Background
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways characterized by persistent symptoms such as cough, sputum production, progressive breathlessness, and airflow obstruction [
1]. Patients with lung cancer have a sixfold greater risk of having COPD than do matched smokers [
2]. Although eligible patients with lung cancer receive a survival benefit from surgical resection, COPD is an important patient-related risk factor for postoperative complications and mortality [
3]. Patients with COPD often have nonspecific airway hyperactivity, suggesting the presence of bronchospasm or latent respiratory tract infection. It is important to alleviate peripheral airway obstruction and to reduce airway secretions to improve surgical outcomes [
4‐
6]. The combination of smoking cessation, physical therapy, and the use of bronchodilators reportedly reduces postoperative complications and improves surgical outcomes in patients with lung cancer and COPD [
7,
8].
Long-acting muscarinic antagonists (LAMAs) prevent the neurotransmitter acetylcholine from binding to muscarinic receptors, leading to relaxation of the airway smooth muscle [
9]. Long-acting β
2 agonists (LABAs) act on β
2-adrenergic receptors and cause relaxation of the smooth muscle [
10]. Patients who receive combined LAMA/LABA therapy for COPD show superior improvement in lung function and clinical outcomes than those who receive bronchodilator monotherapy [
11]. Combined LAMA/LABA therapy also leads to a lower incidence of pneumonia than the combination of inhaled corticosteroids (ICS) and a LABA [
11].
Because the prognosis of patients with lung cancer complicated by COPD is reportedly poor [
7], it is important to provide respiratory care for an extended duration, not just during the perioperative period. The aim of this study is to determinate the effects of perioperative LAMA/LABA therapy on preoperative lung function, postoperative morbidity and mortality, and long-term prognosis for patients with COPD and lung cancer. We hypothesize that perioperative LAMA/LABA therapy will improve surgical outcomes.
Methods
This study was approved by the Ethics Committee of Faculty of Medicine, Toho University (A19039_27128_25095_25047).
Study design and population
We performed a retrospective review of the medical records of patients who underwent surgical resection of lung cancer at Toho University Hospital between January 2005 and October 2019. We included patients over the age of 40 with both airflow limitation (AFL) and a smoking history of greater than 10 pack-years. Patients who had characteristics of asthma such as wheezing, shortness of breath, chest tightness, or allergic conditions were excluded. We defined AFL as a ratio of expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) less than 70%, as determined by spirometry at the patient’s initial visit. We excluded patients with a history of asthma or a history of inhaled therapy, and those who were missing data.
All patients with newly defined COPD received perioperative rehabilitation. The patients were divided into 3 groups according to their perioperative management: a LAMA/LABA group, a LAMA group, and a group that did not receive bronchodilators (No-BD group). The severity of AFL was classified according to the spirometric grades outlined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [
12].
Classification criteria for the three groups are based on changes in perioperative management for COPD patients as follows.
In our institute, we have executed perioperative respiratory rehabilitation and perioperative LAMA therapy for COPD patients with moderate to severe AFL since 2005 to March 2013. Since April 2013, when LABA have been developed for COPD, perioperative inhaled agent has been changed to LAMA/LABA. Eventually, therapeutic target has been expanded to COPD patients with mild AFL since July 2015. From January 2005 to June 2015, COPD patients with mild AFL, glaucoma, or severe benign prostatic hyperplasia were executed perioperative respiratory rehabilitation only.
Reassessment of respiratory function is performed on patients who received bronchodilators 1 or 2 days before surgery during hospitalization. All patients use inhaled medication early in the morning and have a respiratory function test in the afternoon.
Postoperative complications
Pneumonia was defined as the presence of at least 3 of the following: a persistent lung infiltrate on chest radiography, chest computed tomography or both; a temperature of > 37.5 °C; and a leukocyte count > 10,000/mm3. Acute respiratory failure was defined as postoperative ventilator dependence > 12 h or reintubation for mechanical ventilation. Prolonged air leakage was defined as the continuation of air leakage for more than 7 days after surgery. Atrial fibrillation was diagnosed by electrocardiography and required to persist for at least 1 h.
Statistical analysis
The data were presented as the mean ± standard deviation (SD) or as the median value with interquartile ranges. Categorical variables were shown as the percentage of the sample. Comparisons between 2 groups were assessed using Student's t‑test for normally distributed variables or using the Mann–Whitney U test for nonnormally distributed variables. Differences were considered statistically significant when the p value was less than 0.05. Survival curves were prepared using the Kaplan–Meier method, and univariate comparison was performed using the log-rank test. To determine which factors were significantly associated with survival, we performed multivariate analysis using the Cox proportional hazards model. All statistical analyses were performed using JMP software, version 14.0 (SAS Institute Inc., Cary, NC, USA).
Cox hazard regression models were constructed to calculate adjusted 95% confidence intervals (CIs).
Discussion
In patients with lung cancer, COPD is an independent risk factor for morbidity and mortality. In the present study, we clarified the efficacy of perioperative LAMA/LABA therapy for pulmonary function, postoperative complications, and long-term prognosis in patients with newly diagnosed COPD requiring surgery for lung cancer.
The utility of perioperative bronchodilator therapy has been validated in several previous reports, but the most suitable agent has not been clarified. We previously analyzed the data of 32 patients with moderate to severe COPD and lung cancer and reported that perioperative LAMA/LABA therapy improves lung function and reduces postoperative complications to a greater degree than LAMA therapy [
13]. In the present study, we assessed 130 patients with COPD of all severity levels, with similar results.
Some previous studies reported that preoperative LAMA monotherapy improves lung function or prevents postoperative respiratory complications, but other reports do not [
14,
15]. Bolukbas et al. reported that adding ICS to LAMA and LABA led to improvement in lung function and fewer respiratory complications [
8]. However, the use of ICS is associated with severe pneumonia [
16], and steroid use is a significant risk factor for bronchopleural fistula formation [
17]. Therefore, the use of perioperative ICS is controversial. Combined LAMA/LABA therapy during the perioperative period may provide a rapid and powerful bronchodilating effect, by the dual action of LAMA and LABA without adverse events such as pneumonia.
The effect of perioperative bronchodilator use on postoperative long-term prognosis in COPD patients with lung cancer has not been reported. We found that perioperative LAMA/LABA therapy is associated with a favorable prognosis compared with LAMA therapy or rehabilitation alone, especially in patients with moderate to severe COPD.
COPD is a strong promoting factor for lung cancer, and patients with COPD have poorer postoperative long-term survival due to a higher recurrence rate and poor health status [
18]. Chronic inflammation of the bronchial and alveolar mucosa [
19], direct effects to DNA restoration by oxidative stress [
20], and genetic mutation or variation [
21] are associated with COPD and the development of lung cancer. Recent reports propose that bronchodilators are able to inhibit inflammation and oxidative stress in mouse model [
22]. Muscarinic receptors expressed on lung cancer cells can reportedly stimulate tumor growth via acetylcholine [
23]. The M
3 muscarinic receptor subtype is associated with cell proliferation [
23], and LAMAs have the potential to inhibit the growth of lung cancer cells as M3 receptor antagonists. Li et al. reported that indacaterol induces apoptosis in lung cancer cells harboring the epidermal growth factor receptor
T790M mutation and may be a novel candidate for treatment of gefitinib-resistant lung cancer [
24]. Our results and these previous in vitro studies suggest the possibility of the dual anticancer effects of LAMA/LABA—prevention of cancer development and inhibition of proliferation signals of lung cancer—may contribute to a favorable prognosis and inhibition of recurrence. On the other hand, high proportion of stage I in patients who received LAMA/LABA therapy may also affect lung cancer prognosis. Randomized controlled trials would be necessary to prove the anticancer effect by LAMA/LABA therapy.
This retrospective study has limitations and biases. The duration of bronchodilator use and the individual bronchodilators employed was inconsistent. This discrepancy about selection of bronchodilators was due to the different study periods. Differences in the study period or severely of AFL between LAMA/LABA and the other groups may have affected the postoperative complications and survival rate. Finally, changes in surgical technique, surgical methods, or anesthetic agents over the years of the study period may have affected the incidence of postoperative complications.
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