As the leading cause of cancer death in the world, lung cancer is currently a public health problem of enormous magnitude. In 2008 more than 1.6 million people were newly diagnosed with lung cancer, comprising 13% of all new cancer diagnoses; furthermore, 1.4 million, or 18% of all cancer deaths, were from lung cancer. In contrast, at the start of the 20th century, lung cancer was considered a rare disease. However, its epidemic rise across the first decades of that century was soon identified as clinicians began to provide care for increasing numbers of patients with lung cancer and routine vital statistics documented rising mortality. Although tobacco had been widely used throughout the world for centuries, the pandemic of lung cancer followed the introduction of manufactured cigarettes with addictive properties, which resulted in a new pattern of sustained exposure of the lung to inhaled carcinogens. Epidemiologic research linked smoking to lung cancer in investigations that began in the 1930s and provided convincing and consistent evidence from the 1950s forward. Whereas its predominant cause—tobacco smoking—is now well known, there are other causes of lung cancer as well, some acting in concert with smoking to increase risk synergistically.
This chapter provides a summary of the epidemiologic evidence on lung cancer. It is based primarily on summaries of the evidence prepared by expert committees, and it includes findings of representative and particularly informative studies. Syntheses have been periodically carried out by expert review groups, dating back to reports such as the 1962 report of the Royal College of Physicians and the landmark 1964 Report of the U.S. Surgeon General. More recent reports include those prepared by the International Agency for Research on Cancer in 2004, the 2004 and 2006 reports of the Surgeon General on active and passive smoking, respectively, and the 2010 report of the Surgeon General on the mechanistic basis of smoking-caused pathogenesis. The 2014 U.S. Surgeon General’s Report commemorated the 50th anniversary of the landmark 1964 report and once again updated the evidence on the adverse health effects of cigarette smoking. The U.S. Surgeon General’s Reports have provided evidence syntheses and inferences that have guided the conclusions that active and passive cigarette smoking are causally associated with the risk of lung cancer. In turn, the evidence on these topics have been historically important in the development of epidemiology.
Because of the high case-fatality rate of lung cancer, incidence and mortality rates are nearly equivalent; consequently, routinely collected vital statistics provide a long record of lung cancer. We are amidst an epidemic of lung cancer that dates to the mid-20th century ( Fig. 52-1 ). The epidemic among women followed that among men, with a sharp rise in rates from the 1960s to the present, making lung cancer the most frequent cause of female cancer mortality in the United States. The epidemic among women not only arose later but also will not peak as high as among men because smoking prevalence crested at substantially lower levels among women than among men.
Trends of age-specific lung cancer mortality rates in the United States show differing epidemic patterns in men than in women ( Fig. 52-2 ). In the older age groups, the rates continue to increase in both sexes, but the rates of increase are decelerating more in men than in women. The rates of lung cancer are now decreasing in the younger age groups, more for men but also becoming evident in women.
Notable shifts have taken place in the incidence rates of lung cancer by histologic type. After steadily increasing in incidence between 1973 and 1987, adenocarcinoma supplanted squamous cell carcinoma as the most frequent form of lung cancer ( Table 52-1 ).
|Group||Subtype||1973–1977 *||1978–1982 *||1983–1987 *||1990–2000 †|
|Squamous cell carcinoma||13.4||15.1||15.3||14.4|
|Squamous cell carcinoma||24.3||26.8||25.5||22.3|
|Squamous cell carcinoma||4.0||5.5||6.6||8.2|
|African American males|
|Squamous cell carcinoma||43.9||46.3||48.5||39.7|
|African American females|
|Squamous cell carcinoma||5.6||6.8||9.5||11.4|
Race and Ethnicity
In the United States, whereas lung cancer incidence rates and mortality rates are similar among African American women and white women, incidence rates are 26% higher and mortality rates are 23% higher in African American men than in white men. A marked reduction in cigarette smoking among African American youths forecasts a possible reversal of this trend. In addition, lung cancer mortality rates among African Americans and non-Hispanic whites are significantly higher than rates among Hispanics, Native Americans, and Asian/Pacific Islanders. However, racial differences in historical patterns of cigarette smoking do not fully account for the racial disparities in lung cancer incidence and mortality rates. The high rates in African Americans may be partially due to greater susceptibility of African American smokers to smoking-induced lung carcinogenesis. The higher mortality rates of lung cancer in African Americans than in white Americans reflect not only their higher incidence rate but also poorer survival. In 2009, the 5-year relative survival rate was 19% lower in African Americans than in white Americans.
Lung cancer is the most commonly diagnosed cancer worldwide, but its geographic distribution shows marked regional variation : age-standardized incidence rates vary over a wide range, more than fourfold among men and fivefold among women ( Fig. 52-3 ). This marked variation in rates cannot be explained on the basis of diagnostic practices and data quality alone. Lung cancer tends to be most common in developed countries, particularly in North America and Europe, and less common in developing countries, particularly in Africa and South America. However, the lung cancer epidemic is on the rise in the developing world.
The epidemic of tobacco addiction in China illustrates the ongoing trend of a shift in the global lung cancer burden from high-income Western countries to low- and middle-income countries, particularly in Asia. In 2008, newly diagnosed lung cancers in developing countries exceeded the number in developed countries by 22% (884,500 and 724,300, respectively). The situation in China is particularly serious. Due to a striking increase in active smoking, Chinese males are a population of particular concern. Per capita cigarette consumption in Chinese men increased from one cigarette per day in 1952, to four in 1972, and to 10 in 1992. As a consequence, the lung cancer mortality rates have already increased 27% from 1990 to 2010 and will continue to rise substantially in the absence of aggressive tobacco control measures. The increase in lung cancer among Chinese males will have a major impact on the global burden of lung cancer in the 21st century, given the size of this population of smokers, which is more than 300 million. A unique feature of the epidemiology of lung cancer in China is the high lung cancer mortality rates among Chinese women despite the low prevalence of cigarette smoking. The inordinately high rates in women seem to be attributable to exposure to risk factors such as secondhand smoke exposure and indoor air pollution from cooking fumes.
Substantial geographic variation in lung cancer mortality rates has also been observed within countries, providing clues about the determinants of lung cancer. In the past, rates tended to be highest in urban areas, which led to conjecture that air pollution might be a cause of the lung cancer epidemic. High rates in coastal areas in the United States from 1950 to 1969 were linked to asbestos exposure in shipyards. Now lung cancer mortality rates among white males are highest in the South and lower in the Northeast, likely reflecting patterns of cigarette smoking.
LUNG Cancer by Histologic Type
Lung cancer manifests itself in multiple histologic types as classified by conventional light microscopy. The four major types, as traditionally identified by histologic appearance, include squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell undifferentiated carcinoma; together these four types of lung cancer account for more than 90% of lung cancer cases in the United States. These primary bronchogenic carcinomas are composed of a family of epithelial tumors that represent a subset of a larger collection of lung and pleural tumors classified by the World Health Organization (WHO) in 2004. However, recent advances in molecular biology, surgery, and clinical medicine have rendered these traditional histologic classifications inadequate for optimal patient care. The need for more refined classifications was necessitated by several developments: (1) adenocarcinoma with epidermal growth factor receptor (EGFR) mutations was found to be sensitive to tyrosine kinase inhibitors, (2) eligibility for certain novel medications was limited to those with adenocarcinoma, and (3) computed tomography (CT) screening studies were detecting ground-glass infiltrative lesions that posed diagnostic challenges for both radiologists and pathologists. Consequently, the classification of adenocarcinoma was refined as part of a multidisciplinary, international effort to incorporate molecular and clinical parameters, define terms uniformly, and optimize relevance to patient care. The evidence-based recommendations created new adenocarcinoma subtypes according to prognostic criteria and molecular patterns, and discontinued the term “bronchioloalveolar carcinoma.” Reports have subsequently corroborated the new classification and documented its improved relevance to patient care. This topic is covered in detail in Chapters 14 and 53 , but is included here because future research into the etiology of lung cancer would be strengthened by integrating these new lung cancer classification criteria.
Few links have been made between particular etiologic agents and the development of a particular histologic type of lung cancer. Cigarette smoking increases risk for all major histologic types. The dose-response relationship of increased lung cancer risk according to number of cigarettes smoked varies across the types, being steepest for small cell undifferentiated carcinoma. A few occupational exposures, such as chloromethyl ethers and radon, have been linked to small cell lung cancer.
In the United States, during the initial decades of the smoking-caused epidemic of lung cancer, the most frequent type of lung cancer was squamous cell carcinoma, followed by small cell carcinoma. In the 1970s, a shift toward a predominance of adenocarcinoma was noted, and with the persistence of this trend, adenocarcinoma is now the most common histologic type. In U.S. men, the shift to adenocarcinoma developed in part because, whereas lung cancer incidence and mortality rates began to decline during the 1990s, the decline in lung cancer rates was more rapid for squamous cell and small cell carcinomas than for adenocarcinoma, which is just beginning to show a lower incidence rate ( Fig. 52-4 ). In U.S. women, the increase in lung cancer incidence rates was more pronounced for adenocarcinoma than for any other cell type, perhaps because lung cancer rates increased most rapidly among U.S. women during the time period of changing histology.
Similar trends have been noted throughout the globe. Worldwide, adenocarcinoma tends to be the most common cell type seen in female lung cancer patients, accounting for approximately one-third of all lung cancer diagnoses in most regions. In males, squamous cell carcinoma is still the most common cell type in some geographic regions where the lung cancer epidemic has peaked, but trends indicate that the overall percentage of this cell type has fallen over time to 40% or less.
Hypotheses concerning the shift from squamous cell carcinoma to adenocarcinoma have focused on the potential role of changes in the characteristics of cigarettes and consequent changes in the doses and types of carcinogens inhaled. The resulting evidence from studies that have tested these hypotheses indicates that the trend of increasing rates of adenocarcinoma is primarily due to changes in cigarette smoking behavior and features of cigarettes (see later).
The Etiology of Lung Cancer: Overview
Although the causes of lung cancer are almost exclusively environmental, there is likely substantial individual variation in susceptibility to respiratory carcinogens. For example, lung cancer develops in only a minority of smokers. The disease can be conceptualized as the consequence of the interrelationship between (1) exposure to etiologic (or protective) agents and (2) individual susceptibility to these agents. Given lung cancer’s multifactorial etiology, synergistic interactions among risk factors have substantial consequences for lung cancer risk. These interactions have typically been considered on an agent-by-agent basis, for example, as in studies of the synergistic effect of cigarette smoking on the lung cancer risk from asbestos exposure. Our emerging understanding of cancer genetics indicates the additional relevance of gene-environment interactions.
Given the many risk factors that have been identified for lung cancer, a practical question is: What is the relative contribution of these factors to the overall burden of lung cancer? In the United States, active smoking is estimated to be responsible for about 85% of lung cancer ; occupational exposures to carcinogens account for approximately 5% to 10%; radon causes 15% of lung cancer, and outdoor air pollution perhaps 1% to 2%. These known causes may not fully account for the development of lung cancer in never smokers, an important group for whom further epidemiologic research is needed. Because these attributable risk estimates include joint contributions of risk factors, for example, smoking and occupation, the total percentage can exceed 100%.
Environmental and Occupational Agents
Smoking ( Chapter 46 )
Cigarette smoking is by far the leading cause of lung cancer, accounting for approximately 80% to 90% of lung cancer cases in the United States and in other countries where cigarette smoking is common. Compared with never smokers, current smokers have about a 25-fold increase in lung cancer risk, far higher than the risks for diseases associated with other environmental agents. Cigar and pipe smoking are also established causes of lung cancer. In general, lung cancer trends closely reflect patterns of smoking, but rates of lung cancer lag smoking rates by about 20 years. According to the Centers for Disease Control and Prevention, in the United States, 156,900 men and women die of smoking-related lung cancer each year. Worldwide, 5.4 million people die of smoking-related lung cancer each year.
The risk of lung cancer among cigarette smokers increases with the duration of smoking and the number of cigarettes smoked per day ( Table 52-2 ). In one widely cited analysis, Doll and Peto proposed a quantitative model for lung cancer risk based on data from the cohort study of British physicians. This model predicted a stronger effect from the duration of smoking than from the amount smoked per day. Thus a tripling of the number of cigarettes smoked per day was estimated to triple the risk whereas a tripling of duration of smoking was estimated to increase the risk 100-fold. These quantitative dimensions of the dose-response relationship between smoking and lung cancer have implications concerning the now widespread smoking among youths. Those starting at younger ages have a greater likelihood of becoming heavier smokers and remaining smokers. The exponential effect of duration of smoking on lung cancer risk markedly increases the lifetime risk for those who become regular smokers in childhood.
|SMOKED 20 CIGARETTES PER DAY FOR||SMOKED 40 CIGARETTES PER DAY FOR|
|Group||Never Smokers||30 Years||40 Years||30 Years||40 Years|
Cigarette smokers of any age can benefit from quitting smoking. Among those who quit smoking, the likelihood of developing lung cancer decreases when compared with those who continue to smoke ( Table 52-3 ). As the period of abstinence from smoking cigarettes increases, the risk of lung cancer decreases. However, even for periods of abstinence of more than 40 years, the risk of lung cancer for former smokers remains elevated compared with that for never smokers (see Table 52-3 ). The benefits derived from smoking cessation also depend on the prior duration of smoking: for a given period of abstinence, the risk decreases with a decrease in the duration of previous smoking.
|Cigarettes Smoked per Day|
|Years Since Smoked||1–9||10–20||21–39||40||Total|
The Changing Cigarette and Expanding Marketplace
The composition and design of cigarettes has changed considerably since the 1950s. The marketplace has shifted from mainly unfiltered cigarettes to predominantly filtered cigarettes and to products that are labeled “light” or “mild.” In the mid-1960s, ventilation holes were added to the filter, which draw in air and dilute the inhaled smoke. However, whereas these holes effectively decrease the tar measured by the testing machines, smokers can readily block the holes with their fingers, thereby increasing their tar inhalation and exposure to carcinogens. Reconstituted tobacco, essentially reprocessed tobacco leaf wastes, has been used increasingly since the 1960s, and there have been changes to the cigarette paper and additives. These changes in design and content may also have affected carcinogenicity.
Despite product marketing that would make these changes appear to be less harmful, the evidence indicates that, if anything, the changes in cigarettes have yielded greater—not lower—risks for lung cancer. A comparison of three U.S. cohorts, each comprised of more than 500,000 participants followed from 1959 to 1965, 1982 to 1988, and 2000 to 2010, provide very strong evidence to assess temporal trends in the association between cigarette smoking and lung cancer. The relative risks of current smoking in relation to lung cancer mortality increased across these three time periods, a trend that was most pronounced in women among whom the relative risk increased across these three time periods from 2.7 to 12.7 to 25.7. In men, the relative risk increased and then plateaued, from 12.2 to 23.8 to 25. With respect to lung cancer risk, these data provide strong evidence that cigarettes have become more harmful rather than less harmful over time. These findings are consistent with the conclusions of several expert panels that reviewed prior evidence.
During the past decade, the marketplace for tobacco products and devices that deliver nicotine has greatly expanded even as smoking bans have increasingly limited the locations where cigarette smoking is allowed. This diversification exists for both tobacco products and nontobacco products that deliver nicotine. In addition to the traditional smokeless tobacco products of loose leaf chewing tobacco and moist snuff, newer or more broadly marketed products include snus (a tobacco powder product packaged in a bag that is moister than snuff and does not require spitting) and dissolvable tobacco. Furthermore, an increase in the prevalence of smoking roll-your-own cigarettes has been observed in the United States and elsewhere. The prevalence of smoking tobacco through a waterpipe, also referred to as “hookah,” has increased worldwide. Electronic cigarettes (or “e-cigarettes”) are non–tobacco-containing nicotine delivery devices that have experienced a rapid upsurge in use and are now marketed by the major U.S. tobacco companies.
Drawing upon past experience with the changing cigarette, it is clear that monitoring this expansion in products and how the products are used is not only critical to tobacco control but also directly relevant to the prevention of lung cancer. A product such as the e-cigarette that ostensibly decreases delivery of carcinogens to the lung would reduce the risk for development of lung cancer if current cigarette smokers switched from smoking cigarettes to exclusive use of the e-cigarette. In contrast, the risk for lung cancer could be increased if the e-cigarette maintained nicotine addiction and its users continued to smoke cigarettes as well in the increasingly common pattern of use of multiple products that deliver nicotine. Furthermore, these alternative products may serve as a gateway for youths to initiate smoking and thus start on a path that eventually leads to tobacco addiction. Questions such as these, along with the direct adverse health effects associated with use of these alternative products, are important lines of inquiry for future research.
Passive smokers inhale a complex mixture of smoke now widely referred to as “environmental tobacco smoke” or “secondhand smoke.” Passive smoking was first considered as a possible risk factor for lung cancer in 1981 when two studies were published that described increased lung cancer risk among never-smoking women who were married to smokers. Additional evidence rapidly accrued so that by 1986, two reports, from the National Research Council and the 1986 Surgeon General’s Report, both concluded that passive smoking causally increased risk for lung cancer. Estimates indicate that passive smoking accounts for about 3400 lung cancer deaths per year in the United States.
Since these conclusions were reached, numerous studies have been carried out to characterize further the association of passive smoking with lung cancer, while taking into account some of the limitations of earlier studies, particularly small sample sizes, exposure misclassification, and omission of some potential confounding factors. Various panels since 1986 have also concluded that passive smoking increases lung cancer risk, including the International Agency for Research on Cancer, the California Environmental Protection Agency, and once again, the U.S. Surgeon General.
Passive smoking is more weakly associated with lung cancer than is active smoking, as expected given the lower doses of carcinogens received by the nonsmoker compared with the smoker. Marriage to a smoker is associated with about a 20% increase in risk and exposure in the workplace is associated with between a 24% increase in risk up to a twofold increase at the highest levels of exposure. In general, the risk of lung cancer increases as the exposure to secondhand smoke increases.
The possible role of diet in modifying the risk for lung cancer has been the focus of intensive investigation, driven initially by the rationale that specific micronutrients might have anticarcinogenic activity. The most thoroughly investigated dietary factors are also those that at present appear to have the greatest implications for prevention: fruits, vegetables, and specific antioxidant micronutrients that are commonly found in fruits and vegetables.
The results of case-control and prospective cohort studies have tended to show that individuals with high dietary intake of fruits or vegetables have a lower risk for lung cancer than those with a low intake. To understand the basis of this protective association, researchers have grouped fruits and vegetables into classes and examined them individually in relation to lung cancer risk. For example, tomatoes and cruciferous vegetables have been associated with a reduced risk for lung cancer in a number of studies. These food-based analyses can help clarify whether protection arises from the complex mixture that composes fruits and vegetables or from specific biochemical constituents present in particular fruits and vegetables.
Fruits and vegetables are the major dietary source of antioxidant micronutrients. Much of the research on diet and lung cancer has been motivated by the hypothesis that diets high in antioxidant micronutrients may protect against oxidative DNA damage and thereby protect against cancer. For example, this was one of the hypothesized roles for β-carotene, the focus of now controversial clinical trials. Two different strategies are used to evaluate the relationship of micronutrients to lung cancer risk in observational epidemiologic studies: (1) estimating micronutrient intake from food-frequency questionnaires and (2) measuring serum concentrations of micronutrients. Prospective studies of both dietary intake and prediagnostic blood concentrations suggest that carotenoids are inversely associated with lung cancer risk.
The protective association predicted between β-carotene and lung cancer on the basis of these observational epidemiologic studies was not confirmed in three randomized, double-blind, placebo-controlled chemoprevention trials. In fact, two of these studies with participants at high risk for lung cancer (heavy smokers and asbestos-exposed workers) were stopped early because significantly increased risk for lung cancer was observed in the β-carotene group compared with the placebo group.
The results of the randomized chemoprevention trials stand in sharp contrast to the considerable observational epidemiologic evidence favoring a protective association. Among the potential explanations for the contradictory findings are that the randomized trials used relatively high doses of β-carotene and that the observational epidemiologic studies may have been flawed by uncontrolled confounding or selection bias. Because of the powerful role of smoking as a cause of lung cancer, disentangling the effects of other lifestyle-related factors, such as diet, from the effect of smoking may be particularly difficult. Further complicating the assessment of protection by dietary factors is the narrow range of likely effects, much smaller than the effect of smoking, and the unavoidable problem of measurement error, that is, the inevitable inaccuracy in estimating usual dietary consumption of particular foods or groups of foods.
Studies of fruits, vegetables, and micronutrients have been the centerpiece of studies of diet and lung cancer, but other factors have also been investigated. For example, the results of a meta-analysis showed alcohol drinking in the highest consumption categories was associated with increased risk for lung cancer. In addition, anthropometric measures have been studied, indicating a tendency for persons with lower body mass index to have increased lung cancer risk relative to heavier persons. However, both alcohol drinking and low body mass index may be difficult to separate from the concomitant effects of smoking. At present, when considering the possible relationships between lung cancer and factors such as alcohol drinking and lower body mass index, residual confounding by cigarette smoking cannot be dismissed as a possible explanation.
Lung cancer has been found to be associated causally with many workplace exposures, including arsenic, beryllium, cadmium, chromium, and nickel in addition to those described later. Occupational exposure to lung carcinogens have been estimated by case-control studies to account for 9% to 15% of lung cancer cases. As lung carcinogens have been identified in the workplace and regulations established to prevent workers from being exposed, this proportion has been decreasing over time. Cigarette smoking also potentiates the effect of some of the known occupational lung carcinogens.
Asbestos, a well-established occupational carcinogen, refers to several forms of fibrous, natural silicate minerals. The epidemiologic evidence that asbestos causes lung cancer dates to the 1950s. In a retrospective cohort study published in 1955, Doll observed that asbestos textile workers at a factory in the United Kingdom had a ten-fold elevation in lung cancer risk and that the risk was most heavily concentrated during the timeframe before regulations were implemented to limit asbestos dust in factories. A sevenfold excess of lung cancer was subsequently observed among insulation workers in the United States, with peak incidence at 30 to 35 years after the initial exposure to asbestos. The risk of lung cancer has been noted to increase with increased exposure to asbestos and to be associated with each of the principal commercial forms of asbestos. Whether asbestos acts directly as a carcinogen or indirectly, for example, by causing chronic inflammation that eventually leads to cancer, remains controversial. For the mechanism of asbestos-induced lung cancer, two competing hypotheses have been posed: (1) lung cancer arises as a consequence of the asbestos-induced lung disease asbestosis and (2) lung cancer arises directly from asbestos exposure while the asbestosis merely serves as a marker of asbestos dose. Regardless of mechanism, asbestos is a known lung carcinogen and the number of exposed workers is increasing in South America, Asia, and the former Soviet Union.
Asbestos and cigarette smoking are both independent causes of lung cancer but, in combination, they act synergistically to increase risk. Uncertainty remains as to the precise quantitative characterization of this synergy, reflecting limitations of the available data and lack of understanding of the underlying mechanisms. Nonetheless, the risk of the combined exposure is much higher than would be expected if one merely added the risks together, showing a strong interaction between the two. In fact, the risks are approximately multiplicative. A person who smokes and has been exposed to asbestos has a greater than 50-fold elevated risk for lung cancer than does a nonsmoker with no asbestos exposure, and a much higher risk than a person exposed to cigarette smoke alone (relative risk, 10.9) or to asbestos alone (relative risk, 5.2) ( Table 52-4 ).
|MORTALITY RATES||DIFFERENCE IN RATES||RATIO OF RATES|
|Yes||122.6||601.6||111.3||590.3 †||10.9||53.2 ‡|