Lung cancer incidence and risk factors in chronic obstructive pulmonary a systematic review and meta-analysis of cohort studies

Authors: Xiaowei Gong, Zhifeng Zhao, Yadong Yuan

Abstract

Background

Patients with chronic obstructive pulmonary disease (COPD) face a substantially elevated risk of developing lung cancer, significantly complicating their clinical management and prognosis. We therefore performed this study to investigate lung cancer incidence and risk factors in patients with COPD.

Methods

Comprehensive searches were conducted in PubMed, Embase, and the Cochrane Library up to December 2024. To estimate lung cancer incidence in COPD, we applied a random-effects model with log transformation of raw data. Risk factors were quantified through pooled odds ratios (ORs) and 95% confidence intervals (CIs), also computed under a random-effects framework.

Results

Twenty-six cohort studies involving 613,373 patients with COPD were selected for the meta-analysis. The incidence of lung cancer in patients with COPD was 6.0% (95% CI: 5.0–6.9; P<0.001). Moreover, older age (OR: 2.16; 95% CI: 1.15–4.05; P=0.02), current smoking (OR: 1.69; 95% CI: 1.42–2.00; P<0.001), and presence of emphysema (OR: 2.73; 95% CI: 2.02–3.69; P<0.001) were associated with increased risk of lung cancer in COPD patients. Subgroup analyses showed that the incidence of lung cancer in COPD patients was higher in retrospective cohort studies, studies conducted in Asia, those with sample sizes <5,000, follow-ups <5.0 years, and studies with low quality.

Conclusions

This study identified the incidence and risk factors for lung cancer in patients with COPD. Regular screening is recommended for high-risk populations with COPD to improve patient outcomes.

Introduction

As one of the most prevalent malignancies worldwide, lung cancer exhibits substantial mortality rates, responsible for an estimated 1.8 million deaths in 2020 (1). Its clinical course is frequently complicated by comorbidities, particularly chronic obstructive pulmonary disease (COPD), a progressive respiratory disorder characterized by persistent airway inflammation and irreversible obstruction. These two conditions collectively represent major contributors to global disease burden (2,3), with epidemiological studies consistently reporting elevated lung cancer incidence among COPD populations. Therefore, COPD is one of the most influential risk factors for lung cancer in smokers, increasing the risk by 4.5 times (4). Additionally, studies indicate that COPD is an independent risk factor for lung cancer development and progression, even when smoking exposure is excluded (5). Therefore, early detection and treatment of lung cancer are particularly urgent for patients with COPD.

COPD and lung cancer are complex diseases caused by the interplay between genetic predisposition and environmental factors, involving multiple pathophysiological mechanisms, such as chronic airway inflammation, abnormal immune responses, and oxidative stress (6,7). Clinically, these conditions present with overlapping symptomatology, including chronic cough, sputum production, and dyspnea (8). Substantial evidence demonstrates that COPD patients harbor a significantly elevated risk of lung cancer development (9). Moreover, COPD reduces the effectiveness of anti-tumor treatments, leading to poorer survival rates. This is evident in reduced surgical opportunities, higher postoperative complications, prolonged oxygen therapy and hospitalization durations, and diminished efficacy of chemotherapy and radiotherapy (10-12).

The risk factors for patients with COPD developing lung cancer require further investigation, early diagnosis of lung cancer is crucial for improving patient outcomes. Current research highlights factors such as age, weight loss, smoking history, exposure to air pollution, dust exposure, previous lung disease, and underlying inflammatory states as contributors to increased risk among these patients developing lung cancer (13). However, there is currently a lack of comprehensive meta-analyses systematically evaluating the precise risk of lung cancer in patients with COPD and associated risk factors. Therefore, this study aimed to assess lung cancer incidence and risk factors in patients with COPD. We present this article in accordance with the MOOSE reporting checklist (14) (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0245/rc).

Methods

Data sources, search strategy, and selection criteria

Our study was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) platform (number: INPLASY202510093). This study aimed to comprehensively analyze the incidence of lung cancer and its associated risk factors in patients with COPD. To achieve this, we extensively collected relevant cohort studies without any language or publication status restrictions to cover a global range of research findings. The literature search was primarily conducted in three authoritative databases, PubMed, Embase, and the Cochrane Library, using the keywords “lung cancer” and “chronic obstructive pulmonary disease”. The search cutoff date was set to December 2024 to ensure the timeliness and comprehensiveness of the data. The detailed search strategies for each database, including the combination of search terms and filtering criteria, are provided in Appendix 1, which allows other researchers to replicate our search process. In addition to the electronic database searches, we also performed manual screening by carefully examining the reference lists of all identified studies and review articles. This step aimed to identify studies potentially missed due to database indexing limitations or human oversight, ensuring comprehensive coverage. By combining automated searches with manual verification, we aimed to establish a robust and reliable evidence base regarding the incidence of lung cancer and its risk factors in patients with COPD.

Following a predefined protocol, two reviewers independently conducted the literature search and study selection. Disagreements were resolved through team consensus. Inclusion criteria (I) COPD patients of any severity; (II) those developing lung cancer during follow-up; (III) COPD patients without lung cancer; (IV) measured lung cancer incidence and associated risk factors; and (V) study studies employing either prospective or retrospective cohort designs.

Data collection and quality assessment

Two independent investigators systematically extracted data from eligible studies using a standardized form. Collected variables first author’s name, publication year, study design, country of origin, sample size, participant demographics (mean age, gender distribution, smoking prevalence), COPD diagnosis/COPD staging system, lung cancer cases (number and diagnostic methods), follow-up period, and key outcomes. Study quality was independently evaluated by both reviewers using the Newcastle-Ottawa Scale (NOS), which assesses three selection (4 items), comparability (1 item), and outcome/exposure (3 items) (15). Discrepancies during data extraction or quality assessment were resolved by a third reviewer through consultation with the original literature to ensure data accuracy and consistency.

Statistical analysis

We performed a meta-analysis of lung cancer incidence in COPD populations using a random-effects model with log-transformed raw data to ensure comparability (16). Model parameters were estimated via restricted maximum likelihood to enhance precision. Risk factors were quantified as pooled odds ratios (ORs) with 95% confidence intervals (CIs) using the same modeling approach (16,17). Heterogeneity was evaluated through I^2^ statistics (with ≥50% indicating substantial heterogeneity) and Cochran’s Q tests (P<0.10 threshold) (18,19). To validate findings, we (I) sensitivity analyses via leave-one-out sequential exclusion (20); (II) prespecified subgroup analyses (by study design, geographic region, sample size, diagnosis of COPD, follow-up duration, and quality score) with interaction tests (21); and (III) publication bias assessment using funnel plots complemented by Egger’s and Begg’s tests (22,23). All analyses were two-tailed with statistical significance set at P<0.05, executed in STATA 12.0 (StataCorp).

Results

Literature search

A total of 8,574 articles were identified from electronic databases. After removing duplicates, 4,098 studies remained. Of these, 4,023 were excluded because they addressed topics unrelated to our study. The remaining 75 studies were assessed in full-text review, with 49 excluded for the following the population was not patients with COPD (n=26), the study design did not meet the criteria for cohort studies (n=19), and the studies did not report relevant outcomes (n=4). Additionally, reference list searches of relevant literature identified no new eligible studies. Ultimately, 26 cohort studies were included in the meta-analysis (24-49). A detailed overview of the literature search and study selection process is shown in Figure 1.

Study characteristics

The 26 included cohort studies (13 prospective, 13 retrospective) comprised 613,373 patients with COPD, with 32,902 new lung cancer cases identified during follow-up (Table 1). For each study, the reference group for outcome comparisons was COPD patients in the same cohort who remained free of lung cancer throughout follow-up. Sixteen studies were conducted in Europe and the USA, while 10 were conducted in Asia (4 in China, 3 in Japan, and 3 in Korea). The follow-up duration ranged from 1.0 to 17.9 years. Study quality, assessed using the NOS, showed that 5 studies received 8 stars, 11 received 7 stars, and 10 received 6 stars.

Incidence of lung cancer in patients with COPD

The pooled incidence of lung cancer in patients with COPD was 6.0% (95% CI: 5.0–6.9; P<0.001), and significant heterogeneity was observed across included studies (I^2^=99.6%; P<0.001) (Figure 2). Sensitivity analysis revealed that after sequential removal of a single study, the incidence of lung cancer in patients with COPD ranged from 5.2% (95% CI: 4.3–6.2%) to 6.2% (95% CI: 5.2–7.1%) (Figure S1). Subgroup analyses of the incidence of lung cancer in patients with COPD were performed, and the results are shown in Table 2. We noted that lung cancer incidence in patients with COPD was higher when pooling retrospective cohort studies, studies conducted in Asia, studies sample sizes <5,000, applied clinical or radiological diagnoses COPD, follow-up <5.0 years, and studies with low quality.

Risk factors for lung cancer in patients with COPD

The summary results for the risk factors for lung cancer in patients with COPD are shown in Figure 3. We noted older age (OR: 2.16; 95% CI: 1.15–4.05; P=0.02), current smoking (OR: 1.69; 95% CI: 1.42–2.00; P<0.001), and presence of emphysema (OR: 2.73; 95% CI: 2.02–3.69; P<0.001) were associated with an increased risk of lung cancer in patients with COPD. However, sex, education level, former smoking, airway obstruction, hypertension, diabetes, inhaled steroids, and long-acting beta-2-agonists were not associated with the risk of lung cancer in patients with COPD. Furthermore, there was significant heterogeneity among included studies for sex (I^2^=93.6%; P<0.001), age (I^2^=89.5%; P<0.001), education duration (I^2^=67.3%; P=0.08), former smoking (I^2^=63.3%; P=0.03), and current smoking (I^2^=60.8%; P=0.01), whereas no significant heterogeneity was observed for emphysema (I^2^=0.0%; P=0.52), airway obstruction (I^2^=0.0%; P=0.47), hypertension (I^2^=0.0%; P=0.67), diabetes (I^2^=43.8%; P=0.18), inhaled steroids (I^2^=46.7%; P=0.17), and long-acting beta-2-agonists (I^2^=0.0%; P=0.87).

Publication bias

Publication bias for lung cancer incidence in patients with COPD was assessed. The funnel plot suggested potential publication bias. Although Egger’s test did not indicate a significant publication bias, Begg’s test revealed a significant publication bias (Figure 4). Adjustments showed no significant changes in the incidence of lung cancer among patients with COPD.

Discussion

This study used meta-analysis to investigate the incidence of lung cancer and its associated risk factors in patients with COPD. Through a systematic review, we included 26 cohort studies involving 613,373 patients with COPD, identifying 32,902 lung cancer cases during the follow-up period. The characteristics and severity of COPD varied significantly across the studies. The pooled analysis revealed a lung cancer incidence of patients with COPD was 6.0% (95% CI: 5.0–6.9%). Further analysis showed that the incidence was higher in retrospective cohort studies, studies conducted in Asia, studies with sample sizes <5,000, follow-up periods <5 years, and studies of lower quality. Additionally, advanced age, current smoking, and emphysema were associated with increased lung cancer risk in patients with COPD.

A previous systematic review involving 31 studies found a lung cancer prevalence of 5.08% in patients with COPD, noting that sex, smoking, and COPD severity influenced prevalence (50). However, this study had several limitations. First, it included cross-sectional, case-control, and cohort studies which reflected different effect sizes. For example, cross-sectional studies have primarily focused on the prevalence or frequency of lung cancer in patients with COPD, whereas cohort studies have focused on its incidence. Second, the analysis of risk factors was mainly limited to sex, COPD severity, and smoking status, which was not comprehensive. Finally, given that recent studies have explored lung cancer incidence and risk factors in patients with COPD, these new studies need to be incorporated into the analysis. Therefore, this study updates the previous research by providing a systematic evaluation of the incidence and risk factors of lung cancer in patients with COPD.

Our study found that lung cancer incidence in patients with COPD is 6.0%, which is higher than that reported in previous studies (50). Given that all the studies included in this review were cohort studies, the results more accurately reflected the higher risk of lung cancer in patients with COPD. Subgroup analysis revealed that when retrospective cohort studies, studies from Asian regions, and studies with a sample size <5,000 were combined, lung cancer incidence in patients with COPD was higher in the corresponding subgroups. First, retrospective studies may be subject to selection and recall biases affecting the results’ accuracy. These biases could have led to an overestimation of lung cancer incidence. Second, environmental factors, lifestyle, medical conditions, and diagnostic criteria can vary across regions. In some Asian regions, high smoking rates and severe environmental pollution may increase the risk of lung cancer. Finally, small-sample studies are more susceptible to random errors, leading to potential instability in the results. Additionally, small-sample studies may not adequately represent the overall population, resulting in biased outcomes.

We found that advanced age, current smoking, and emphysema were associated with an increased risk of lung cancer in patients with COPD. With increasing age, cumulative DNA damage rises, and immune system function declines, impairing the ability to recognize and eliminate abnormal cells, thereby facilitating cancer cell evasion. Additionally, chronic inflammation in patients with COPD leads to tissue damage and abnormal proliferation during repair, increasing carcinogenesis risk (51,52). Tobacco smoke contains carcinogenic substances, and free radicals and oxidants from smoking induce oxidative stress, damaging cell membranes, proteins, and DNA while promoting abnormal proliferation and carcinogenesis. The chronic inflammatory response triggered by smoking further stimulates respiratory epithelial cells, leading to abnormal differentiation and heightened carcinogenesis risk (53-55). A recent study further corroborates that tobacco smoking induces oxidative stress in smokers, with direct relevance to COPD and lung cancer risk (56). In a cohort of 54 smokers, Pezzuto* et al. *[2025] found that oxidative stress was significantly correlated with smoking intensity—specifically, pack-years and cigarettes per day—reinforcing that cumulative smoking exposure amplifies oxidative damage (56). Notably, the study also identified COPD patients with higher vitamin D levels exhibited lower oxidative stress, suggesting that antioxidant-related factors may modulate the interplay between smoking, oxidative stress, and COPD progression—with implications for lung cancer risk, as reduced oxidative damage could mitigate carcinogenic cell mutations (56). This finding is particularly relevant to our study’s focus on lung cancer risk, as oxidative stress-driven DNA damage is a well-established initiator of lung carcinogenesis—suggesting that targeting oxidative stress could potentially reduce lung cancer risk in high-smoking COPD populations. Emphysema destroys lung tissue, thins alveolar walls, and reduces elastic fibers, impairing gas exchange and creating favorable conditions for tumor growth. Furthermore, impaired immune function in patients with emphysema hampers the elimination of abnormal cells, enabling cancer cells to survive and spread (57-59).

There are several limitations in this study. First, this study included both prospective and retrospective cohort studies, and the results may have been affected by recall and confounding biases. Second, the severity of COPD varied, and most studies did not provide data on lung cancer incidence in patients with different severities of COPD. Third, the lack of available data to calculate the incidence of lung cancer in COPD patients without emphysema. While we confirmed that emphysema is an independent risk factor, the absence of stratified data for lung cancer in COPD patients without emphysema prevents a direct comparison of lung cancer incidence between COPD subgroups. Fourth, although sensitivity and subgroup analyses were conducted, the heterogeneity between the studies was not significantly controlled. Fifth, the factors associated with lung cancer risk in most patients with COPD have been reported in only a few studies, which can lead to unstable results. Finally, Begg’s test identified potential bias, but trim-and-fill adjustment showed in change in the pooled incidence. This aligns with the observation that most included studies were large and published in peer-reviewed journals, reducing the likelihood that small, null findings drastically alter our conclusions.

Conclusions

This study found that lung cancer incidence in patients with COPD is 6.0%, with a higher incidence in Asia than in Europe and the United States. Additionally, risk factors for lung cancer in patients with COPD include advanced age, current smoking status, and the presence of emphysema. In future studies, enhanced follow-up monitoring for lung cancer should be implemented for patients with COPD with the high-risk factors to facilitate early detection and improve patient outcomes.

Supplementary