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Classic Epidemiology of Lung Cancer
Summary of Key Points
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Lung cancer incidence and mortality has declined among men in many countries, following a decline in the prevalence and level of smoking. Among women, lung cancer incidence and mortality is still increasing in many countries and has become the main cause of cancer death.
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Despite important advances in lung cancer screening, primary prevention through tobacco control remains the main approach in the fight against lung cancer, especially in low-income countries.
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Occupational factors, passive smoking and other indoor pollutants, including radon, and air pollution are other important modifiable causes of lung cancer; nutritional factors and infectious agents are additional potential risk factors. Control of exposure to lung carcinogens other than tobacco, in both the general and the occupational environment, has had a substantial impact in several high-risk populations.
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Lung cancer in never-smokers is not an uncommon disease. While there is an interaction between tobacco smoking and other lung carcinogens, several agents have been shown to cause lung cancer also in never-smokers.
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Lung cancer was the most important epidemic of the 20th century, and it is likely to remain a major public health problem in the 21st century. It is also a paradigm of the importance of primary prevention and a reminder that scientific knowledge is not sufficient per se to ensure human health.
The history of lung cancer epidemiology parallels the history of modern chronic disease epidemiology. In the 19th century, an excess of lung cancer was observed among miners and some other occupational groups, but otherwise the disease was very rare. An epidemic increase in lung cancer began in the first half of the 20th century, with much speculation and controversy about its possible environmental causes.
Among both women and men, the incidence of lung cancer is low in persons under 40 years of age, it increases up to age 70 or 75 years ( Fig. 1.1 ), and it declines thereafter. The decline in incidence in the older-age groups can be explained, at least in part, by incomplete diagnosis or by a generation (birth cohort) effect.
Age-specific incidence rate of lung cancer per 100,000, by gender, according to the US Surveillance, Epidemiology End-Result (SEER) database for 2003–2007.
Methodologically, epidemiologic studies of lung cancer have been straightforward because the site of origin is well defined, progressive symptoms prompt diagnostic activity, and the predominant causes are comparatively easy to ascertain. Novel approaches to the classification of lung cancer based on molecular techniques will likely bring new insights into its etiology, especially among nonsmokers.
Descriptive Epidemiology
Lung cancer, a rare disease until the beginning of the 20th century, has become the most frequent malignant neoplasm among men in most countries and the main neoplastic cause of death in both men and women. In 2012, lung cancer accounted for an estimated 1,242,000 new cancer cases among men, which is 17% of all cancers excluding nonmelanoma skin cancer, and 583,000, or 9%, of new cancers among women. After nonmelanocytic skin cancer, lung cancer is the most frequent malignant neoplasm in humans and the most important cause of neoplastic death. Approximately 58% of all cancers occur in developing countries.
The geographic and temporal patterns of lung cancer incidence are determined chiefly by consumption of tobacco. An increase in tobacco consumption is paralleled a few decades later by an increase in the incidence of lung cancer, and a decrease in consumption is followed by a decrease in incidence. Other factors, such as genetic susceptibility, poor diet, and indoor air pollution, may act in concert with tobacco smoking in shaping the descriptive epidemiology of lung cancer.
The pattern found today in men ( Fig. 1.2 ) is composed of populations at high risk, in which consumption of tobacco has been persistently high for decades, and populations at low risk, either because tobacco consumption has not been increasing for long (e.g., China, Africa) or because a decrease in consumption has been present for several decades (e.g., Sweden).
In countries with populations made up of different ethnic groups, differences in lung cancer rates are frequently observed. For example, in the United States, the rates are higher among black men than among other ethnic groups ( Table 1.1 ).
TABLE 1.1
Age-Standardized Incidence Rates of Lung Cancer per 100,000 by Gender and Ethnic Group a
| Ethnic Group | Men | Women |
|---|---|---|
| Asian and Pacific Islander | 31.6 | 17.5 |
| Black | 66.8 | 35.5 |
| Hispanic white | 25.0 | 16.5 |
| Non-Hispanic white | 51.2 | 38.1 |
a Data from the US Surveillance, Epidemiology End-Result database for 2003–2007.
Over the past 25 years, the distribution of histologic types of lung cancer has been changing. In the United States, squamous cell carcinoma, which was formerly the predominant type, is decreasing, whereas adenocarcinoma has increased in both genders. In Europe, similar changes are occurring in men, whereas in women, both squamous cell carcinoma and adenocarcinoma are increasing. Although the increase in the incidence of adenocarcinoma may be due, at least in part, to improved diagnostic techniques, changes in composition and patterns of tobacco consumption (deeper inhalation of low-nicotine and tar tobacco smoke) are additional explanations.
Risk Factors
Tobacco Smoking
The evidence is very strong that tobacco smoking causes all major histologic types of lung cancer. A carcinogenic effect of tobacco smoke on the lung has been demonstrated in epidemiologic studies conducted since the early 1950s and has been recognized by public health and regulatory authorities since the mid-1960s. Tobacco smoking is the main cause of lung cancer in most populations, and the geographic and temporal patterns of the disease largely reflect tobacco consumption during the previous decades. Because of the high carcinogenic potency of tobacco smoke, a major reduction in tobacco consumption would result in the prevention of a large fraction of human cancers.
The excess risk among continuous smokers relative to the risk among never-smokers is on the order of 10-fold to 20-fold. The overall relative risk reflects the contribution of the different aspects of tobacco smoking: average consumption, duration of smoking, time since quitting, age at start, type of tobacco product, and inhalation pattern, as well as the absolute risk in never-smokers.
Several large cohort and case–control studies have provided detailed information on the relative contributions of duration and amount of cigarette smoking to excess lung cancer risk. Doll and Peto analyzed data from a large cohort of British doctors and concluded that the excess lung cancer risk rises in proportion to the square of the number of cigarettes smoked per day but to the fourth power of the duration of smoking. Therefore duration of smoking should be considered the strongest determinant of lung cancer risk in smokers. Analysis of the same cohort after 50 years of follow-up confirmed these results.
An important aspect of tobacco-related lung carcinogenesis is the effect of cessation of smoking. The excess risk sharply decreases in ex-smokers, starting approximately 5 years after quitting, and an effect is apparent even for cessation late in life. However, an excess risk throughout life likely persists even in long-term quitters.
The risk of lung cancer is lower among smokers of low-tar cigarettes than among smokers of high-tar cigarettes and lower among smokers of filtered cigarettes than among smokers of unfiltered cigarettes. Smokers of black (air-cured) tobacco cigarettes are at twofold to threefold higher risk of lung cancer than smokers of blond (flue-cured) tobacco cigarettes. Tar content, the presence or absence of a filter, and the type of tobacco are not independent, however. High-tar cigarettes tend to be unfiltered, and in countries where both black and blond tobacco are used, cigarettes are more frequently made from black tobacco.
Although cigarettes are the main tobacco product smoked in Western countries, an exposure–response relationship with lung cancer risk has also been shown for cigars, cigarillos, and pipes, indicating a carcinogenic effect of these products as well. An increased risk of lung cancer has also been shown after consumption of local tobacco products, such as bidi and hookah in India, khii yoo in Thailand, and water pipe in China. Limited data suggest an increased lung cancer risk after consumption of other tobacco products, such as narghile in western Asia and northern Africa and toombak in Sudan.
Differences in the Effect of Tobacco Smoking According to Histology, Gender, and Race
Although the evidence is abundant that tobacco smoking causes all major histologic types of lung cancer, the associations appear to be stronger for squamous cell and small cell carcinoma and weaker for adenocarcinoma. The incidence of adenocarcinoma has greatly increased during the past decades. Some of the increase may be attributable to improved diagnostic techniques, but aspects of tobacco smoking may also have played a role; it is unclear, however, which aspects of smoking might explain these changes.
A few studies have suggested a difference in the risk of lung cancer between men and women who have smoked a comparable amount of tobacco, but most of the available evidence does not support this gender difference.
The higher rate of lung cancer among the black population compared with the rates in other ethnic groups in the United States is probably explained by the higher tobacco consumption in that population. The lower risk of lung cancer among smokers in China and Japan compared with the risks among smokers in Europe and North America may be due to the relatively recent beginning of regular heavy smoking in Asia, although differences in the composition of traditional smoking products and in genetic susceptibility may also play a role.
Secondhand Tobacco Smoke
The epidemiologic evidence and biologic plausibility support a causal association between secondhand exposure to cigarette smoke and lung cancer risk in nonsmokers. The evidence of a high relative risk in the original studies has been challenged on the basis of both possible confounding by active smoking, diet, or other factors and possible reporting bias. However, when these factors were taken into account, the association was confirmed, and the excess risk was on the order of 20% to 25%.
The effect of involuntary smoking appears to be present for both household exposure, mainly from the spouse, and workplace exposure. By contrast, little evidence has been found for an effect of childhood involuntary smoking exposure.
Confounding Effects of Tobacco Smoking
The importance of tobacco smoking in the causation of lung cancer complicates the investigation of the other causes of this disease because tobacco smoking may act as a powerful confounder. For example, a population of industrial workers exposed to a suspected carcinogen may smoke more than the unexposed comparison population. An excessive lung cancer risk in the exposed group, especially if small, might be due to the difference in smoking rather than to the effect of the occupational agent. One solution is to restrict the investigation to lifetime nonsmokers. However, they may represent a selected group, with low prevalence of exposure to many agents of interest. An alternative is to collect detailed information on smoking habits and to compare the effect of the suspected carcinogens across different groups of smokers. This approach has shown that tobacco smoking as a confounder rarely completely explains excess risks larger than about 50%.
Interaction Between Tobacco Smoke and Other Lung Carcinogens
Other carcinogens may interact with tobacco smoke in the determination of their carcinogenic action on the lung. In other words, the absolute or relative risk from exposure to another agent may be greater (or smaller) among heavy smokers compared with the corresponding risk among light smokers and nonsmokers. The interaction may take place at the stage of exposure; that is, the other agent has to be absorbed on the tobacco particles to penetrate the lung. Or it may take place at some stage of the carcinogenic process, for example, on induction of common metabolic enzymes or activation of common molecular targets. The empirical evidence for an interaction between tobacco smoking and other agents is scanty, mainly because of lack of data among light smokers and nonsmokers. The interaction between asbestos exposure and tobacco smoking falls between the additive and the multiplicative model. The interaction between radon exposure and tobacco smoking best fits a submultiplicative model; data for other agents are too sparse to allow conclusions.
Use of Smokeless Tobacco Products
Few studies have investigated the risk of lung cancer among users of smokeless tobacco products. In two large cohorts of US volunteers, the relative risk of lung cancer associated with spit tobacco use among nonsmokers was 1.08 (95% confidence interval [CI], 0.64–1.83) and 2.00 (95% CI, 1.23–3.24). In a Swedish cohort, the relative risk of lung cancer for every use of snus was 0.80 (95% CI, 0.61–1.05). In a large case–control study from India, the relative risk of lung cancer for every use of tobacco-containing chewing products was 0.74 (95% CI, 0.57–0.96). Overall, the evidence of an increased risk of lung cancer from use of smokeless tobacco products is weak; the apparent protective effect detected in studies including smokers may be due to uncontrolled negative confounding.
Dietary Factors
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