF%), and maximal voluntary ventilation percent predicted (MVV%). Serum parameters included lactate dehydrogenase (LDH) albumin (ALB) levels and counts for neutrophils, lymphocytes, monocytes, and eosinophils.

End point events

Clinical response was determined according to modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapeutics (11), which includes complete response, partial response, stable disease, and progressive disease as possible outcomes. Progression-free survival (PFS) and OS were respectively measured as the time interval between the start of immunotherapy and disease progression or death.

Statistical analyses

Continuous variables are presented as the mean and standard deviation (SD) or as the median and range. Categorical variables are presented as counts and percentages. Missing values for LDH, ALB, neutrophils, lymphocytes, monocytes, and eosinophils were imputed via the predictive mean matching method. The cutoff values of continuous variables, including pulmonary function and serum parameters, were determined via the survminer R package (The R Foundation for Statistical Computing), with OS being considered the end point. Variables with P<0.05 in the univariate Cox analysis were incorporated into the multivariate Cox analysis. For the identification of predictive features, multivariate Cox regression was conducted with a backward step-wise selection method and the Akaike information criterion serving as the stopping criterion. Variables with a two-sided P<0.05 were considered significant. Statistical analyses were conducted with R v.4.4.1.

Results

Clinical characteristics of patients with ES-SCLC

During the median follow-up period of 19 (range: 13.9–27.7) months, 100 patients with ES-SCLC undergoing first-line chemoimmunotherapy and additional pulmonary function tests were retrospectively enrolled. The majority of the patients were diagnosed with COPD (59%) and male (87%) and had a history of smoking (74%). In terms of treatment regimens, most patients received programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy agents (61%), while there was greater variety of chemotherapies, including etoposide plus cisplatin (19%), etoposide plus lobaplatin (45%), etoposide plus carboplatin (27%), and etoposide (4%), among others (5%). The contralateral lung was the most common site of metastasis (91%), followed by the liver (84%), brain (81%), and bone (67%).

Similarly, in the subgroup of patients with ES-SCLC and comorbid COPD, the majority were male (n=55, 93.2%) and smokers (n=45, 76.3%) and received PD-1 inhibitor-based treatment (n=38, 64.4%). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, the majority of patients had grade 1–2 disease (n=46, 78.0%), while a much smaller proportion had grade 3–4 disease (n=13, 22%) (Table 1).

Relationship between COPD and survival

Within a median follow-up period of 19 (range: 13.9–27.7) months, 18 (43.9%) and 26 (44.1%) patients in the no-COPD and COPD groups died, respectively and the median OS was 13.1 [range: 10.5–not achieved] months and 13.2 (range: 10.6–20.4) months, respectively (Table 1).

To determine whether comorbid COPD was associated with the efficacy of immunotherapy, we conducted a Kaplan-Meier survival analysis comparing patients with and without COPD. The survival curves for the two clusters intersected (P=0.25), leading to the selection of a 9-month time point as a landmark. Subsequent analysis revealed that at the 9-month follow-up, patients with COPD exhibited superior OS compared to those without COPD (P=0.04), but thereafter, those with COPD had a worse OS (P=0.01) (Figure 1A,1B). However, there were no significant differences in PFS between these two subgroups (P=0.76) (Figure 1C).

Figure 1 The association between COPD and the prognosis of patients with ES-SCLC receiving immunotherapy. (A) Kaplan-Meier survival curves for the OS of patients with and without COPD. (B) Landmark analysis for the OS of patients with and without COPD. (C) Kaplan-Meier survival curves for PFS of patients with and without COPD. COPD, chronic obstructive pulmonary disease; ES-SCLC, extensive-stage small cell lung cancer; OS, overall survival; PFS, progression-free survival.

Using the GOLD criteria, we further subcategorized the patients into no-COPD, GOLD grade 1–2, and GOLD grade 3–4 subgroups. Survival analysis indicated that there were no significant differences between these three subgroups (P=0.37); however, compared to the no-COPD group, the GOLD grade 1–2 group had a more favorable OS within 8 months (P=0.02) but a worse OS after 8 months (P=0.01) (Figure 2A,2B).

Figure 2 The association between GOLD grade and the prognosis of patients with ES-SCLC receiving immunotherapy. (A) Kaplan-Meier survival curves for OS between patients with no COPD, GOLD grade 1–2, and GOLD grade 3–4. (B) Landmark analysis for the OS of patients with no COPD and GOLD grade 1–2. COPD, chronic obstructive pulmonary disease; ES-SCLC, extensive-stage small cell lung cancer; GOLD, Global Initiative for Chronic Obstructive Lung Disease; OS, overall survival.

Predictors of survival for patients with ES-SCLC and comorbid COPD

We further sought to identify the predictors for the prognosis of patients with COPD by examining pulmonary function and serum parameters (Table 2). In the subgroup of patients with ES-SCLC and COPD, univariate Cox analysis identified that the protective factors for OS were FEV₁% >57.9% [hazard ratio (HR) =0.25, 95% confidence interval (CI): 0.09–0.67; P=0.006], inspiratory percent of VC >62.4% (HR =0.32, 95% CI: 0.12–0.83; P=0.02), expiratory percent of VC >73.8% (HR =0.33, 95% CI: 0.12–0.90; P=0.03), FVC% >73.4% (HR =0.33, 95% CI: 0.12–0.87; P=0.03), FEV₁/FVC >63.8% (HR =0.28, 95% CI: 0.11–0.74; P=0.01), PEF% >65% (HR =0.21, 95% CI: 0.06–0.71; P=0.01), and neutrophil count >3.80×10⁹/L (HR =0.27, 95% CI: 0.11–0.69; P=0.006). Eight candidate parameters with P<0.05 in the univariate analysis were included in the subsequent Multivariate Cox regression analysis, which indicated three of these were predictors prognosis: VC_MAX% >68.8% (HR =0.23, 95% CI: 0.08–0.72; P=0.01), PEF% >65% (HR =0.37, 95% CI: 0.10–1.34; P=0.13), and neutrophil count >3.80×10⁹/L (HR =0.20, 95% CI: 0.07–0.59; P=0.004) (Figure 3).

Figure 3 Univariate and multivariate Cox regression analyses for OS in immunotherapy-treated patients with ES-SCLC and comorbid COPD. Values in italicized indicate statistical significance (P<0.05). CI, confidence interval; COPD, chronic obstructive pulmonary disease; ES-SCLC, extensive-stage small cell lung cancer; FEV₁%, forced expiratory volume in 1 second percent predicted; FEV₁/FVC, ration of forced expiratory volume in 1 second to forced vital capacity; FVC%, forced vital capacity percent predicted; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HR, hazard ratio; LDH, lactate dehydrogenase; MEF50%, maximal expiratory flow at 50% of FVC; MVV%, maximal voluntary ventilation percent predicted; OS, overall survival; PD-L1, programmed death-ligand 1; PEF%, peak expiratory flow percent predicted; VCEX%, expiratory vital capacity percent predicted; VCIN%, inspiratory vital capacity percent predicted; VC_MAX%, maximum predicted percentage of vital capacity.

Discussion

In this study, we found that in patients with ES-SCLC receiving chemoimmunotherapy, comorbid COPD was a protective factor for OS in the short term but a risk factor in the long term; meanwhile, no significant differences for PFS were observed. Specifically, patients classified as GOLD grade 3–4 had the worst prognosis, and patients with GOLD grade 1–2 had better survival than did those without COPD in the short term; in the long term, patients with GOLD grade 1–2 had worse survival than did those with grade 1–2 or no COPD. For patients with comorbid COPD, those with a higher VC_MAX% and neutrophil count were more likely to have a favorable prognosis.

In our study, patients with ES-SCLC and COPD were more responsive to immunotherapy in the short term. Due to the relatively small proportion of SCLC cases in the lung cancer population, few studies have examined the mechanisms related to SCLC, and thus we resorted to referring to the NSCLC population. Clinical evidence indicates that patients with NSCLC and comorbid COPD can better benefit from PD-1 or programmed death-ligand 1 (PD-L1) inhibitor-based treatments as compared to those without COPD (12,13). It has been further demonstrated that patients with NSCLC and comorbid COPD have a higher proportion of exhausted CD8⁺ tumor-infiltrating lymphocytes (TILs) compared to those without COPD, which can be attributed to a high density of CD8⁺ TILs pretreatment that are revitalized by PD-1 or PD-L1 inhibitors (14,15). Typically, COPD is characterized by the increased infiltration of CD8⁺ T cells and neutrophils in the airway (16), which enhances the response to immunotherapy. Latest study also found that COPD induces epithelial remodeling towards a basal-like tumor cell subset with progenitor-like features in NSCLC, which further recruits macrophages and promotes cytotoxic T cell infiltration (9). Moreover, in patients with NSCLC and COPD, DNA damage repair pathways tend to be upregulated, which reflects an increase in genomic instability and neoantigen abundance, potentially promoting the efficacy of immunotherapy (17). Likewise, whether CD8⁺ T abundance and tumor mutation burden affect work in the short-term survival of SCLC comorbid with COPD need further validation. However, in the long term, the higher frequency of acute exacerbation of COPD, steroid administration, and immune-related adverse events such as interstitial pneumonia may impair pulmonary function, thus rendering COPD an adverse factor for immunotherapy. Furthermore, we found that patients with GOLD grade 1–2 ES-SCLC had the best prognosis among stage subgroups within 8 months. In a previous study, it was reported that patients with GOLD grade 1–2 NSCLC had a higher expression of PD-L1 compared to either smokers or patients with GOLD grade 3–4 (18). Thus, we hypothesized that patients with GOLD grade 1–2 SCLC can receive enhanced benefit from immunotherapy due to the upregulation of PD-L1.

Neutrophils are crucial agents in both the inflammatory response of COPD and antitumoral response (19). Neutrophils are a major component of type 1 inflammatory responses, which are driven by CD4⁺ T helper cells, CD8⁺ T cells, and M1-like macrophages, and these may also synergistically exert an antitumor effect in various malignancies. It was recently found that a minority of the COPD population with the eosinophilic phenotype exhibit a type 2 inflammatory response (20). However, eosinophil count was not found to be a significant risk factor for survival in our cohort, and thus further in-depth investigation is warranted. Moreover, the presence of both antitumoral and protumoral neutrophil subpopulations suggests that neutrophil function within the tumor microenvironment is determined by their differentiation into distinct phenotypic states (19). Notably, the antigen-presenting-like program in neutrophils has been associated with favorable survival in multiple malignancies and could be stimulated by leucine metabolism and subsequent histone H3K27ac modification. This may explain why a high neutrophil count was associated with a better prognosis from immunotherapy in our cohort and emphasize the need for future single-cell phenotyping for neutrophils. Moreover, it must be acknowledged that this parameter only reflects the neutrophil count from peripheral blood, which is not equivalent to the count of tumor-infiltrating neutrophils. In the future, we intend to collect bronchoalveolar lavage fluid and the tissue samples from patients with SCLC and comorbid COPD and to examine the potential effects of tumor-infiltrating neutrophils at single-cell level on immunotherapy.

To our knowledge, this is the largest study to investigate the effect of COPD on the prognosis of patients with ES-SCLC receiving first-line chemoimmunotherapy and to identify potential predictive factors for patients with ES-SCLC and comorbid COPD. However, certain limitations should be acknowledged. First, the sample size of this study was relatively limited due to the requirements of a complete pulmonary function test. Second, the single-center design reduces the generalizability of the results. Third, the type of COPD intervention was not specified in the electronic medical documents since the retrospective data lacked the granularity to accurately quantify cumulative steroid exposure during the follow-up period. However, it is still worth mentioning that the use of inhaled or systemic corticosteroids for COPD management might antagonize chemoimmunotherapy, potentially driving the long-term mortality risk observed in our cohort. Moreover, it should be mentioned that there existed potential immortal time bias resulting from excluding non-cancer deaths, and careful extrapolation of our research findings to all-comer COPD-lung cancer population are warranted. Further prospective studies with large sample sizes and careful monitoring of the management of COPD are needed to validate our preliminary findings.

Conclusions

For patients with ES-SCLC treated with immunotherapy, comorbid COPD was found to be a protective factor in the short term but a risk factor in the long term. A high neutrophil count and a higher VC_MAX% were associated with improved prognosis in patients with ES-SCLC and comorbid COPD. This implies that we should reconsider the effect of COPD on the survival of patients with SCLC; moreover, these findings may help guide the selection of patients with SCLC and COPD particularly suited to benefitting from immunotherapy.

Acknowledgments

This manuscript has been presented as a E-poster for WCLC 2025 and have been accepted as a Poster for WCLC 2026.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0496/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0496/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0496/prf

Funding: This work was supported by the China Postdoctoral Science Foundation 12th Batch Special Fund (No. 45786) and the Jiangsu Provincial Postdoctoral Science Foundation (No. 2018K049A).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0496/coif). Y.S. serves as an Editor-in-Chief of Translational Lung Cancer Research. 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 study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of Jinling Hospital (registration ID 2024NZKY-050-01). The requirement for written informed consent was waived due to the retrospective nature of the 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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(English Language Editor: J. Gray)