Screening for Lung Cancer Has Limited Effectiveness Globally and Distracts From Much Needed Efforts to Reduce the Critical Worldwide Prevalence of Smoking and Related Morbidity and Mortality

Lung cancer is the leading cause of cancerrelated mortality worldwide in both men and women. Efforts to reduce lung cancer mortality using chest x-rays (CXRs) for early detection did not show improvements in mortality. More recently, results of the National Lung Screening Trial (NLST), which used low-dose computed tomography (LDCT) scans, appear to improve mortality outcomes. However, LDCT imaging comes at prohibitive costs because of the high number needed to screen as well as inadequate biopsy yields from screen-positive cases. Thus, it is imperative that attempts be made to either improve the efficiency of lung cancer screening or reduce the prevalence of smoking. The latter is especially important considering population increases and the consequently higher prevalence of active smokers. The 2015 WHO report on the global tobacco epidemic highlights that tobacco-related deaths continue to claim more lives than AIDS, malaria, and tuberculosis combined. Hence, continued attempts to reduce the prevalence of smoking are more likely to produce greater mortality reductions than lung cancer screening strategies. Primary preventive strategies have proven benefits but remain underused.


Introduction
Lung cancer is the leading cause of cancerrelated mortality worldwide in both men and women. Efforts to reduce lung cancer mortality using chest x-rays (CXRs) for early detection did not show improvements in mortality. More recently, results of the National Lung Screening Trial (NLST), which used low-dose computed tomography (LDCT) scans, appear to improve mortality outcomes. However, LDCT imaging comes at prohibitive costs because of the high number needed to screen as well as inadequate biopsy yields from screen-positive cases. Thus, it is imperative that attempts be made to either improve the efficiency of lung cancer screening or reduce the prevalence of smoking. The latter is especially important considering population increases and the consequently higher prevalence of active smokers. The 2015 WHO report on the global tobacco epidemic highlights that tobacco-related deaths continue to claim more lives than AIDS, malaria, and tuberculosis combined. Hence, continued attempts to reduce the prevalence of smoking are more likely to produce greater mortality reductions than lung cancer screening strategies. Primary preventive strategies have proven benefits but remain underused.
We describe the effectiveness of strategies for smoking control and tobacco-related diseases. We also explain why it is more relevant to increase implementation of these methods than the promotion of screening techniques for lung cancer, especially in low-and middle-income countries.

Methods
Data were collected after literature review for studies of methods used to reduce smoking prevalence. Information was analyzed in terms of education efforts, effects of increased taxation, and outcomes of media campaigns. Analysis was extended to cost savings from less absenteeism related to smokingrelated illnesses, reductions in pregnancy-related complications, increased human productivity from life years preserved, and health care benefits from reduced morbidity. Comparisons were then made with outcomes of the NLST in terms of costs accrued from serial LDCT scans, bronchoscopies, pathology protocols, procedural complications, and absolute improvements in mortality. Incremental costs from individual screenings along with those projected by Medicare over extended periods of screening were analyzed. Last, the potential utility of molecular tumor risk stratification in improving yield of LDCT scanning was assessed.

Observations
Screening for lung cancer with LDCT appears to improve on results of screening using CXRs. However, two issues need further evaluation: (1) lung cancer is a biologically diverse disease with regard to tumor heterogeneity 1 and (2) it is not the only way smoking causes morbidity and mortality. Tumor heterogeneity raises questions about biology and which kinds of lung cancers are suitable for early detection and, therefore, have a better chance of cure. In addition, it has become clearer that smoking is directly responsible for many other diseases than lung cancer or obstructive airway disorders. 2

Brian Fink
Author affiliations and support information (if applicable) appear at the end of this article. This is of concern because the global prevalence of smoking is high and worsening in medium-and low-income countries (Table 1). 3 Rates in the Americas range from 6% in Suriname to 29% in Chile; the average smoking rate is 16% in the United States. There are approximately 48 million active smokers in Latin America and the Caribbean alone. In Russia and France, the prevalence is 33% and 31%, respectively. At 390 million, the Southeast Asia and Oceania regions, however, have the highest concentration of smokers. 4 All of this has directly increased the worldwide burden of smokingrelated illnesses. Carter et al showed that cigarettes accounted for 83% of excess mortality in current smokers, going beyond the 2014 Surgeon General's report that correlated smoking with excess mortality in 21 disease categories. 2 The study also revealed associations between smoking and breast cancer, hypertensive heart disease, prostate cancer, intestinal ischemia, and renal failure.
According to NLST data, screening for lung cancer appears to improve survival, with a 20.3% mortality reduction. 5 In the study by Aberle et al, 53,454 people were screened between the ages of 55 and 74 years, 26,722 to LDCT scanning and 26,732 to CXRs, with one of either test performed once a year for 3 years, representing T0, T1, and T2 images. Most study subjects (91%) were white, limiting generalizability ( Table 2). Study participants were followed for a median of 6.5 years. A total of 1,060 lung cancer cases were detected in the LDCT arm (645 per 100,000 person-years) compared with 941 in the CXR arm (572 per 100,000 person-years). Lung cancer-specific mortality in the LDCT arm was 247 per 100,000, compared with 309 per 100,000 in the CXR group (ie, 2.47 per 1,000 v 3.09 per 1,000).Therefore, the number needed to screen to prevent one death from lung cancer is 320 individuals. If the cost of an LDCT scan is $500, the cost will be $480,000 to prevent one death. The cost of an LDCT scan in the NLST conducted between 2002 and 2010 was approximately $285.
These numbers do not take into account the finding that for every 5.4 deaths prevented by LDCT screening, one death was from complications related to the screening itself. Also, 23.3% of tests in the LDCT arm were for false-positive CT findings as compared with 6.5% in the CXR arm. The NLST data have yet to include procedural mortality or costs from procedures and complications resulting from workup for findings that were false positive 94% of the time.
In contrast to LDCT scans, Papanicolaou smears cost only $13 to $66.15 per test, amounting to about $5,392 per life-year saved. Predictive models indicate that implementation of the 2014 hypertension guidelines for US adults between the ages of 35 and 74 years may prevent 56,000 cardiovascular events and 13,000 deaths at , $50,000 per quality-adjusted life year (QALY) gained. 6 Colonoscopy is also a costeffective screening modality. However, oncogenesis from smoking is not a simple process and smoking is involved in more disease processes than only cancer. Nearly 8.6 million individuals live with a serious illness caused by smoking and, on average, smokers die more than a decade earlier than nonsmokers. 7 Currently, one in five deaths is related to smoking, amounting to 443,000 deaths per year in the United States. Worldwide, more than 6 million people die every year from smoking-related illnesses, including lung cancer. Thun et al 8 looked at 50-year trends in mortality from smoking-related diseases in the United States. Using data from the Cancer Prevention Studies I and II and the US National Health Survey, they showed that death from any cause among active smokers was three times higher than among those who had never smoked. Jha et al 9 looked at 113,752 individuals ages 25 to 79 years from 1997 to 2004 and confirmed that allcause mortality was three times higher in current smokers. In fact, smoking cessation at ages 45 to 54 years added nearly 6 years of life compared with those who continued to smoke. And if smoking was stopped by age 40 years, the risk of death was reduced by a significant 90%.
Currently, approximately 3,800 persons younger than 18 years of age start smoking every day and nearly 1,000 become regular smokers. 4 Worldwide, the burden of new smokers is increasing, and current initiation rates indicate that smoking could be expected to cause the deaths of nearly    24 More importantly, 75% of the related mortality is borne by men, further endangering the well-being of families and communities because, in many developing countries, men are the primary workers. Thus, in developing countries where the tobacco epidemic is still considered by WHO to be at an early stage, it is probably more meaningful to reduce substantially the burden of smoking than it is to screen for lung cancer. This is especially important because 61.7% of the age-standardized disability-adjusted life years are attributable to cardiovascular and respiratory illnesses, with lung cancer accounting for only part of the 20.5% disability-adjusted life years attributable to all cancers caused by smoking. 25 These social and economic factors make it important to reduce the prevalence of smoking and its burden to society as a whole. It will be difficult to achieve this by implementing a cost-intensive program that must screen 320 individuals to prevent one death due to lung cancer. The costs accrue from expenses related to three LDCT scans each for the 320 needed to screen, in addition to the costs from additional tests, such as positronemission tomography CT scans (1,868), biopsy procedures (494), bronchoscopies (896), and other surgical procedures, including mediastinoscopy (458). 5 28 In another subanalyses, Kovalchik et al 29 divided the NLST population into five quintiles and looked at the incidence of early-stage lung cancer in the different quintiles. Variables included age, body mass index, family history, pack years of smoking, years since smoking cessation, and chronic obstructive pulmonary disease. False-positive results per CT scan-prevented death due to lung cancer decreased from 108 to 78 in the three highest-risk quintiles, and the number needing to be screened to prevent one death changed from 302 to 208 among 60% of participants at highest risk. The yield of LDCT imaging in lung cancer screening could also be augmented through nonclinical methods. Sozzi et al 30 reported data from the Multicenter Italian Lung Detection trial on the utility of plasma-based microRNA. This reduced the false positivity of LDCT imaging by a factor of five. However, it is questionable as to how much any of these efforts to make lung cancer screening more efficient would improve upon the recent Medicare cost analysis estimating additional costs of LDCT screening at $9.3 billion over 5 years. 31 Interestingly, efforts were made as early as 2005 to define the cost effectiveness of reducing lung cancer mortality through screening and early detection. Basing their analysis on Markov modeling and using a 2002 price year, Manser et al 32 suggested that lung cancer screening using low-dose spiral CT was potentially cost effective when calculated for a 27% reduction in mortality against an annual incidence of 552 per 100,000. In their analysis, the incremental cost-effectiveness ratio for men ages 60 to 64 years was $57,325 per life-year saved (in Australian dollars) or $105,090 per QALY saved. They concluded that if $50,000 per life-year saved was used as the measure of cost effectiveness, then reductions in lung cancer mortality would have to be . 20%. 32 Clearly, costs have since escalated and studies have yet to provide mortality benefits . 20%.
Therefore, alternative measures, including education, taxation, and changing the legal age for smoking from 18 to 21 years, are more likely to have profound cost-effective improvements in morbidity and mortality due to smoking than screening for lung cancer using LDCT scans, especially in developing countries. The effectiveness of behavioral modification, taxation policies, and educational efforts is evident in the recent reductions in the prevalence of smoking. Since 2009, the prevalence has been declining by 0.78% points every year due to factors such as these. 33 And the CDC estimates that its Tips From Former Smokers program, which educates the public about the harmful effects of tobacco use, may have helped . 400,000 individuals stop smoking and prevented the deaths of nearly 17,000 individuals since its inception in 2012. 33 Despite this evidence, preventive measures continue to be neglected while screening is being disproportionately promoted. During the fiscal year 2017 in the United States, local governing bodies will collect $26.6 billion from the tobacco settlement. However, they will be spending only about 1.8% of these fund on programs to prevent children from starting smoking and helping adults quit the habit. This is in stark contrast to tobacco companies, which will spend $9.9 billion promoting tobacco products. 34 This means that for every $1 spent on preventive measures, tobacco companies will outspend the local governments by at least $18. To makes matters worse, even as nearly all states are moving toward implementing lung cancer screening and take advantage of federal funds by doing so, only three of the 50 states in the United States currently fund preventive programs at > 50% of CDC-recommended levels. 35 Such adverse measures are reflected at the global level as well: WHO data indicate only 37 countries as being on track to achieve the 30% tobaccoreduction target set by the Global Action Plan for prevention and control of noncommunicable diseases from 2013 to 2020. The inadequacy of preventive measures can be seen as a stark contrast to the success of the marketing strategies by tobacco companies-despite a decreasing prevalence of smoking, net population growth has increased the number of cigarettes smoked worldwide to . 6 trillion a year. In fact, smokers in 75 countries continue to consume . 20 cigarettes per person every day. Smoking, therefore, represents a public health issue of grave significance in developing nations, especially considering that the epidemic is still in its early phase in many of these countries.
In conclusion, the findings of the NLST are not precise enough in defining the risk groups in whom screening is cost effective. It is unlikely that the incorporation of other clinical and molecular data will make lung cancer screening with LDCT scans cost effective, especially in developing countries where the smoking epidemic is still in its early stages. It is also necessary to consider the morbidity of smoking and the worldwide burden of cigarette use if actual mortality from smoking is to be reduced. Therefore, it is important to work toward decreasing the prevalence of smoking if the disease burden from smoking is to be reduced. As highlighted in Table 4, educational efforts, limiting access to cigarettes, taxation policies, and legal processes, such as increasing the minimum age to purchase tobacco products, should all be considered in order to reduce the burden of smoking. These strategies are more likely to decrease prevalence and reduce morbidity and mortality from smoking. It is important first to reduce the uptake of smoking by adolescents and young adults through educational measures and, second, to curtail as much as possible the continued use of cigarettes by adults through taxation policies, while also considering raising the legal age for smoking. It is unlikely that the number of labor years lost will be improved by transferring scarce economic resources to lung cancer screening without first reducing the global burden of smoking and all smoking-attributable diseases, particularly in developing countries.  Lung cancer screening with low dose CT scans is cost prohibitive.
Morbidity and mortality from smoking is not limited to lung cancer.
Reducing the prevalence of smoking is more important than screening for lung cancer.
Education, taxation policies, and raising the legal age for smoking are cost-effective solutions.