Exposure to cigarette smoke causes inflammatory cells, particularly neutrophils and macrophages, to be recruited at the site of lung injury and activated to release neutrophil elastase (NE), serine and matrix metalloproteinases (MMPs), and ROS. A defect in A1AT contributes to degradation of elastin due to activation of NE and oxidative stress-mediated inflammation in the lung, resulting in development of emphysema and lung tumorigenesis [40, 41]. Many studies have shown that chronic inflammation in lung tissue and associated repair processes in COPD may initiate lung cancer [42, 43]. An excess of circulating inflammatory mediators such as IL-6, TNF-α, and IL-8 released from inflammatory cells maintains chronic systemic inflammation in patients with COPD and, thus, further contributes to carcinogenesis [44, 45]. Current therapies for COPD, including inhaled corticosteroids (ICS), long-acting muscarinic receptor antagonists (LAMAs), long-acting β2-agonists (LABAs), and theophylline, suppress inflammation in the lung and prevent spillover of inflammatory mediators into the systemic circulation. Theophylline indirectly suppresses NF-kB, which is a cause of persistent airway inflammation, and may reduce the risk of tumorigenesis by activating histone deacetylase 2 (HDAC2), which restores sensitivity to ICS in patients with COPD [46]. Thus, patients with COPD who are treated with ICS have a reduced incidence of lung cancer and lower mortality, which suggests that inhibition of inflammation can slow lung tumor onset [47]. However, large prospective trials have failed to demonstrate a survival benefit in chronic use of ICS with or without LABAs [48].

The free radical hypothesis suggests that reactive nitrogen and oxygen species (RNOS) drive accumulation of cell and DNA damage, which results in mutations and cancer initiation if incorrectly repaired. RNOS can degrade proteins, including tumor suppressors, leading to cell division and decreased apoptosis and DNA repair [49], which results in cancer promotion and progression. Antioxidant therapy for reduction of the risk of lung cancer using vitamin C, vitamin E, or N-acetyl cysteine (NAC) may be of benefit for patients with COPD. However, supplementation with vitamins E or C was shown to have no significant effect on total cancer incidence in the USA [50, 51], and 2-year NAC supplementation resulted in no survival or event-free survival benefit in patients with lung cancer, most of whom were previous or current smokers [52].

A recent study suggested that hypoxic regions of the lung may have a role in the association between COPD and lung cancer. The hypoxia-inducible factor (HIF) family, HIF-1α and HIF-2α, is well known as inducers of VEGF-mediated angiogenesis and is likely to play a role in the increased cancer risk in COPD [53, 54]. HIF-2α overexpression in a conditionally expressed mutant mouse model of lung carcinogenesis resulted in larger tumors [55]. However, HIF-2α deletion unexpectedly showed an increase in tumor burden, associated with a decrease in a candidate tumor suppressor gene.

Serum VEGF levels are significantly associated with clinical staging and lower survival of patients with NSCLC [56]. Bevacizumab is a recombinant, humanized, monoclonal antibody against VEGF that is approved as first-line treatment of NSCLC based on data from randomized phase III clinical trials [57]. In COPD pathogenesis, epithelial cell injury mediated by oxidative stress may induce a decrease in lung VEGF levels, resulting in promotion of COPD. Inhibition of VEGF receptors induces alveolar septal cell apoptosis and leads to enlargement of air spaces, indicative of emphysema [58]. These results suggest that bevacizumab-based chemotherapy for COPD-associated lung cancer may be disadvantageous for COPD management. However, some studies have linked COPD with increased expression of VEGF in bronchial tissue [59], and activation of NF-kB in COPD promotes HIF stabilization [60]. The significance of VEGF production in patients with COPD remains unclear, but inflammation and hypoxia regulation may have some impact on the prognosis of COPD-associated lung cancer. Thus, the response to specific treatment for tumors arising in a hypoxic lung-induced VEGF production might be exploitable in patients with underlying COPD.

Neutrophil elastase (NE) has a well-known effect on elastin fiber degradation that results in emphysema and promotes lung tumor growth in a Kras mouse model of lung adenocarcinoma [61]. The relationship of NE activity with poor outcomes in human lung cancer has not been established, but drugs that inhibit NE activity might be of value as therapeutic prevention for COPD-associated lung cancer.

Members of the MMP family are matrix-degrading enzymes in emphysema and lung cancer and may be mechanistic links between COPD and lung cancer by contributing to lung tissue destruction in emphysema and promoting lung tumor growth and invasiveness. The activities of MMP9 (gelatinase B) in BAL fluid and serum correlate with COPD severity [62, 63], and MMP9 is essential for tumor angiogenesis in animal models [64]. MMP1 (collagenase I) contributes to growth of most solid tumors and promotes metastasis [65]. Overexpression of MMP1 in transgenic mice causes development of emphysema [66], and polymorphisms in the MMP1 promoter predict disease severity in patients with COPD [67]. MMP12, a somewhat macrophage-specific proteinase, is a stimulator of emphysema, and its activity has been associated with disease severity in COPD [68]. Interestingly, MMP12 is known more as a tumor suppressor and not as a target for treatment of lung cancer [69] (Table 18.2).

The effects of AZD1236, a selective MMP9 and MMP12 inhibitor, on emphysematous lung tissue degradation were evaluated in patients with moderate-to-severe COPD, but AZD1236 and other MMP inhibitors do not improve lung function and symptoms [70]. Similarly, other MMP inhibitors, marimastat (BB2516) and BAY12-9566, failed to improve survival in patients with advanced NSCLC [71]. Clinical trials have yet to demonstrate significant increases in overall survival and toxicity remains an issue.

Increasing intracellular levels of cAMP induce cancer cell death in vitro. Theophylline, which elevates intracellular cAMP, induces cancer cell apoptosis and thus may be a potential anticancer drug in combination with other chemotherapeutic agents [72]. COX2 generates prostaglandin E2 (PGE₂), which strongly elevates intracellular cAMP, but PGE₂ also promotes carcinogenesis in several ways, including increased resistance to apoptosis, increased angiogenesis, and enhanced invasion [73]. Celecoxib, a COX2-selective inhibitor, may reduce the cancer risk in a high-risk smoking population based on reduction of proliferation markers in the bronchial epithelium [74]. Celecoxib increased progression-free survival in combination treatment in patients with lung adenocarcinoma cancer with biomarkers for high metabolism of PGE₂ in urine [75] and reduced progression of cigarette smoke-induced pulmonary emphysema by suppression of NF-kB-regulated anti-inflammatory effects in an animal model [76]. Oral prostacyclin (iloprost) also has a tumor-suppressive effect and displays antiproliferative and antimetastatic properties [77]. However, the proven benefits of celecoxib and iloprost are limited to patients with established COPD. A nonselective COX inhibitor, indomethacin, and a nonselective PDE inhibitor, IBMX, significantly inhibit proliferation of SCLC cells with neuronal characteristics in vitro [78]. Beta-adrenergic receptors co-express COX2 in lung adenocarcinoma tissue [79], and indacaterol, an ultra-long-acting inhaled β2-agonist (LABA), inhibits NF-kB activity and reduces expression of NF-kB target genes related to COPD and lung cancer, including MMP9 [80]. This suppresses tumor cell invasion and migration in vitro, but the effect on outcomes for lung cancer in human study is unknown.

Non-neuronal ACh activates downstream NF-kB signaling and acts as an autoparacrine growth factor to stimulate cell proliferation and promote epithelial-mesenchymal transition (EMT) in NSCLC via activation of the M2 muscarinic receptor (M2R) [81, 82]. Expression of another mAChR, M3R, is significantly increased in NSCLC and is correlated with tumor metastasis and poor survival. M3R enhances expression and activity of MMP9 through PI3K/Akt, which promotes migration and invasion of NSCLC cells, and blockade of M3R suppresses proliferation, invasion, and migration of NSCLC and SCLC cells [83–85]. R2HBJJ has high affinity to M3 and M1 AChRs and markedly suppresses growth of NSCLC cells [86]. These findings indicate that M2R and M3R antagonists may be beneficial therapy for COPD-associated lung cancer. Such compounds are currently used for COPD treatment, including LAMAs, LABAs, and theophylline, but they may be toxic at higher concentrations required for anticancer treatment according to the results from these in vitro experiments. There are currently no clinical trials of these drugs in lung cancer patients.

Severe airway obstruction, advanced clinical stage, and higher age are independent factors associated with an indication for thoracic surgery in COPD-associated lung cancer [87]. Comorbidities such as COPD can have a significant effect on long-term survival due to an influence on treatment indication, complication rate, and treatment efficacy. COPD and smoking are significant independent risk factors for postoperative pulmonary complications such as atelectasis and pneumonia and are associated with a poorer long-term outcome [88]. Patients receiving curative surgery for NSCLC who have co-existing COPD have worse survival than their counterparts with better pulmonary function. Notably, the treatment-naïve COPD patients who have improved preoperative symptoms and pulmonary function by inhaled tiotropium starting 2 weeks prior to surgery demonstrated better postoperative pulmonary functions than expected [89].

Higher COPD grades have more postoperative pulmonary complications and poorer long-term survival because of higher rates of recurrence of lung cancer (Fig. 18.1) [90]. In patients with stage I resected NSCLC, COPD is an independent predictor of reduced recurrence-free survival, and these patients are at higher risk of recurrence than patients without COPD [91, 92]. Therefore, it is important to identify patients with early-stage NSCLC for more aggressive treatment. Clinical studies are needed in patients with lung cancer to determine how COPD promotes recurrence and affects the indication for adjuvant chemotherapy following curative resection.

Although there is not yet strong evidence for specific difference in management for lung cancer comorbidity with COPD, the patients with high age, poor overall PS, and severe impaired lung function associated with COPD are generally restricted to receive the appropriate platinum-based standard chemotherapy for the high risk of adverse effects. Thus, they often receive single-agent chemotherapy or choose best supportive care due to rapid progression to death. The mild COPD patients with advanced metastatic disease who received chemotherapy can delayed progression, palliate symptom, and improved overall survival and did not find significant differences in improved treatment outcome between mild COPD and non-COPD [93]. However, COPD exacerbations by airway infections and other factors often prevent the chemotherapy, and once acute exacerbation has occurred, the mortality rate is high in patients with COPD-associated lung cancer during chemotherapy.

EGFR mutations and ALK rearrangements are major drivers in non-smoker lung adenocarcinoma, and these patients may be particularly responsive to molecular targeted therapy. In contrast, patients with COPD-associated NSCLC have a low prevalence of EGFR mutations and ALK rearrangements, but these are linked to COPD severity and more frequent poorly differentiated lung cancer with a poor prognosis [87, 94]. In a comparison of the molecular features of COPD-associated adenocarcinoma with those of smoke-related adenocarcinoma without COPD, Schiavon et al. found that EGFR mutation did not differ between the two groups, but KRAS mutation was higher in smokers than in COPD patients [95].

In contrast to idiopathic interstitial pneumonias, the presence of COPD is not recognized as a significant risk factor for drug-induced interstitial lung disease associated with lung cancer treatment. Expression of EGFR is higher in lung cancer patients and in COPD patients [96]. Thus, EGFR inhibition has been examined in COPD as a method to prevent stimulation of mucous hypersecretion, but the initial studies have produced negative findings [97].

Stereotactic body radiotherapy (SBRT) is standard of care for early-stage non-small cell lung cancer at high risk of surgical complications and associated with excellent local control (∼90 % at 3 years). In previous retrospective study, 32 % of stage I lung cancer patients with COPD who underwent SBRT had radiation pneumonitis, and COPD and the Brinkman index were statistically significant risk factors for the development of radiation pneumonitis. However, SBRT-mediated radiation pneumonitis did not associate OS, and thus SBRT can be tolerated in early lung cancer patients with COPD [98]. Severity of radiation pneumonitis associated higher in patients with a high V20 (≥25 %) value and severe low-attenuation area (LAA) grade on CT scans [99]. In contrast, patients with severe emphysema had a low risk of radiation pneumonitis following SBRT rather than normal lung function and with mild emphysema. Furthermore, fewer pack-years smoked among COPD patients were the strongest predictor for severe radiation pneumonitis [100, 101].

SBRT can be considered as therapeutic option in patients with higher operative risks, such as the elderly and patients with severe COPD. However, previous studies still provide controversial results about the risk of radiation pneumonitis in severe COPD patients. Further follow-up study might be needed to evaluate the tolerability to SBRT in COPD-associated lung cancer patients.

Chronic inflammation is a common feature in COPD and lung cancer, but the characteristics of immune cells in COPD differ from those found in lung cancer. Immune cells in BAL fluid from COPD patients tend to shift toward the T helper 1 (T_H1) phenotype with interferon-γ (IFNγ) production [102]. In contrast, immune cells in most solid tumors show a trend for the T_H2 phenotype with infiltration of immunosuppressive cells in tumor tissue. These cells include myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T_Regs) and express programmed cell death protein 1 (PD-1) on the cell surface, which results in suppression of cytotoxic T lymphocyte function and enhanced tumor viability [103, 104]. The use of PD-1- and PD-L1-blocking antibodies in therapy for NSCLC is focused on increasing cytotoxic T cell activity, which increases the cancer antigen-mediated immune response. Increasing PD-L1 expression in tumor tissue was observed in smokers and associated with more pack-years [105] and anti-PD-1/PD-L1 treatment prolonged OS in NSCLC patients with smoking history [106]. An increased proportion of CD8+ T cells in lung parenchyma in COPD patients has been described, and the PD-1 pathway has been suggested to be relevant in COPD pathogenesis. CD8+ T cells expressing PD-1 are present at higher levels in blood from COPD patients and are correlated with disease severity [107–109]. Furthermore, virus-induced expression of PD-L1, the ligand for PD-1, is decreased in COPD macrophages, with a corresponding increase in IFNγ release from infected COPD lungs resulting in increased severity of viral infection, prolonged viral shedding, and structural lung damage associated with exacerbations [110]. Although, anti-PD-1/PD-L1 treatment may associate better clinical outcome in smoking related lung cancers patients with COPD, we should note that the use of PD-1- and PD-L1-blocking antibodies may have indirect effects against chronic inflammation-mediated COPD development and aberrant immune regulation, especially during exacerbation of COPD. Aminophylline, which is often used as a bronchodilator for COPD patients, also has an unexpected effect on lymphocyte regulation and synergistically accelerates lymphocyte cell division in patients with lung cancer undergoing chemotherapy [111].