Study population
This study analyzed data from the NHIS-NSC. The NHIS-NSC is a population-based cohort established by the National Health Insurance Service (NHIS) in South Korea [14]. The NHIS is a single-payer health insurance system in South Korea that covers the entire South Korean population (approximately 48 million in 2003). The NHIS provides biennial health screening to all insured adults aged 40 years or older. The NHIS-NCS database consists of 514,795 participants who were aged between 40 and 79 in 2002 and underwent health screening programs in 2002 or 2003 (2002 for participants born in an even year and 2003 for participants born in an odd year) (Fig. 1). Data on smoking history, body mass index, blood pressure, fasting serum glucose, total cholesterol, and exercise status of participants were obtained.
After excluding 20,837 patients (14,691 never smokers, 2,169 former smokers, and 3,977 smokers) with previous histories of cancer diagnoses before January 1, 2004, classified by the International Classification of Diseases 10th revision (ICD-10) codes for cancer diagnoses or questionnaires on previous medical history, 317,789 never-smokers, 41,477 former smokers, and 113,883 smokers were included in the final study cohort (Fig. 1). After excluding subjects (N = 156,440) who had taken medication due to COPD symptoms (≥ 4 times in two years), 127,884 never smokers without a COPD diagnosis were assigned to the healthy control group. Finally, the cohort consisted of four arms, the healthy control group, never-smokers with COPD (N = 29,799), former smokers with COPD (N = 3,267), and smokers with COPD (N = 8,335) (Fig. 1). We investigated the development of new cancers, including lung cancer, stomach cancer, colorectal cancer, liver cancer, and acute myeloid leukemia (AML) from January 1, 2004, to December 31, 2015, a 12-year period (Fig. 1–2).
Definition and covariates
COPD was identified by the combination of ICD-10 codes J41-J44 for COPD (simple and mucopurulent chronic bronchitis, unspecified chronic bronchitis, emphysema, and other chronic obstructive pulmonary diseases) and use of the following medications for COPD (≥ 4 times in two years) : long-acting muscarinic antagonists (LAMA), long-acting beta-2 agonists (LABA), LAMA + LABA, inhaled corticosteroids (ICS) + LABA, triple therapy (LAMA + LABA + ICS), short-acting muscarinic antagonists (SAMA), short-acting beta-2 agonists (SABA), phosphodiesterase-4 (PDE-4) inhibitors, mucolytics, or theophylline [15, 16]. Former smokers were defined as those who had not smoked for at least one year [17].
Smoking history and exercise status were evaluated by self-administered questionnaires at baseline in 2002 or 2003. Data on body mass index, blood pressure, fasting serum glucose, total cholesterol, and exercise status were measured at baseline. Body mass index (BMI) was calculated as body weight in kilograms divided by height in meters squared (kg/m2).
Main outcome measures
The primary outcome was the incidence of lung cancer. The secondary outcomes were the incidence of stomach cancer, colorectal cancer, liver cancer, and AML. The outcome measures were ascertained by health insurance claims data in the NHIS from January 1, 2004, to December 31, 2015. The first incident event was only used in the analyses for participants with more than one event. ICD-10 codes were used to identify outcome measures as follows: lung cancer (C33, C34), stomach cancer (C16), colorectal cancer (C18, C19, C20), liver cancer (C22), and AML (C92.0).
Statistical analyses
As shown in Fig. 1, the study participants were stratified into four groups: healthy control group (never smokers without COPD), never smokers with COPD, former smokers with COPD, and current smokers with COPD.
All values were described as mean ± standard deviation. One-way analyses of variance for continuous variables were used for continuous data and chi-square statistics tests were for categorical data. Cox proportional hazards regression analysis was used to identify significant variables predicting the occurrence of an event. Cox proportional hazard models were performed to evaluate the independent effects of COPD on the development of cancer, after adjusting for age, gender, hypertension, diabetes, body mass index, and exercise. Variables selected via univariate test (p < 0.01) were evaluated in a multivariate Cox regression analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the risk of lung, stomach, colorectal, and liver cancers, and AML. P-values < 0.01 were deemed statistically significant and all analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
Ethics statement
The present study was approved by the Institutional Review Board of Ajou University Hospital (No. AJIRB-MED-EXP-17-167).