Lung cancer has been linked to the changes in lung function characteristic of chronic obstructive pulmonary disease (COPD) and to the changes in lung morphology seen in emphysema. It seems that a common thread of smoking-induced lung injury can be traced to all three diseases. However, the association is not as straightforward as it may seem; for example, even never-smokers with emphysema have an increased risk of lung cancer. Whether lung cancer, COPD, and emphysema are linked by common genes, mechanisms, causes, or a combination thereof, understanding the associations between them has become a priority for research regarding tobacco-related illnesses. A better delineation of the relationships between these three entities may lead to significant improvements in the effectiveness of lung cancer screening programs, and to reductions in the morbidity and mortality associated with these deadly diseases.
Lung cancer in patients with COPD
Lung cancer and COPD not only go hand in hand in some patients, they also seem to be synergistic insofar as their combined impact on mortality is concerned. Lung cancer appears to be especially deadly in patients with COPD and/or emphysema. A recent meta-analysis found that COPD is associated with stage-independent poor overall and disease-free survival, while emphysema in lung cancer patients predicts worse overall survival. The NLST investigators also found that lung cancer in patients with altered lung function is more aggressive. This finding, common to other screening studies, including the Danish Lung Cancer Screening Trial (DLCST), suggests that screening-related overdiagnosis is less common in patients with COPD; since overdiagnosis is a frequently noted pitfall of screening, this finding arguably makes lung cancer screening more effective in patients with altered lung function.
COPD and emphysema as selection criteria for lung cancer screening
Most recommendations regarding lung cancer screening rely on the NLST’s age and pack-year entry criteria, with only slight variations in smoking abstinence (Table 2).[75-80] However, concerns about the cost of screening so many at-risk individuals or missing cancers in younger, lighter smokers, especially women, have been raised. After all, the NLST entry criteria were arbitrary, not based on scientific evidence. That notwithstanding, current estimates suggest that as many as 7 million US adults are NLST-eligible. Screening all of them is an expensive proposition. Making matters worse is the fact that many cancers are diagnosed in patients who do not meet NLST entry criteria.[19,81,82] In one study alone, less than 50% of lung cancers diagnosed in Olmsted County, Minnesota, between 2005 and 2011 occurred in NLST-eligible patients. Furthermore, only 37% of women with lung cancer in that cohort would have been offered lung cancer screening if current recommendations were complied with, suggesting that a significant proportion of lung cancers may be missed by existing screening programs. Because the NLST and other studies have shown that a considerable number of screening-detected cancers are found in patients with altered lung function or morphology, it is only rational to assume that both emphysema and COPD may be considered clinically useful in this regard. In fact, it is rare for a patient with lung cancer to have neither. In some studies, almost 80% of screened patients with lung cancer had COPD, emphysema, or both.
KEY POINTS regarding the links between lung cancer, COPD, and emphysema
- Lung cancer risk is higher in patients with emphysema and COPD, and the prognosis of lung cancer is worse in patients with altered lung function and morphology.
- Proposed mechanisms linking all three tobacco-related diseases include: a common genetic susceptibility, DNA damage and abnormal repair, chronic inflammation, and a favorable milieu.
- Both emphysema and COPD may be considered biomarkers capable of refining patient selection criteria for lung cancer screening programs.
In light of this, some medical societies have proposed modified inclusion criteria for screening, suggesting that NLST-ineligible smokers with at least one additional risk factor should also be offered screening.[77,78] This strategy was put to the test in three combined hypothetical cohorts from US and Spanish screening programs employing the I-ELCAP protocol in patients older than 40 years of age with at least a 10-pack-year smoking history. Had screening been offered only to NLST-eligible patients in those cohorts, a large number of cancers would have been missed. However, if emphysema detected on a baseline CT scan had been used in order to recommend ongoing screening for those not meeting NLST criteria, most of the screening-detected lung cancers would have been included in a hypothetical cohort formed by emphysematous and NLST-compliant subjects. This strategy would not only improve lung cancer screening results, but might also limit the number of patients considered at-risk who do not meet current screening recommendations. Kovalchik’s study highlighting the importance of emphysema in the NLST cohort has already been mentioned. In that study, a risk-based strategy for lung cancer screening of NLST-ineligible smokers was thought to be a rational starting point for expanded criteria. Pursuant to this and other considerations, a lung cancer screening score has been proposed for COPD patients in order to identify those at greatest risk for lung cancer. The score, known as the COPD-LUCSS, blends traditional lung cancer screening criteria, such as age and tobacco exposure, with alternative criteria, including emphysema and body mass index, in order to stratify COPD patients by risk. High-risk patients (COPD-LUCSS ≥ 7 points) identified using this score have a threefold increase in lung cancer risk compared with those who have the lowest scores (COPD-LUCSS = 0–6 points). Diffusing capacity for carbon monoxide (DLCO) measurements in patients with COPD may be an alternative criterion when CT phenotyping is not available, since DLCO correlates with the presence of emphysema in those patients. Although the correlation may not be robust in asymptomatic smokers, an alternative score that incorporates DLCO, known as the COPD-LUCSS-DLCO, can also help clinicians select those COPD patients at highest risk.[86,87] It is important to keep in mind that lung cancer is especially deadly in patients with COPD. Contrary to what some believe, existing evidence suggests that COPD patients stand to benefit most from lung cancer screening, despite the risks and premature mortality associated with obstructive airways disease. de Torres et al reported that lung cancer mortality in patients with COPD is dramatically reduced by screening this patient population: 0.08 vs 2.48 deaths per 100 person-years in screened and control cohorts, respectively. Similar findings were reported by the DLCST investigators, who could only demonstrate a benefit for screening in their cohort of persons with COPD, proving that a screening strategy based solely on age and tobacco exposure and eschewing key inclusion criteria such as COPD and emphysema may be flawed. In fact, validated simulations have shown that a lower pack-year threshold for screening eligibility may benefit COPD patients.
Finally, it is worth mentioning that lung cancer screening programs may offer a unique opportunity to improve COPD underdiagnosis rates. A myriad of studies have demonstrated that tobacco-related alterations in lung function are not only deadly, but common and frequently missed.[89-91] Lung cancer screening–eligible patients share the combination of age and risk factors that might help identify COPD in otherwise seemingly healthy current or former smokers. An Australian study found that symptoms may be an appropriate surrogate for spirometry when determining the presence of COPD in this population. Low-dose CT imaging is also an excellent tool capable of detecting not only emphysema, but COPD as well. Low-dose CT performed in the context of lung cancer screening has a 63% sensitivity and an 88% specificity for the diagnosis of COPD. Visual scoring of chest CT findings can also characterize the presence, pattern, and progression of early emphysema, showing that continued smoking leads to progression of that disease. In any case, future recommendations should stress the need for combined lung cancer and COPD screening.
The links between lung cancer and tobacco-related alterations in lung function and lung morphology are strong, and research is ongoing to determine how far-reaching they may be. Current interest in lung cancer screening and the widespread availability of CT imaging continue to nurture a growing body of evidence supporting the existence of ties binding these deadly diseases together, as well as new strategies for fighting them. Ongoing cost-effectiveness studies will tell us whether a strategy of expanded inclusion criteria for screening that incorporates altered lung function and/or emphysema is viable. Meanwhile, more studies are needed in order to determine whether the NLST entry criteria should be set in stone, or whether the current age and tobacco exposure criteria can be modified in order to screen all persons at risk. In our opinion, all patients with CT-detected emphysema, as well as COPD patients with high COPD-LUCSS scores, should be offered lung cancer screening, irrespective of age or smoking history.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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