Global Lung Cancer Trends

Globally, lung cancer cases and deaths are rising. In 2018, GLOBOCAN estimated 2.09 million new cases (11.6% of total cancer cases) and 1.76 million deaths (18.4% of total cancer deaths), ^, higher than 2012 reported rates (1.8 million new cases and 1.6 million deaths), making it the most frequent cancer and cause of cancer death in men and women combined ( Fig. 1 A, B ), ^, and in women, the third most common cancer type and the second most common cause of cancer death ( Fig. 1 C). ^,

Distribution of cases and deaths for the 10 most common cancers in 2018 for ( A ) both sexes, ( B ) males, and ( C ) females. For each sex, the area of the pie chart reflects the proportion of the total number of cases or deaths.

(GLOBOCAN 2018. Global Cancer Observatory (http://gco.iarc.fr/) © International Agency for Research on Cancer 2019.)

Between countries, significant variation in lung cancer incidence and demographic distribution are noted, and tobacco smoking rates and stage of economic development influence these patterns. Although cancer statistics in developing countries are less reliable, lung cancer incidence is expected to increase in developing regions with the recent increase in smoking prevalence in China, Indonesia, Eastern Europe, and the Northern and Southern parts of Africa. ^, Up to 80% of current smokers now live in low- or middle-income countries, and more than one-half of lung cancer deaths occur in less developed regions. By contrast, lung cancer incidence is decreasing or expected to decrease in countries that “took up” smoking the earliest and are now successfully implementing smoking cessation and avoidance campaigns. These countries are generally high income and include the United States, the United Kingdom, the Nordic countries, Australia, New Zealand, Singapore, Germany, and Uruguay. ^,

Although the increasing lung cancer burden globally is driven by lung cancer cases in men, most countries are also observing an increasing incidence in women. Although breast cancer is the leading cause of cancer-associated deaths in women globally, lung cancer is the leading cause of cancer death in women in several areas, including North America, Northern/Western Europe, Australia, and New Zealand (see Fig. 1 ). The higher mortality rates in these areas likely reflect local smoking patterns. The World Health Organization estimates that 48% of men and 10% of women globally are smokers. Although smoking prevalence is similar between men in developed and developing countries, smoking prevalence is significantly lower in women in developing countries ( Fig. 2 ). In areas where tobacco smoking rates in women are low, nontobacco risk factors likely play a more significant role in lung cancer development. For example, despite a lower smoking prevalence in Chinese women, the incidence rate of lung cancer is similar to that of many European countries, which may be related to the inhalation of smoke from charcoal, heating, or cooking.

Estimated age-standardized prevalence of daily smoking and annualized rate of change, 1980 to 2012. ( A ) Prevalence of smoking by year. ( B ) Annualized rate of change in the prevalence of daily smoking by year.

( From Ng M, Freeman MK, Fleming TD, et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014;311(2):183-192; with permission.)

Unfortunately, owing to the global increase in the number of smokers since 1980, the burden of lung cancer will likely continue to increase in the coming years primarily in developing countries, where high-quality cancer registry data are unavailable. ^, These trends underscore 2 important points. First, the role of tobacco avoidance and cessation efforts cannot be underestimated, because a country’s tobacco cessation efforts may not be recognized for many years after reductions in smoking rates. In the United States, for example, lung cancer incidence and mortality improved 20 to 30 years after smoking prevalence began to fall. ^, Second, more emphasis and resources for high-quality data collection on tobacco smoking patterns, cancer development, and cancer outcomes in developing countries are needed to implement tobacco cessation and cancer control programs.

Lung Cancer Trends in the United States

In the United States, lung cancer remains the second most common cancer and the leading cause of cancer death ( Fig. 3 ). ^, According to the Surveillance, Epidemiology, and End Results program, lung cancer currently accounts for approximately 12.9% of all new cancer cases in the United States and 538,243 people in the United States were estimated to be living with lung cancer in 2016. Data from 2016 revealed deaths from lung cancer in men and women were 80,775 and 68,095, respectively, which exceeded the combined number of deaths for breast cancer, prostate cancer, colon cancer, and leukemia. For 2019, Siegel and colleagues estimated 228,150 new cases of lung cancer and 142,670 deaths. There is a trend in both sexes of more lung cancer cases but fewer deaths. ^{, ,} When stratifying by sex, the estimated number of new cases and deaths in 2019 for men continues to exceed those values in women.

Estimated new cancer cases and deaths by sex, United States, 2019.

( From Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69(1):7-34; with permission.)

Although lung cancer incidence and mortality were rising in women before 2000, both values are now steadily improving in males and females. Fig. 4 shows the overall incidence and mortality of lung cancer in the United States since 1975. ^, Owing to lung cancer’s high case fatality rate, disease incidence is paralleled by disease mortality. Although lung cancer incidence and mortality rates are higher in males, they continue to decrease more rapidly in men compared with women, possibly attributed to earlier decreases in smoking prevalence among men and women’s increased uptake of smoking around World War II. Fig. 5 shows steady reduction in US smoking prevalence in both sexes since 1965; however, if current trends continue, lung cancer mortality rates in women are estimated to exceed those in men by 2045.

Cancer of the lung and bronchus Surveillance, Epidemiology, and End Results delay-adjusted incidence and US death rates, 1975 to 2016, all races, by sex.

( From Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016. 2019; https://seer.cancer.gov/csr/1975_2016/ . Accessed May 26, 2019; with permission.)

Percentage of adults aged 18 years and older who were current cigarette smokers, overall and by sex; National Health Interview Survey, United States, 1965 to 2017.

( From Wang TW, Asman K, Gentzke AS, et al. Tobacco Product Use Among Adults – United States, 2017. MMWR Morb Mortal Wkly Rep 2018;67(44):1225-1232; with permission.)

The 5-year survival of lung cancer reported by the Surveillance, Epidemiology, and End Results program in 2011 was 15.6% and in 2019 19.4%. Improvement in lung cancer survival is likely multifactorial and owing to decreases in tobacco smoking, increased thoracoscopic surgeries and stereotactic radiation for early stage disease, and better treatments for advanced stage disease (ie, targeted and immunologic therapies). ^, Tobacco smoking trends and broader implementation of lung cancer screening (LCS) suggest that lung cancer survival will continue to improve. Fig. 5 shows that tobacco smoking rates in the United States are improving in both sexes, and modeling studies estimate that if smoking rates continue to decline, age-adjusted lung cancer mortality may decrease by up to 79% by 2065. Although improvements in smoking rates and lung cancer survival are encouraging, both values are not uniformly falling across the country. Demographic, socioeconomic, and geographic variables are related to smoking prevalence and (therefore) lung cancer rates.

Despite modest improvements in outcomes in the United States, lung cancer survival remains heavily influenced by stage at diagnosis, and most lung cancers (57%) are diagnosed when the cancer has metastasized outside the lung ( Fig. 6 ). ^, Although LCS efforts will likely “shift” the diagnosis of lung cancer to earlier stages, uptake has been slow with only 4% of eligible Americans undergoing low-dose computed tomography screening in 2015. Continued implementation of LCS combined with therapeutic advances for early and advanced stage disease may help reverse our current trends of late-stage diagnosis and low overall survival.

Percent of cases and 5-year relative survival by stage at diagnosis: lung and bronchus cancer. ( A ) Surveillance, Epidemiology, and End Results 18 data (2009 to 2015), all races, both sexes by ( B ) Surveillance, Epidemiology, and End Results summary stage (2000).

( From Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016. 2019; https://seer.cancer.gov/csr/1975_2016/ . Accessed May 26, 2019.)

Perhaps the greatest change in our understanding of lung cancer epidemiology in the United States is the recognition of the disease’s “diversity.” That is, lung cancer can no longer be stereotyped as a disease of older male smokers. Fig. 4 demonstrates the meaningful change in lung cancer development and outcomes by gender in the last 50 years. Although smoking history and older age remain the predominant risk factors for lung cancer development, current estimates are that 10% to 20% of patients who develop lung cancer are never smokers, and lung cancer incidence in women is approaching that in men. Also, although the overall trend in the United States is toward fewer lung cancer deaths and longer survival, many groups struggle with more lung cancer cases and worsening outcomes. Several demographic factors have been identified that influence lung cancer development and outcomes, including gender, age, race, geography, and socioeconomic status (SES).

Gender

Christina R. MacRosty and M. Patricia Rivera’s article, “ Lung Cancer in Women: A Modern Epidemic ,” in this issue, of this Clinics issue is dedicated to lung cancer in women. Owing to the significant changes in lung cancer epidemiology, we mention 3 points here. First, lung cancer incidence and mortality are consistently lower in women compared with men (see Fig. 4 ), although the gender “gap” is narrowing owing to both values falling more rapidly in men. If current trends continue, modeling studies suggest that the number of lung cancer deaths in women will exceed those in men in 2045. Second, the demographics of women diagnosed with lung cancer are different than those in men. Specifically, women tend to be diagnosed with lung cancer at a younger age, are more likely to be nonsmokers, and are more likely to be diagnosed with an adenocarcinoma. Finally, women have improved lung cancer survival across all disease stages than men. In combination, these findings support unique biological and genetic mechanisms of lung cancer between men and women. Refer to Christina R. MacRosty and M. Patricia Rivera’s article, “ Lung Cancer in Women: A Modern Epidemic ,” in this issue, for a complete discussion of lung cancer in women.

Age

Lung cancer is most common in men and women 70 years of age and older ( Fig. 7 ). Lung cancer has become the most common cause of cancer death in men ages 40 and older and women ages 60 and older. The median age at lung cancer diagnosis is 70 years, and the median age at lung cancer death is 72 years. In general, lung cancer mortality increases with age until approximately ages 80 to 85 ( Fig. 8 ), after which heart disease exceeds cancer as the most common cause of death in both genders. ^, Interestingly, a recent study identified higher incidence rates of lung cancer among young Hispanic and non-Hispanic white women (compared with men) between the ages of 30 and 49 years. Although smoking patterns likely contribute to this finding, the authors noted that smoking behaviors did not entirely explain the recognized differences. The discovery of higher incidence of lung cancer in younger women demonstrates how our “traditional” view of lung cancer is changing.

Percent of new cases by age group: lung and bronchus cancer. Surveillance, Epidemiology, and End Results 21 data (2012 to 2016), all races, both sexes. AI/AN, American Indian/Alaska Native; API, Asian/Pacific Islander.

( From Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016. 2019; https://seer.cancer.gov/csr/1975_2016/ . Accessed May 26, 2019.)

Lung cancer incidence and mortality rates by sex and age, United States, 2006 to 2010. Rates are 100,000 and age-adjusted to the 2000 US standard population.

( From Torre LA, Siegel RL, Jemal A. Lung Cancer Statistics. Adv Exp Med Biol 2016;893:1-19; with permission.)

Race

Overall, lung cancer incidence and mortality are highest in African American men and lowest in Hispanic women. In data from 2008 to 2014, compared with Caucasians, African Americans had lower rates of localized disease at diagnosis (13% vs 17%) and worsened 5-year relative survival for localized (52% vs 56%), regional (27% vs 30%), and all-stage disease (16% vs 19%). Higher lung cancer-associated mortality by race is likely multifactorial, including smoking prevalence, access to health insurance, and SES. American Indians/Alaska Natives currently have the highest overall smoking rate in the United States (21.9%). Whereas lung cancer mortality has been decreasing in most races since the early 1990s, lung cancer mortality in American Indians and Alaska Natives did not start falling until approximately 2010 ( Fig. 9 ).

Surveillance, Epidemiology, and End Results incidence and US death rates. Cancer of the lung and bronchus, both sexes.

(Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016. 2019; https://seer.cancer.gov/csr/1975_2016/ . Accessed May 26, 2019.)

There are significantly lower rates of surgical and chemotherapy treatments in African Americans. ^, Worse survival in Hispanics with early stage non small cell lung cancer has been noted, which was largely explained by lower resection rates. Racial differences in lung cancer mortality have also been noted in screening efforts. In the National Lung Screening Trial, all-cause mortality was higher in black participants and low-dose computed tomography screening decreased lung cancer-associated mortality more in African Americans. In combination, these reports suggest that racial differences in lung cancer therapy and screening persist and achieving equivalent outcomes will require a multifaceted approach including access to health care, smoking cessation, early diagnosis, and equivalent stage-appropriate treatments.

Geography

Much like trends globally, geography influences lung cancer epidemiology in the United States, and smoking patterns determine the higher and lower risk areas. Currently, the highest lung cancer incidence and mortality rates are in Kentucky, where the age-adjusted incidence per 100,000 people is 112.8 for men and 79.0 for women. The age-adjusted mortality per 100,000 people is 84.5 in men and 52.2 in women. In contrast, the lowest incidence and age-adjusted lung cancer death rates are in Utah, with incidences of 32.4 and 23.7 and mortality rates of 23.4 and 15.6 in men and women, respectively. Although lung cancer incidence and mortality rates are decreasing nationally, several areas of the country with higher smoking prevalence have not observed the same improvements in lung cancer outcomes. Comparing the time periods 1990 to 1999 and 2006 to 2015, Ross and colleagues used county-level data and identified 2 hotspots (Appalachia and the Midwest) where lung cancer death rates in women actually increased with time, which is consistent with prior work showing higher lung cancer rates for women living in southern and midwestern states. Greater smoking cessation rates in western states and decline in smoking prevalence correlating with cigarette taxes and indoor air legislation has been reported. Nationwide differences in lung cancer incidence and mortality are likely to persist until similar smoking cessation rates are achieved.

Socioeconomic Status

Lower SES and education contribute to lung cancer risk and worse outcomes, particularly in men. Men and women with less than a high school education or annual incomes of less than $12,500 and with lower SES including educational, occupational, and income-based positions have higher lung cancer rate ratios. ^, Because lower income counties have much higher rates of tobacco smoking, lung cancer disparities owing to SES are analogous to those seen geographically. In poor counties (compared with affluent counties), lung cancer mortality in men is more than 40% higher, and low SES may increase the risk of death during hospitalization for a lung cancer resection. However, studies have shown that controlling for education, SES, and smoking status decreased but did not normalize lung cancer risk. It seems clear that the individual’s risk of developing and surviving lung cancer is the result of a complex relationship involving age, gender, race, smoking status, geographic location, and SES.

Tobacco Smoking

Tobacco use in the form of cigarettes has significantly increased with the average adult smoking fewer than 100 cigarettes per year in the 1900s to the estimated maximum of approximately 4400 cigarettes per person per year in the 1960s. ^, The seminal US Public Health Service report by the Surgeon General in 1964 was instrumental in highlighting the adverse effects of cigarette smoking on health, concluding that cigarette smoking was associated with a 70% increase in the age-specific death rates for men, a lesser increase in the death rates for women, and that cigarette smoking was causally related to lung cancer. Moreover, cigarette smoking was believed to be more important than occupational exposures in the cause of lung cancer. Since the report, smoking has decreased from 20.8% of all US adults aged 18 years or older in 2005% to 14.0% in 2017. The proportion of ever smokers that have quit has also increased.

The effects of cigarette smoking outweigh all other factors that lead to lung cancer. In 1912, Adler described 374 cases of primary lung cancer in autopsy cases from the United States and western Europe; this represented only 0.5% of all cancer cases at the time. Lung cancer constituted 1% of all cancers in the United States in 1920. In 1938, an association of cigarette smoking with increased risk of death was described in moderate and heavy white male smokers greater than 30 years of age. A 1941 review of lung carcinoma reported that “the increase in the incidence of pulmonary carcinoma is due largely to the increase in smoking.” Two large landmark studies in 1950 established tobacco smoking as a causal factor in bronchogenic carcinoma and concluded that (1) excessive and prolonged use of tobacco was an important factor in lung cancer induction, (2) lung cancers in nonsmokers were rare (current experience show that this is not the case anymore), and (3) that there could be a lag of 10 or more years between smoking cessation and the clinical onset of carcinoma. ^, In 2004, the United States Surgeon General re-emphasized the message that “cigarette smoking is the major cause of lung cancer.” To this day, there is no question that tobacco smoking remains the most important modifiable risk factor for lung cancer with about 90% of lung cancers arising owing to tobacco use.

Tobacco Smoke Carcinogens

Tobacco cigarette smoke is a complex aerosol composed of gaseous and particulate compounds. The smoke consists of mainstream smoke and side stream smoke components. Mainstream smoke is produced by inhalation of air through the cigarette and is the primary source of smoke exposure for the smoker. Side stream smoke is produced from smoldering of the cigarette between puffs and is the major source of environmental tobacco smoke (ETS). The main determinant of tobacco addiction is nicotine, whereas the tar is the total particulate matter (PM) of cigarette smoke after nicotine and water have been removed. Cumulative exposure to tar seems to be a major component of lung cancer risk. There are more than 4000 chemical constituents of cigarette smoke. The International Agency for Research on Cancer has identified at least 50 carcinogens in tobacco smoke.

Mainstream smoke contains many potential carcinogens, including polycyclic aromatic hydrocarbons, aromatic amines, N -nitrosamines, and other organic and inorganic compounds, such as benzene, vinyl chloride, arsenic, and chromium. The polycyclic aromatic hydrocarbons and N -nitrosamines require metabolic activation to become carcinogenic. Metabolic detoxification of these compounds can also occur, and the balance between activation and detoxification likely affects individual cancer risk. Radioactive materials, such as radon and its decay products, bismuth, and polonium, are also present in tobacco smoke.

The agents of particular concern in lung cancer are the tobacco-specific N -nitrosamines formed by nitrosation of nicotine during tobacco processing and smoking. Of the tobacco-specific N -nitrosamines, 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone seems to be the most important inducer of lung cancer. The mechanisms of carcinogenesis from tobacco also include formation of DNA adducts, their metabolites, and free radical damage. The primary factor determining the intensity of cigarette use is the nicotine dependence of the smoker, and, although modern cigarettes contain less nicotine and tar, smokers tend to smoke more intensively with a greater number of puffs per minute and deeper inhalations to satisfy their nicotine need. Interestingly, low-yield filtered cigarettes might be a contributing factor to the increase in the incidence of adenocarcinoma of the lung. With deeper inhalation, higher-order bronchi with more susceptible peripheral lung epithelium are exposed to carcinogen-containing smoke linked to the induction of adenocarcinoma.

The relative risk of lung cancer in long-term smokers has been estimated as 10-fold to 30-fold compared with lifetime nonsmokers. The cumulative lung cancer risk among heavy smokers can be as high as 30% compared with a lifetime risk of less than 1% in nonsmokers. One in 6 smokers eventually develops lung cancer. The lung cancer risk is proportional to the quantity of cigarette consumption, and important factors include the number of packs per day smoked, the age of onset of smoking, the degree of inhalation, the tar and nicotine content of cigarettes, and use of unfiltered cigarettes. Up to 20% of all cancer deaths worldwide could be prevented by the elimination of tobacco smoking. Although more than 80% of lung cancers occur in persons with tobacco exposure, fewer than 20% of average smokers develop lung cancer. This variability in cancer susceptibility is likely affected by other environmental factors or by genetic predisposition.

Rate of Tobacco Use

In the United States, cigarette smoking prevalence is steadily decreasing in both sexes (see Fig. 4 ) and recent estimates show cigarette smoking at its lowest prevalence to date (14% or 34.3 million US adults). Interestingly, analogous to the risk of lung cancer development, several demographic, social, and medical factors influence an individual’s likelihood of smoking ( Table 1 ). The number of adult smokers in the United States is likely to continue decreasing. The Centers for Disease Control and Prevention reported increases in the proportion of smokers trying to quit, recently quitting, receiving advice to quit, and using proven cessation methods. For additional details regarding tobacco cessation and treatment, we direct the reader to Hasmeena Kathuria and Enid Neptune’s article, “ Primary and Secondary Prevention of Lung Cancer: Tobacco Treatment ,” in this issue.

Environmental Tobacco Smoke

ETS or secondhand smoke is known to contribute to an increased risk for lung cancer. Longitudinal studies have shown this increased risk relationship between ETS and lung cancer in never smokers. ^, A recent meta-analysis evaluating cancer risk associated with ETS across all cancers found an increased risk of lung cancer (odds ratio [OR], 1.24) involving never smokers with tobacco smoke exposure compared with never smokers without such exposure with the association strongest in women. At least 17% of lung cancers in nonsmokers are attributable to exposure to high levels of ETS during childhood and adolescence. One large epidemiologic study found an excess risk for lung cancer of 24% in nonsmokers who lived with a smoker. Nonsmoking women married to men who smoke have an increased risk of lung cancer.

ETS consists of both mainstream (exhaled) smoke and side stream smoke (from burning end of cigarettes) and contains carcinogens that include benzene, benzo-a-pyrene, and 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone. Nonsmokers exposed to side stream smoke generated by machine smoking of cigarettes had measurable carcinogenic metabolites in their urine. Eighty-eight percent of nontobacco users had detectable levels of serum cotinine, a metabolite of nicotine, suggesting the exposure to ETS and the pervasive presence of ETS. However, with 14% of the American adult population still smoking, ETS will continue to be a major public health issue until cigarette smoking altogether is eliminated.

The majority (80%–90%) of lung cancers develop in current or former tobacco smokers and could be avoided with tobacco smoking prevention and cessation. If individuals are able to quit smoking before middle age, up to 90% of associated risk from tobacco smoking can be avoided. Decreases in the number of smokers will also decrease the number of individuals exposed to ETS. If smoking cessation patterns in the United States continue, lung cancer mortality will be greatly reduced in the future. Thus, the importance of smoking cessation in reducing risk of lung cancer cannot be over-estimated. Refer to Hasmeena Kathuria and Enid Neptune’s article, “ Primary and Secondary Prevention of Lung Cancer: Tobacco Treatment ,” in this issue on tobacco treatment.

Electronic Nicotine Delivery Systems and E-Cigarettes

The newest and most controversial products potentially influencing lung cancer risk are electronic nicotine delivery systems (ENDS) including electronic cigarettes (e-cigarettes), e-pens, e-pipes, e-hookah, and e-cigars. These products are marketed as a safer alternative to tobacco smoking by delivering nicotine without the other combustible exposures inherent to tobacco smoke and a mechanism of tobacco smoking cessation. ENDS allow liquid to be heated to create an aerosol containing nicotine and substances such as flavorings, propylene glycol, vegetable glycerin, and other ingredients that the user inhales. About 12.6% of adults in the United States have tried an e-cigarette at least once and the overall prevalence of ENDS use in adults was 3.2% in 2016. Almost one-half of current cigarette smokers (47.6%) and more than one-half of recent former cigarette smokers (55.4%) had ever tried an e-cigarette. The use of e-cigarettes has become popular with teenagers and young adults, resulting in a 900% increase in e-cigarette use in high school students between 2011 and 2015, with more than 2 million middle and high school students using ENDS in 2016. Although ENDS are advertised as a smoking cessation tool, previous nonsmokers of traditional cigarettes comprised a good proportion of ENDS users. E-cigarette use is associated with a greater risk for subsequent cigarette smoking initiation underscoring the urgency for strong regulation to curb use among youth and limit the future population-level burden of cigarette smoking.

The alarming increased use of ENDS with unregulated multiple brands and flavorings have made it difficult to evaluate the safety of these devices. Although the components of e-cigarette vapor are different from those in traditional tobacco cigarettes, available data suggest that formaldehyde, acetaldehyde, and reactive oxygen species are present in sufficient concentrations to cause inflammatory damage to the airway and lung epithelium. Aerosols for ENDS can contain polycyclic aromatic hydrocarbons, nitrosamines, and trace metals, and their contribution to tumorigenesis is unclear.

Presently, conclusive evidence regarding the safety of e-cigarettes overall or compared with tobacco smoking is unavailable. A position statement from the Forum of International Respiratory Societies suggest the devices should be restricted or banned until more convincing evidence is available. Since Because -cigarette use is popular and growing in middle and high school students, and could actually promote tobacco use, underage use must be avoided. ^,

Marijuana and Other Recreational Drugs

The effects of inhaling smoke from recreational drugs, such as marijuana and cocaine, are less studied and there is no clear consensus on whether marijuana use is associated with cancer risk. The main psychoactive ingredient in cannabis, Δ9-tetrahydrocannabinol, is not known to be carcinogenic but, like nicotine, produces addiction. An association between marijuana smoking and initiation of tobacco use in young people has been described. The number of marijuana users has increased given the legalization for nonmedical recreational use in some places. Marijuana continues to be the most commonly used illegal substance in the United States, with up to 12% of adolescents and adults admitting use. Abnormal metaplastic histologic and molecular changes similar to premalignant alterations have been described in the bronchial epithelium in habitual smokers of marijuana or cocaine. However, a clear association has not been fully established between such inhalant drug use and lung cancer. A case-control study reported an 8% increased risk for lung cancer for each joint-year of marijuana smoking after adjusting for tobacco cigarette smoking. In fact, tar levels in marijuana smoke and carcinogenic polyaromatic hydrocarbon concentrations can be much higher than those in tobacco. However, lung cancer studies largely seem not to support an association with marijuana use, possibly because of the smaller amounts of marijuana regularly smoked compared with tobacco, but more investigations are warranted. The relationship between other inhalational recreational drug use such as cocaine and lung cancer are not well-studied.

Never Smokers

The term never smoker refers to persons who have smoked fewer than 100 cigarettes in their lifetime, including lifetime nonsmokers. The overall global statistics estimate that 15% of lung cancers in men and up to 53% in women are not attributable to smoking, highlighting a strong gender bias in never smokers. In addition, never smokers account for up to 25% of all lung cancer cases worldwide. If lung cancer in never smokers was considered separately, it would rank as the seventh most common cause of cancer death worldwide before cervical, pancreatic, and prostate cancers. In the United States, 1 study estimated that 19% of lung cancer in women and 9% of lung cancer in men occurs in never smokers. In South Asian countries, up to 80% of women with lung cancer are never smokers. The proportion of never smokers with adenocarcinoma non small cell lung cancer increased from 8.0% to 14.9% from 1990 to 1995 to 2011 to 2013, which was not the case for never smokers with small cell lung cancer or squamous cell non small cell lung cancer. With the decreasing smoking prevalence and increasing rate of lung cancer in nonsmokers, there is heightened urgency to better understand other etiologic factors contributing to lung cancer aside from smoking tobacco.

Biomass Burning

Wood is burned for cooking and heating purposes in many parts of the world, and approximately 3 billion people worldwide rely on solid fuels as their primary source of domestic energy. Combustion of coal in homes has been linked with lung cancer in China. A study of residents living who burn coal and unprocessed biomass (crop residues, wood, sticks, and twigs) for heating and cooking found increased lung cancer risk associated with coal use (OR, 1.29) after adjusting for smoking. Indoor emissions from household coal combustion are classified by the International Agency for Research on Cancer as carcinogenic and emissions from biomass fuel primarily from wood as probable carcinogenic. Compared with nonsolid fuel users, predominant coal users (OR, 1.64; coal users in Asia with OR, 4.93), and wood users in North American and European countries (OR, 1.21) exhibited a higher risk for lung cancer. It has been suggested that the lung cancer that arises from wood smoke may behave differently from lung cancer owing to tobacco smoke.

Air Pollution

Air pollution, a serious global problem owing to climate change and the staggering rate of industrialization, is worsening in many large populated cities across the globe where the highest concentrations of suspected particulates, sulfur dioxide, and smoke have been recorded. Epidemiologic studies suggest that air pollution, especially PM exposure, is associated with increased lung cancer risk and mortality independent of cigarette smoking.

Early studies involving urban–rural comparisons showed that there was an “urban factor,” which was associated with a 10% to 40% increase in lung cancer deaths. Two large cohort studies suggest that there is an excess risk for lung cancer of approximately 19% per 10 mg/m ³ increment in the long-term average exposure to fine particulates. ^, Fine particulate and sulfur oxide-related pollution were associated with 8% increased risk for lung cancer mortality. Despite these studies, it is difficult to pinpoint the carcinogenic role played by single constituents of air pollution. There is a gradient range of relative risk for lung cancer associated with exposure to combustion products, from 7.0 to 22.0 in cigarette smokers, to 2.5 to 10.0 in coke oven workers, to 1.0 to 1.6 in residents of areas with high levels of air pollution, to 1.0 to 1.5 in nonsmokers exposed to ETS. ^, Diesel exhaust found in air pollution contain gaseous components, such as benzene, formaldehyde, and 1,3-butadiene has known carcinogenic effects. There is strong support that occupational exposures to diesel exhaust, especially those in the trucking industry, is associated with 30% to 50% increase in the relative risk for lung cancer. Data linking gasoline engine exhaust and lung cancer are less clear. A meta-analysis of European cohort studies found statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR], 1.22 per 10 μg/m ³ ) and PM2.5 (HR, 1.18 per 5 μg/m ³ ). An increase in road traffic of 4000 vehicle-kilometers per day within 100 m of the residence was significantly associated with an HR for lung cancer of 1.09. Significant associations were found with specific PM components (PM2.5 Cu, PM10 S, PM10 Ni, PM10 Zn, PM10 K) and lung cancer.

Uranium, Radium, and Radon

The natural decay of uranium produces radium, which decays into radon gas when alpha particles are emitted. Uranium and radium are found in soil, rock, and mines with variable concentrations. Likely owing to these exposures, mining is the oldest occupation associated with lung cancer. Although the etiologic factors causing the increased lung cancer risk were originally speculated as dust-related pneumoconiosis, arsenic, or cobalt, the actual carcinogens have been identified as radioactive materials, primarily radon and its decay products. Alpha-radiation is highly damaging to tissues, including the respiratory epithelium. Inhalation of these radon decay products and subsequent alpha particle emission in the lung may cause damage to cells and genetic material. Ultimately, radon decay produces lead, which has a long half-life of 22 years. Radon is a well-established carcinogen with extensive data available both as an occupational hazard as well as exposure experienced by the general population.

A linear relationship between radon exposure and lung cancer risk is reported in underground miners, and pooled data from 11 cohort studies showed that almost 40% of all lung cancer deaths (70% in never smokers and 39% in smokers) were likely due to radon exposure with potential synergistic effect with smoking. The potential importance of radon as a carcinogen in the nonsmoking population was highlighted where nonsmoking miners had a higher relative risk for lung cancer compared with all types of miners. Fortunately, uranium mining has now ceased in the United States; however, radon exposure continues to be an occupational concern in nonuranium mining and underground work and in uranium mines around the world. Occupational exposure to radon is legislatively controlled in the United States where individual exposure records are mandated for all workers with annual cumulative exposure limit. It has been estimated that a 40-year exposure at this level would increase a person’s lifetime risk for lung cancer by approximately 2-fold.

Radon, a ubiquitous indoor air pollutant in many homes, has been projected that to be the second leading cause of lung cancer after smoking, becoming a major concern for the general population. The primary factor determining radon gas concentration in homes is the concentration of radium in the soil and rock beneath those structures. Indoor-to-outdoor air exchange may also affect the radon concentration within the home. A meta-analysis of 8 studies that included 4263 patients with lung cancer and 6612 controls concluded that greater residential exposure levels were associated with an increased relative risk for lung cancer of 1.14. Although there has been some initial question to the estimated lung cancer risk of indoor radon, recent systematic review of 16 studies from 12 different countries found the attributable fraction to range to be from 3% to 17%.

Occupational Exposures (Asbestos)

Occupational exposures suggested or proven to be lung carcinogens include arsenic, asbestos, beryllium, cadmium, chloromethyl ethers, chromium, nickel, radon, silica, and vinyl chloride. It has been estimated that 10% of lung cancer deaths among men and 5% among women worldwide could be attributable to exposure to occupational carcinogens, namely asbestos, arsenic, beryllium, cadmium, chromium, nickel, silica, and diesel fumes. Approximately 6800 to 17,000 lung cancers were a result of exposure to chemicals in the workplace in the United States.

Asbestos is a naturally occurring fibrous mineral consisting primarily of 2 types: serpentine (chrysotile) and amphibole (amosite, crocidolite, and tremolites) and has for centuries been used commercially because of its strong and fire-retardant properties, making it useful for construction and insulation materials. There is a debate as to whether asbestos exposure alone and asbestosis (fibrosis related to asbestos exposure) contribute to actual risk for lung cancer. Some have argued that asbestosis is a necessary precursor to asbestos-attributable lung cancer. Others report that asbestos can act as a carcinogen independent of the presence of asbestosis.

Although the risk for lung cancer from nonoccupational asbestos exposure in the general environment is extremely low, occupational exposure is associated with a relative risk for lung cancer of 3.5 after adjusting for age, smoking, and vitamin use. The risk is dose dependent, but varied with the type of asbestos fiber exposure, with a higher risk for workers exposed to amphibole fibers than for those exposed to chrysotile fibers, after adjusting for similar exposure level. In the United States, chrysotile has been by far the most commonly used type of asbestos.

The interaction between asbestos and smoking regarding lung cancer risk has been described to be between additive and multiplicative. The relative risk for lung cancer with asbestos exposure alone is 6-fold, with cigarette smoking alone it is 11-fold, but with exposure to both asbestos and cigarette smoke, the increase may be as high as 59-fold. Smoking cessation should be the most important goal of cancer prevention programs in this population, with targeting of the subgroup of workers with asbestosis. Fortunately, with recognition of the harmful health risks related to asbestos, its use has precipitously decreased in the United States since the 1970s.

Prevention of Environmental and Occupational Exposures

In the United States, the Occupational Safety and Health Administration defines standards for exposure and worker production in the construction industry and associated employment sectors. From an environmental perspective, radon and environmental and household air pollution (ie, smoke from warming or cooking houses) are the predominant exposures. Because radon is diluted to low concentrations outdoors, the most worrisome exposures are in homes. Prevention via testing for radon in both newly built and existing homes is recommended. Decreasing exposure to air pollution is a particular problem in developing and industrializing nations. Household exposure may be decreased via alternative heating/cooking methods or wearing a mask to avoid direct lung exposure. Toward this end, the World Health Organization is developing a Clean Household Energy Solution Toolkit, which may be implemented to decrease the risks of household fuel combustion. Decreases in environmental air pollution will require national and international efforts to improve air quality.

Genetic Predisposition and History of Cancer

There is a genetic component to the pathogenesis of lung cancer, whether it relates to host susceptibility to lung cancer (with or without exposure to cigarette smoke and to the development of certain types of lung cancer) or to an individual’s responsiveness to therapies. The importance of a family history of cancer, especially for family members with early onset lung cancer, has been highlighted by the incorporation into several lung cancer risk prediction algorithms. ^, A lot has been learned about the molecular epidemiology of lung cancer and on host susceptibility genetic markers to lung carcinogens (see Ramin Salehi-Rad and colleagues’ article, “ The Biology of Lung Cancer: Development of More Effective Methods for Prevention, Diagnosis and Treatment ,” in this issue). The susceptibility genetic factors include high-penetrance, low-frequency genes; low-penetrance, high-frequency genes; and acquired epigenetic polymorphisms. Familial association approaches such as those in rare mendelian cancer syndromes (Bloom and Werner syndromes) have been used to discover high-penetrance, low-frequency genes. There is a 2-fold increased risk for lung cancer in smokers with a family history of lung cancer with an increased risk also present in nonsmokers. Large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 and CHEK2 has recently been described in a European cohort.

Many candidate susceptibility genes that are of low penetrance and high frequency have been reported. There have been more than 1000 candidate gene association studies on genetic susceptibility to lung cancer in the past 2 decades but without clear consensus. One study reported 22 of 21 genes (including ATM, CXCR2, CYP1A1, CYP2E1, ERCC1, ERCC2, FGFR4, SOD2, TERT, and TP53) exhibiting significant associations with lung cancer susceptibility. Genotypic analysis combined with existing data for an aggregated genome-wide association study analysis of lung cancer identified 18 (including 10 new) susceptibility loci that highlighted striking heterogeneity in genetic susceptibility across the histologic subtypes of lung cancer. This work highlighted RNASET2, SECISBP2L, and NRG1 as candidate genes, as well as cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. High-depth, high-accuracy microsatellite genotyping revealed 2 genes (ARID1B and REL) and 2 significantly enriched pathways (chromatin organization and cellular stress response), suggesting lung carcinogenesis to be linked to chromatin remodeling, inflammation, and tumor microenvironment restructuring.

Susceptibility to carcinogenic agents may also be affected by individual differences in mutagen sensitivity as noted by studies of DNA repair and lung cancer risks. Polymorphisms in DNA repair enzymes active in base excision repair (XRCC1 and OGG1), nucleotide excision repair (ERCC1, XPD, and XPA), and double-strand break repair (XRCC3), and different mismatch repair pathways have been linked to lung cancer risks. Chronic inflammation in response to repetitive tobacco exposure has been theorized as being involved in lung tumorigenesis. Genes encoding for the interleukins or cyclo-oxygenase involved in inflammation, or the metalloproteases involve in repair during inflammation have been associated with lung cancer risk. Several cell cycle–related genes have been implicated in lung cancer susceptibility, including tumor suppressor genes p53 and p73, and apoptosis genes FAS and FASL. DNA adducts can be measured as biomarkers to represent the degree of carcinogenesis and lung cancer susceptibility. Acquired or epigenetic changes to DNA chromosome can also lead to increased lung cancer susceptibility. These events include DNA methylation, histone deacetylation, and phosphorylation, all of which can affect gene expression.

Lung cancer susceptibility is determined at least in part by host genetic factors. Persons with genetic susceptibility might therefore be at higher risk if they smoke tobacco. As more is being discovered about genetic risks to lung cancer, it may be possible to target high-risk subgroups for lung cancer for specific interventions, including intensive efforts at smoking cessation, screening, and prevention programs.

Chronic Lung Diseases

Chronic lung diseases have been associated with an increased risk for lung cancer, the strongest association being with chronic obstructive pulmonary disease (COPD), especially in men. The prevalence of COPD in newly diagnosed lung cancer in 1 study was 6-fold greater than matched smokers, suggesting that COPD itself is an important independent risk factor. COPD is characterized by chronic inflammation and a study found that the likelihood of developing lung cancer was increased if C-reactive protein, a nonspecific measure of inflammation, was greater than 3 mg/L compared with patients with lower levels (<1 mg/L). A large retrospective study of patients with COPD found that the risk for lung cancer was lower among patients who took high-dose inhaled corticosteroids (ICS) compared with patients taking lower doses or none at all. A recent study using population-based linked administrative data in Canada showed that ICS exposure was associated with a 30% reduced risk of lung cancer with a HR of 0.70. These results highlight the use of ICS as a potential chemoprevention in lung cancer among patients with COPD. However, this finding must be tempered, given that other investigators have shown that patients with COPD with post-ICS tuberculosis or pneumonia had increased risk of lung cancers.

Alpha1-antitrypsin deficiency carriers have a higher risk for lung cancer (2-fold), after adjusting for tobacco smoke and COPD. The incidence of lung cancer in patients with interstitial fibrosis is reported to be markedly increased with an OR for lung cancer of 8.25 compared with control subjects, even after adjustment for smoking. The risk of development of lung cancer in idiopathic pulmonary fibrosis or usual interstitial fibrosis is higher for older male smokers and significantly higher in those with combined usual interstitial fibrosis and emphysema syndrome compared with fibrosis only. Other fibrosing diseases, including asbestosis and scleroderma-related lung disease, also have an increased association with lung cancer. Although the mechanisms by which pulmonary interstitial disease may predispose to lung malignancy are not clear, various hypotheses have been raised, including malignant transformation related to chronic inflammation, epithelial hyperplasia, impaired clearance of carcinogens, and infections.

Infections

Infection as a causative factor in lung cancer remains debatable. A potential role for human papillomavirus (HPV) has been suggested in lung cancer because it has been detected in bronchial squamous cell lesions. A high incidence of HPV DNA in lung cancer has been reported in Asian cohorts, especially in nonsmokers; however, studies in Western Europe failed to show an etiologic role of HPV in lung cancer. HPV serotypes 16 and 18 have been associated with lung cancer more than other serotypes. E6 and E7 oncogenes from these HPV serotypes have been shown to immortalize human tracheal epithelial cells, which themselves are highly prone to genetic damage. It will take time to see if an HPV-directed vaccine for cervical cancer has any impact on the incidence of lung cancer.

Bioinformatic analyses of The Cancer Genome Atlas data found that viral sequences can be identified in 21% of the lung cancer samples compared with paired adjacent normal tissues. Viral sequences from only 8 viruses were found in lung cancer and these include HPV16, HPV18, HPV30, HPV33, human herpesvirus 4 (or Epstein-Barr virus), human herpesvirus 5 (or cytomegalovirus CMV), human herpesvirus 6 and hepatitis B virus. Epstein-Barr virus, which is associated with Burkitt lymphoma and nasopharyngeal carcinoma, has been strongly associated with lymphoepithelioma-like carcinoma, a rare form of lung cancer, in Asian patients, but this association has not been observed in the Western population. Other viruses suggested as etiologic for lung cancer include BK virus, JC virus, the human cytomegalovirus, simian virus 40, measles virus, and Torque tenovirus; however, the results have remained inconclusive.

Chlamydia ( Chlamydophila ) pneumonia is a common cause of respiratory infection, especially in smokers and might have a role in lung cancer. Although not known as an oncogenic pathogen, the inflammation resulting from Chlamydia infection and or C pneumoniae proteins can lead to DNA damage and cellular injury conferring selective advantages for tumorigenesis. A cohort study of tuberculosis patients showed an increased risk for lung cancer in these patients with hazard ratio of 3.3 after adjusting for COPD. Another study found that tuberculosis was significantly associated with increased risk for lung cancer (HR, 1.37) and mortality (HR, 1.43). Interestingly, there was no evidence for synergism between a history of tuberculosis and smoking. It has been speculated that the tuberculosis-related inflammation and scarring contribute to lung cancer pathogenesis.

Patients infected with the human immunodeficiency virus (HIV) are living longer owing to antiretroviral treatments; however, there is an increase in the proportion of deaths attributable to non–AIDS-defining tumors, especially lung cancer, which has become a leading cause of death among people living with HIV. ^, More than 40% of people living with HIV in the United States smoke cigarettes and HIV itself independently increases the risk of lung cancer. Tobacco use and HIV together may accelerate the development of lung cancer. The risk of lung cancer is increased by the presence of HIV through mechanisms likely involving chronic inflammation, immunomodulation, and other infections. HIV was associated with a hazard ratio of 3.6 for lung cancer after controlling for smoking. An increased risk of lung cancer in veteran patients with HIV was associated with low CD4 cell count, high viral load, and more bacterial pneumonia episodes. Other factors that could contribute to the higher incidence of lung cancer in patients with HIV include the greater prevalence of co-infection with oncogenic viruses (HPV, Epstein-Barr virus, and Kaposi sarcoma virus), the potential direct effects of the HIV virus, and the consequences of long-term immunosuppression. Certain lung microbiota dysbiosis has recently been correlated with development of lung cancer. For example, the lower airways of patients with lung cancer were enriched for oral taxa Streptococcus and Veillonella , which was associated with an up-regulation of the ERK and PI3K inflammatory signaling pathways. Overall, evidence suggests that infection could play a role in lung cancer; however, definite proof of a causal relationship remains lacking.

Diet

Certain dietary items such as red meat, dairy products, saturated fats, and lipids have been suggested to increase the risk for lung cancer. A meta-analysis found a significant (24%) increased risk of lung cancer for high consumption of red meat (relative risk, 1.24) among never smokers and nonsmokers but not for high consumption of other types of meat or fish or for heterocyclic amines. A pooled analysis of 10 prospective cohort studies showed that high intakes of total and saturated fat were associated with increased risk of lung cancer (HR, 1.07 and 1.14, respectively) where the positive association was greater in current smokers than former/never smokers, whereas a high intake of polyunsaturated fat was associated with a decreased risk of lung cancer (HR, 0.92). Moreover, a 5% energy substitution of saturated fat with polyunsaturated fat was associated with a 16% to 17% lower risk of small cell and squamous cell carcinoma, respectively. Other foods with an adverse effect on lung cancer include food that contain nitrosodimethylamines and nitrites (found in salted and smoked meat products).

Many large-scale studies of vitamin supplementation have yielded disappointingly negative results. ^, Because of the large body of epidemiologic literature pointing to the benefits of fruits and vegetables, most health authorities continue to recommend a balanced dietary intake incorporating fruits and vegetables. Vitamin A has both an animal (retinol) and a vegetable (carotenoid) source; the vegetable component may have protective effects against lung cancer. In particular, studies have shown beta-carotene (a prominent carotenoid) and vitamins C and E (alpha-tocopherol) may have some protective effect against lung cancer. ^, However, large trials such as The Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study and the Beta-Carotene and Retinol Efficacy Trial (CARET) not only did not find benefit of dietary supplementation, but they found higher than expected mortality in the group that received beta-carotene and or vitamin A. ^, As a result of these studies, among others, the use of supplemental beta-carotene and vitamin A is discouraged. There have also been suggestions that low dietary intake of certain minerals, including magnesium, zinc, copper, and iron, is associated with increased lung cancer risk; however, later prospective cohort studies observed no associations between total mineral intake and lung cancer. ^, Overall, dietary supplementation in lung cancer prevention is unclear and these studies should serve as a reminder that indiscreet and excessive intake of vitamins or other chemicals can be potentially harmful.

Fruits and vegetables that contain carotenoids and other antioxidants have been hypothesized to decrease lung cancer risk. Comparing the highest with the lowest intakes incorporating a large number of independent studies, the summary relative risk estimates were 0.92 for vegetables and 0.82 for fruits. Significant inverse dose–response associations were observed for each 100 g/d increase for fruits and vegetables with no additional benefit when increasing consumption more than 400 g/d. A meta-analysis of 37 studies showed similar significant associations between vegetables and fruits intake and lung cancer risk with effects stronger in females than in males. Although these studies showed that any types of vegetables and fruits have beneficial effects with lung cancer, the consumption of vegetables described as cruciferous, such as broccoli and cabbage, which are rich in isothiocyanates, has protective effect against lung cancer. Low or no intake of fruits or vegetables has been associated with up to a 3-fold risk for lung cancer. Furthermore, consuming fruits or vegetables raw rather than cooked is associated with a further decrease in the risk for lung cancer because important carotenoids can be destroyed with cooking.

Flavonoid plant metabolites have antioxidant and antiproliferative properties and can be found in foods, such as berries, citrus fruits, tea, dark chocolate, and red wine. A prospective study showed the risk for lung cancer was lower in men with high total flavonoid intake. Consumption of vegetables, tea, and wine, all of which are rich sources of flavonoids, was associated inversely with lung cancer among tobacco smokers.

A pooled analysis of the International Lung Cancer Consortium and the SYNERGY study found an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared with nondrinkers. The lowest risk was observed for persons who consumed 10.0 to 19.9 g/d of alcoholic beverage where 1 drink is approximately 12 to 15 g. There is an inverse association found between the consumption of wine and liquor, but not beer, and lung cancer. Epidemiologic studies investigating the association between coffee consumption and lung cancer risk have yielded inconsistent results, although recent studies have consistently indicated a significantly increased risk by 47% in the population with the highest category intake of coffee compared with the lowest category of intake.

Obesity and Exercise

Globally, more than 1.9 billion adults are overweight and of these 650 million are obese. Although a meta-analysis showed an inverse association between body mass index (BMI) and lung cancer risk, and obesity may even have a protective role, the association between BMI and lung cancer was not significant in the absence of cigarette smoking. The observed BMI and cancer association may be related to residual strong confounding effects of smoking because smokers tend to have a lower BMI than their matched nonsmokers with some gaining weight upon smoking cessation. A meta-analysis of 29 studies showed, that compared with normal weight, the relative risk for lung cancer was 0.77 for excess body weight with a BMI of 25 kg/m ² or greater. Underweight has also been associated with lower lung cancer risk, with a nonlinear, inverted U-shaped relationship. Waist circumference has been found to be positively associated with lung cancer risk in smokers.

The role of physical activity and lung cancer risk has been mixed. Physical activity has been associated with lower lung cancer risk with estimates, ranging from a 20% to a 50% lower risk in the most active study participants. A prospective study found that, in middle-aged men with no history of lung cancer, increasing levels of cardiorespiratory fitness serve as a protective factor against lung cancer. Using a large database of subjects in a cancer prevention study, physical activity was not associated with lung cancer risk within any of the smoking strata except in former smokers less than 10 years since quitting (relative risk, 0.77). Favorable lifestyle including good cardiorespiratory fitness, healthy dietary habits and nonsmoking lifestyle considerably reduces the risk of cancer, especially lung cancer in men.

Lung Cancer Risk Predictive Models

With a better understanding of the risk factors for lung cancer, predictive models have improved. The implementation of LCS has heightened the importance of predicting individual lung cancer risk. Updated lung cancer risk prediction models have built on prior findings and several are currently available. For example, the PLCO _M2012 model using patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial who were current or former smokers incorporated age, race, education, BMI, smoking history, family history of lung cancer, personal history of cancer, and COPD. When compared with established LCS criteria (including age and smoking history; Nina A. Thomas and Nichole T. Tanner’s article, “ Lung Cancer Screening: Patient Selection and Implementation ,” in this issue), PLCO _M2012 had a higher sensitivity and positive predictive value for determining individual risk of developing lung cancers. Risk-based selection of patients for LCS may be associated with a lower number needed to screen. Trials are underway comparing lung cancer predictive models with current LCS criteria.

Chemopreventive Agents

Although multiple potential chemopreventive agents, including beta-carotene supplementation, vitamin E, retinoids, N -acetylcysteine, isotretinoin, aspirin, selenium, prostacyclin analogues, cyclo-oxygenase-2 inhibitors, anethole dithiolethione, inhaled steroids, pioglitazone, myoinositol, tea extract, and metformin have been studied; however, to date none have been identified as effective. Decreasing inflammation is a purported mechanism for reducing lung cancer risk and large retrospective studies have reported lower lung cancer risk in patients receiving cholesterol-lowering statin medications and in patients with COPD treated with ICS. ^, Unfortunately, conflicting results have been reported for both medication classes, showing no effects on lung cancer risk reduction. ^,