The association between chronic obstructive pulmonary disease (COPD) and lung cancer has long been a subject of intense debate. The high prevalence of COPD in elderly smokers inevitably strengthens their coincidence. In addition to this contingent coincidence, recent studies have revealed a close association between the two diseases that is independent of the smoking history; that is, the existence of COPD is an independent risk factor for the development of lung cancer. Molecular-based evidence has been accumulating as a result of the efforts to explain the underlying mechanisms of this association. These mechanisms may include the following: the retention of airborne carcinogens followed by the activation of oncogenes and the suppression of tumor suppressor genes; the complex molecular mechanism associated with chronic inflammation in the distal airways of patients with COPD; the possible involvement of putative distal airway stem cells; and genetic factors that are common to both COPD and lung cancer. The existence of COPD in patients with lung cancer may potentially affect the process of diagnosis, surgical resection, radiotherapy, chemotherapy, and end-of-life care. The comprehensive management of COPD is extremely important for the appropriate treatment of lung cancer. Surgical resections with the aid of early interventions for COPD are often possible, even for patients with mild-to-moderate COPD. New challenges, such as lung cancer CT screening for individuals at high risk, are now in the process of being implemented. Evaluating the risk of lung cancer in patients with COPD may be warranted in community-based lung cancer screening.

Smoking causes many diseases including lung cancer and chronic obstructive pulmonary disease (COPD). These diseases usually affect relatively elderly individuals. Because of the rapidly aging populations of many developed countries, the number of patients with lung cancer and/or COPD is growing. Lung cancer is one of the leading causes of death in many countries and accounted for approximately 1.37 million deaths worldwide in 2008[1]. As was extensively discussed in the Global Initiative of Chronic Obstructive Lung Disease (GOLD)[2], accurate estimations of the prevalence and mortality of COPD are difficult. The prevalence of COPD in a specific region varies because of differences in the survey methods, diagnostic criteria and analytic approaches[3,4], ranging from 7.8% to 19.7% of the total population[2]. COPD is often a primary cause of death. However, COPD can also contribute to death from other diseases, such as pneumonia, ischemic hear diseases and heart failure, making it difficult to estimate the COPD-associated mortality rate. Meanwhile, the Global Burden of Disease Study has projected that COPD will become the third leading cause of death worldwide by 2020[5].

Because of the high prevalence of both conditions and strong common risk factors associated with smoking, the coexistence of lung cancer and COPD is inevitably high. In addition, recent studies have uncovered a non-confounding association between COPD and lung cancer development, together with its molecular mechanisms[6,7]. Investigating and resolving the problems of the coexistence of these two diseases is important in view of their clinical relevance; their interaction leads to worse outcomes. This article reviews the current perspectives on the epidemiological, clinical, and etiological problems associated with the coexistence of lung cancer and COPD.

Because of the high mortality associated with lung cancer, the proportion of deaths from lung cancer among patients with COPD can reasonably be considered to represent the coexistence of lung cancer among patients with COPD. As shown in Table 1, the causes of death reported in patients with COPD vary significantly among studies, and the proportion of deaths from lung cancer ranges from 4% to 33%[8-16], presumably because of different patient characteristics and analytical methods. Among their investigation, a prospective study identified 731 deaths that occurred over 14.5 years out of 5887 asymptomatic non-smoking individuals who had mild or moderate airflow limitations, with an average FEV₁/FVC of 65.0% ± 6.1% and an average age of 48.4 ± 6.8 years. The primary cause of death was lung cancer, representing 33% of the total deaths[16]. Three other prospective studies disclosed a high incidence of lung cancer development or mortality among patients with COPD or individuals with airflow limitations[17-19]. Skillrud et al[17] prospectively observed 113 individuals who had a %FEV₁ of 70% or less by comparing them with 113 age-matched, sex-matched, occupation-matched, and smoking history-matched individuals with a %FEV₁ of 85% or more. The 10-year cumulative rates of lung cancer development were 8.8% and 2.0% in the former and latter groups, respectively, resulting in a statistically significant difference (P = 0.024)[17]. Kuller et al[18] reported an increase in lung cancer mortality according to a reduction in the FEV₁. The lung cancer mortality per 1,000 person-years was 3.02 and 0.43 in the lowest and highest quintiles of the FEV₁, respectively, and this association was not weakened by adjustments for smoking factors[18]. The relative risk of COPD or airflow limitations associated with lung cancer was therefore calculated to be 4.4 and 7.0 in the studies by Skillrud et al[17] and Kuller et al[18], respectively. In a large-scale prospective study involving 448,600 lifelong nonsmokers who were cancer-free at baseline and who had a 20-year follow-up period, Turner et al[19] again found a significant association between lung cancer mortality and pulmonary emphysema, with a hazard ratio of 1.66 (95%CI: 1.06-2.59)[19]. Wasswa-Kintu et al[20] conducted a population-based meta-analysis to reveal that even a relatively small decrease in the FEV₁ (approximately 90% of predicted) increased the risk of lung cancer by 1.3-fold in men (95%CI: 1.05-1.62) and 2.6-fold in women (95%CI: 1.30-5.31), concluding that even a modest reduction in the %FEV₁ is a significant predictor of lung cancer, especially among women[20].

The National Lung Cancer Screening Trial (NLST) for annual low-dose CT screening reported a 20% decrease in lung cancer mortality among heavy smokers between the ages of 55 and 74 years[21]. This great achievement has resulted in several established guidelines recommending low-dose CT lung cancer screening for individuals with defined conditions, and the time when screening will be implemented as a part of community health care is drawing closer[22]. The more common use of chest CT examinations in asymptomatic individuals would increase the chance of detecting pulmonary diseases, including lung cancer and pulmonary emphysema. Because a definitive diagnoses of COPD and pulmonary emphysema are based on functional and pathological criteria, respectively, they cannot, by definition, be diagnosed using CT[2]. Nevertheless, the presence of a substantially distributed low attenuation area (LAA) in the pulmonary fields strongly suggests pulmonary emphysema and COPD. In fact, Goddard et al[23] proposed a scoring system, which is used worldwide, to evaluate pulmonary emphysema using CT.

Six studies, consisting of 2 cohort and 4 case-control studies, evaluating the relationship between CT-based emphysema and the risk of lung cancer have been published[24-29], and Zurawska et al[30] concisely reviewed these studies. The relative risk (RR) for lung cancer, according to CT-based emphysema assessed using semi-quantitative visual methods, ranged from 1.9 to 4.7, with a pooled RR of 2.34 (95%CI: 1.46-3.76). Using multivariate analyses adjusted for covariates including age, sex, and smoking status, the adjusted odds ratio for lung cancer, according to the CT-based detections of emphysema, ranged from 1.73 to 3.14. Mizuno et al[26] analyzed CT images from 947 healthy individuals who underwent a low-dose CT screening and 256 patients with lung cancer. After adjusting for sex and age, 423 matched healthy individuals and 141 patients with lung cancer were extracted for inclusion in multivariate analyses, with stratification according to their smoking status. The results disclosed that many functional and CT image factors indicative of COPD (relative risks for lung cancer; 7.17 with FEV₁/FVC < 70% and 3.63 with LAA score ≥ 1) or interstitial lung diseases (relative risks for lung cancer; 4.73 with %VC < 80%, 5.10 with a fibrosis score ≥ 1 and 2.71 with a GGA score ≥ 1) were also risk factors for coincident lung cancer in a manner that was independent of the smoking status (Table 2). These observations suggesting a close association between COPD and lung cancer seem to imply at least three possibilities: first, airflow limitation itself is a risk factor for the development of lung cancer; second, some putative inter-individual variations in the sensitivity to harmful substances, such as active smoking, passive smoking, air pollutants, and cooking oil fumes, may link COPD and lung cancer; and third, some specific genotypes may predispose individuals to both COPD and lung cancer.

A growing volume of evidence suggests that some molecular mechanisms may link COPD and lung cancer. A genome-wide association study has uncovered some putative common loci responsible for both COPD and lung cancer[31]. Taking advantage of such modern technologies, we are soon likely to benefit from abundant information regarding the molecular mechanisms involving the pathogenesis of COPD and lung cancer. The current major possible explanations are outlined below.

As discussed above and illustrated in Table 1, a substantial proportion of patients with COPD die from lung cancer. The coexistence of lung cancer clearly worsens the prognosis of patients with COPD, but a discussion of how COPD worsens the outcome of patients with lung cancer and how this might be overcome is important.

The deterioration of pulmonary function together with the risk of acute exacerbation of COPD would, in theory, make invasive diagnostic procedures, surgery, radiotherapy and chemotherapy difficult in patients with lung cancer. A retrospective study by Sekine et al reported an increased rate of postoperative complications, including pneumonia and the need for a tracheostomy, increased cancer recurrence, and a decreased 5-year survival rate in patients with completely resected stage IA non-small cell lung cancer (NSCLC) and coexisting COPD; the 5-year survival rates of patients with COPD (n = 80) and of those without COPD (n = 362) were 77.0% and 91.6%, respectively (P = 0.0001)[52]. A recent retrospective study involving 902 patients with stage IA to IIB NSCLC treated with surgical resection also disclosed that 63.4% (572/902) of the patient population had self-reported, physician-diagnosed COPD, and the patients with COPD had a poorer 5-year progression-free survival rate (50.1% vs 60.6%, P = 0.007) and a poorer 5-year overall survival rate (54.4% vs 69.0%, P = 0.0002) than the patients without COPD[53].

Treatment algorithms can be complex when different diseases coexist in the same patient. It seems reasonable to prioritize the treatment of diseases with a more serious impact on the prognosis: for example, the treatment for stage III small cell lung cancer would be given preference over the treatment for a coincidental low-grade prostatic cancer in the same patient. The situation, however, is totally different in patients with coexisting COPD and lung cancer. It is very important to diagnose, evaluate, and manage both the COPD and lung cancer in a comprehensive manner for the following reasons.

Low-dose CT screening effectively detects 10-fold more lung cancers at earlier stages compared with screenings using conventional chest X-rays[58]. As mentioned earlier, the NLST, a randomized trial involving subjects with a high risk of lung cancer, confirmed a 20% reduction in the lung cancer mortality among subjects allocated to a low-dose CT screening group compared with an X-ray screening group[21]. This screening strategy targeting individuals at high risk was based on their smoking history and age. Sekine et al[59] emphasized the importance of the early detection of COPD for the purpose of lung cancer screening and proposed CT screening for individuals with suspected COPD as a strategy to target individuals at high risk. Based on a quick questionnaire that collected information about age, smoking history, and chronic respiratory symptoms, they identified 878 individuals fulfilling the defined criteria out of 89100 participants (1.0%). A total of 567 of the 878 participants (64.6%) underwent further evaluation consisting of CT and spirometry, resulting in the detection of COPD in 161 participants, with 38.5% of them requiring COPD treatment[60]. Although the data regarding lung cancer detection are not yet available because the trial is still ongoing, this strategy for identifying a high-risk population based on suspected COPD could be an alternative to identification strategies based on age and smoking history. We envision that this new approach could enable us to evaluate and manage COPD and lung cancer comprehensively at early stages and from screening through specialized treatment.