This is the first study to investigate the impact of COPD treatment on the survival of patients with advanced NSCLC. The current study demonstrated that COPD treatment was associated with improved OS in patients with advanced NSCLC even though the COPD treatment group had worse baseline lung function than the no-treatment group. When OS was analyzed for each type of COPD treatment, inhalation therapy and the use of ICS were associated with improvements in OS.
COPD is an important comorbidity for lung cancer patients. Therefore, several studies have investigated the relationship between COPD and the prognosis of lung cancer patients. In patients with inoperable NSCLC, FEV1 < 60% predicted or diffusing lung capacity < 60% predicted were both associated with a worse prognosis [11, 21]. FEV1 itself is a predictor of mortality, not only in COPD patients but also in the general population [14, 22]. For patients with operable lung cancer, preoperative spirometry is essential, whereas spirometry may not be necessary for patients with inoperable lung cancer, particularly if they do not complain of respiratory symptoms, in which case clinicians are likely to focus only on lung cancer. Since physical activity usually decreases with age, patients with mild to moderate COPD, usually defined as FEV1 ≥ 50% predicted, do not experience or overlook their respiratory symptoms in many cases. In this study, 86% of patients with advanced NSCLC were diagnosed with COPD for the first time. Unfortunately, out of 190 patients with newly diagnosed COPD, only 94 (49%) were treated for their COPD. These results indicate that the identification of COPD through spirometry and active treatment for COPD are essential before treatment of their cancer.
In COPD patients, inhaled therapy, including LAMA, LABA, ICS, and combination therapy, have shown improvements in lung function, quality of life, and exacerbations [18, 23–25]. However, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) noted a lack of convincing evidence for a survival benefit with inhaled therapy in COPD. Recent large randomized trials showed a survival benefit of ICS-containing combination therapy over dual bronchodilator therapy with LAMA-LABA [18, 19]. Interestingly, according to a nationwide study of COPD patients in Korea, ICS users appear to have a lower risk of lung cancer compared with nonusers . It is hypothesized that ICS, which reduces the risk of acute exacerbations through anti-inflammatory action in COPD patients, reduces the risk of lung cancer, a type of chronic inflammation. In this study, ICS was shown to prolong the survival of patients with advanced NSCLC. It is possible that the anti-inflammatory action of ICS inhibits cancer progression. There is also a report that ICS lowered the risk of coronary heart disease in COPD patients . Therefore, the use of ICS may have had an effect on cardiovascular mortality in our study subjects. Since detailed information on the cause of death was not available for many of our subjects, it was not possible to evaluate whether inhaled therapy was associated with cancer progression or other fatal complications, such as exacerbation of COPD, pneumonia, and cardiovascular events. Inhaled therapy may have also influenced their performance status, which is a major factor in determining whether to treat lung cancer, and is itself an important prognostic factor in lung cancer patients .
In COPD patients, ICS increases the risk of pneumonia [29–31]. Pneumonia is one of the most life-threatening complications of lung cancer patients. However, previous studies have demonstrated consistent results that the use of ICS does not increase pneumonia-related mortality in COPD patients, and instead it is associated with decreased mortality in hospitalized pneumonia patients [17, 32]. This might suggest a double effect of ICS, an immunosuppressive effect and an anti-inflammatory effect. ICS, which achieves locally high concentrations in the lung, up-regulates the production of anti-inflammatory proteins and inhibits the transcription of proinflammatory cytokines and chemokines . In a previous study of patients receiving cisplatin-containing chemotherapy, inhaled fluticasone reduced the incidence of delayed pulmonary toxicity . Because there are also reports that different kinds of ICS have different impacts on the incidence of pneumonia, we need to make careful choices about ICS type and dose [30, 35].
The present study has several limitations. First, it was a single-center study and not all patients with newly diagnosed advanced NSCLC had performed spirometry, so there may have been selection bias. Second, it was not possible to investigate their performance status. Performance status is an important prognostic factor and may affect treatment decision-making [36–38]. Nevertheless, BMI and undergoing cytotoxic chemotherapy might indirectly reflect their performance status, and these factors were adjusted for the analysis. Third, it is not clear why the no treatment group did not receive COPD treatment. As this study was a retrospective study, the respiratory symptoms of the study subjects were not evaluated. Nevertheless, the fact that the no treatment group had better lung function than the COPD treatment group strongly suggests the possibility of not receiving COPD treatment due to no respiratory symptoms. Even if a doctor tried to prescribe an inhalation drug, it is likely that a patient with no symptoms refused it. Fourth, although COPD is characterized by not fully reversible airflow obstruction, we were unable to evaluate whether lung function or dyspnea improved after treatment in the COPD treatment group.