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Epidemiology of Lung Cancer^*

^* From the Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD.

Correspondence to: Anthony J. Alberg, PhD, MPH, Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe St, Baltimore, MD 21205; e-mail: aalberg{at}jhsph.edu

	Abstract

TOP Abstract Introduction Patterns of Occurrence The Etiology of Lung... Environmental and Occupational... Host Factors Conclusions References

 
In the United States, lung cancer remains the leading cause of cancer death in both men and women even though an extensive list of risk factors has been well-characterized. Far and away the most important cause of lung cancer is exposure to tobacco smoke through active or passive smoking. The reductions in smoking prevalence in men that occurred in the late 1960s through the 1980s will continue to drive the lung cancer mortality rates downward in men during the first portion of this century. This favorable trend will not persist unless further reductions in smoking prevalence are achieved.

Key Words: air pollution • asbestos • cigarette smoking • epidemiology • lung cancer • nutrition • passive smoking • occupation • radiation • tobacco

	Introduction

TOP Abstract Introduction Patterns of Occurrence The Etiology of Lung... Environmental and Occupational... Host Factors Conclusions References

 
Epidemiologic evidence is the foundation for primary and secondary disease prevention. Epidemiologic approaches are used to track the occurrence of disease, to characterize natural history, and to identify determinants of disease. The benefits of intervention programs, whether based in risk factor interventions or screening, also are assessed using epidemiologic approaches. For lung cancer, routine mortality statistics have confirmed the clinical impression that the disease became more frequent during the first half of the 20th century. Case-control and cohort studies,^{1 2 3} the epidemiologic study designs that are used to evaluate exposure-disease associations, causally linked smoking to lung cancer in investigations reported from the 1950s forward. As we have continued to follow lung cancer incidence and mortality rates, we have readily shown that their rise and decline parallel past trends of cigarette smoking.⁴ The epidemiologic evidence and the complementary biological understanding of respiratory carcinogenesis have unassailably supported the conclusion that smoking causes lung cancer. Epidemiologic findings are also relevant to patient care, as skilled clinicians weigh alternative diagnoses depending on the risk factor profiles of patients.

This article provides a summary of the epidemiologic evidence on lung cancer, with an emphasis on issues that are currently relevant to prevention. This literature is now extraordinarily large, and we have not attempted to conduct a comprehensive review and systematic synthesis. Such syntheses have been periodically carried out by expert review groups, including the committees assembled to prepare the US Surgeon General’s reports on smoking and health, and other federal documents and expert committees of other governments and organizations, including the Royal College of Physicians and the Scientific Committee on Tobacco of the United Kingdom, and the International Agency for Research on Cancer (IARC) of the World Health Organization. Several relevant reports can be anticipated from these groups, including the 2002 and 2003 reports of the US Surgeon General addressing active and passive smoking, respectively, and a planned new IARC monograph on tobacco smoking. The general topic was reviewed in a 1994 monograph.⁵

At the end of the 20th century, lung cancer had become one of the world’s leading causes of preventable death.⁶ It was a rare disease at the start of that century, but exposures to new etiologic agents and an increasing lifespan combined to make lung cancer a scourge of the 20th century. While tobacco had been widely used throughout the world for centuries, the present 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.⁷ German scientists in Nazi Germany conducted some of the earliest research on the links between smoking and lung cancer.⁸ By the early 1950s, epidemiologic studies^{9 10 11} in Britain and the United States using the case-control method had shown that cigarettes were strongly associated with the risk of lung cancer. This association was corroborated by the pioneering cohort studies of British physicians, US veterans of the armed forces, and volunteers recruited by the American Cancer Society.¹² By 1964, the evidence was sufficient to support a conclusion by the US Surgeon General that cigarette smoking caused lung cancer.¹² The Royal College of Physicians had reached the same conclusion 2 years previously.¹³ Passive smoking, the involuntary inhalation of tobacco smoke by nonsmokers, also has been found to cause lung cancer.^{14 15}

While its predominant cause is now well-known (ie, tobacco smoking), there are other causes as well, some acting in concert with smoking to synergistically increase risk. The suspicion that radon was a cause of lung cancer in underground miners, which was raised early in the century, led to what was probably the first occupational respiratory carcinogen to be identified.¹⁶ Radon in indoor environments is now considered to be a significant cause of lung cancer.¹⁷ The list of human occupational causes of lung cancer also includes arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, and other agents.¹⁸ Outdoor air pollution, which includes combustion-generated carcinogens, is also considered to contribute to the lung cancer burden in urban dwellers. Indoor air contains several respiratory carcinogens, including radon, asbestos, and cigarette smoke. In some developing countries, exposure to fumes from cooking stoves and fires is associated with lung cancer risk. Beginning in the 1980s, associations of diet with lung cancer risk have been vigorously investigated with the anticipation that dietary micronutrients might be found that modify the high lung cancer risk in smokers. The biological basis for the prevention of cancer through supplementation of micronutrients is addressed in another article in this supplement.

Even though the epidemiology of lung cancer has been extensively investigated for > 50 years, there are still active areas of research, some quite relevant to prevention. Investigation of lung cancer and diet continues, using both observational and experimental approaches, and concern remains over the risk of indoor and outdoor pollutants including, for example, radon and diesel emissions. There also has been a need for research to track the risks of smoking over time, as the cigarette has evolved in its design characteristics and yields of tar and nicotine, as assessed by standard protocol using a machine, have declined since the 1950s. The histologic characteristics of lung cancer in a number of developed countries, including the United States, also have changed in recent decades so that the frequency of adenocarcinoma has risen and that of squamous cell carcinoma has declined.⁴ There is also emerging evidence on the genetic determinants of lung cancer risk. A current research approach, termed molecular epidemiology, melds the population and laboratory tools that are used to address susceptibility to environmental carcinogens. While the evidence from the "traditional" epidemiologic approaches conclusively established the carcinogenicity of tobacco smoke, molecular epidemiology should characterize the sequence of molecular and cellular changes as a nonmalignant cell becomes malignant and the factors determining susceptibility to tobacco smoke. Biomarkers of exposure, dose, susceptibility, and genetic damage may allow epidemiologic investigations to uncover specific pathways of human lung carcinogenesis.

	Patterns of Occurrence

TOP Abstract Introduction Patterns of Occurrence The Etiology of Lung... Environmental and Occupational... Host Factors Conclusions References

 
Temporal Trends
Because of the high case-fatality rate of lung cancer, the incidence and mortality rates are nearly equivalent, and, consequently, routinely collected vital statistics provide a long record of the occurrence of lung cancer. We are presently amid an epidemic of lung cancer that dates to the mid-20th century (Fig 1 ).^{19 20 21} Lung cancer was rare until the disease began a sharp rise around 1930 that culminated by mid-century with lung cancer becoming the leading cause of cancer death among men.²² The epidemic among women followed that among men, with a sharp rise in rates from the 1960s to the present, propelling lung cancer to become the most frequent cause of female cancer mortality.²² The epidemic among women not only occurred later, but will not peak at as high a level as that among men because smoking prevalence crested at substantially higher levels among men than among women.^{4 23 24}

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Lung cancer mortality rates for the United States from 1930 to 1998, age-standardized to the 1970 US population. Adapted from Gordon et al,19 and Mckay et al,20 and Ries et al.21

View larger version (26K): [in this window] [in a new window] [Download PPT slide]   Figure 2. US age-specific mortality rates (white men and women) by 2-year age intervals from 26 to 27 years of age through 48 to 49 years of age, plotted against the birth cohort. Adapted from the American Cancer Society.22

Lung cancer mortality rates among Hispanics, Native Americans, and Asians/Pacific Islanders are significantly lower than rates among AfricanAmericans and non-Hispanic whites.³⁰ Nevertheless, lung cancer occurs sufficiently often among these groups to pose a considerable public health burden.

Geographic Patterns
Lung cancer is the most commonly diagnosed cancer worldwide,³⁰ but its geographic distribution shows marked regional variation.³¹ The global variation in age-standardized incidence rates is greater than fourfold among men, and a fivefold among women (Fig 3 ).³² Because of differences in cancer registration between countries, caution is needed in interpreting these data. However, 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.³³ The low rates of lung cancer in Africa³⁴ are comparable to United States rates in 1930, when rates of lung cancer were under 5 cases per 100,000 for both sexes.¹⁹ In contrast, African-Americans in the United States, an epicenter of the disease, now experience lung cancer incidence rates that are among the highest in the world. As the lung cancer epidemic begins to subside in the developed countries, it is on the rise in the developing world.³⁵

View larger version (79K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Age-adjusted lung cancer death rates from 1986 to 1988 per 100,000 population for men and women. Adapted from The National Cancer Institute.22

Substantial geographic variation in lung cancer mortality rates also has been observed within countries. Trends in its regional distribution can provide 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.³⁶ Later on, several hypotheses^{37 38} were prompted by patterns observed in a systematic review of US lung cancer mortality rates for the period 1950 to 1969,³⁹ particularly the rates among men. For example, high lung cancer rates in coastal areas were postulated to reflect employment in shipyards with attendant asbestos exposure. This hypothesis then was tested in a series of population-based, case-control studies, which showed that employment in the shipbuilding industry was indeed associated with an excess risk of lung cancer.⁴⁰ Another shift then took place in the distribution of lung cancer within the United States, with lung cancer mortality rates among white men becoming highest in the South and lower in the Northeast.⁴¹ This fluidity in the geographic variation underscores the value of regularly monitoring lung cancer mortality patterns.

	The Etiology of Lung Cancer

TOP Abstract Introduction Patterns of Occurrence The Etiology of Lung... Environmental and Occupational... Host Factors Conclusions References

 
Overview
Although the causes of lung cancer are almost exclusively environmental, it is likely that there is substantial individual variation in the susceptibility to respiratory carcinogens. The risk of the disease can be conceptualized as reflecting the joint consequences of the interrelationship between (1) exposure to etiologic (or protective) agents and (2) the individual susceptibility to these agents. The term environment in its broadest sense may influence the risk of disease through direct exposures or indirectly by affecting the likelihood of exposure to exogenous agents. Given the multifactorial etiology of lung cancer, synergistic interactions among risk factors may have substantial consequences for lung cancer risk. These interactions typically have been considered on an agent-by-agent basis, as for example the synergistic effect of cigarette smoking on the lung cancer risk from asbestos exposure.⁴² Our emerging understanding of cancer genetics indicates the additional relevance of gene-environment interactions.

When the environment is considered more holistically, an even broader set of interactions can be proposed. For example, socioeconomic status is associated with a constellation of the following interacting determinants of lung cancer risk: smoking; diet; and exposures to inhaled agents in the workplace and general environment. Lower socioeconomic status is associated with an unfavorable profile for all of these factors. Risk factor patterns at the individual and societal levels identify persons and populations at high risk and can be used to target prevention approaches toward those who are at greatest risk.

Given the many risk factors that have been identified for lung cancer, a practical question is the relative contribution of these factors to the overall burden of lung cancer. The "population attributable risk" approach takes into account the magnitude of the relative risk that is associated with an exposure along with the likelihood of exposure in the general population. Because of the interactions between exposures, the combined population attributable risk for diseases such as lung cancer that have a well-characterized set of important risk factors can exceed 100%. As reviewed below, population attributable risk estimates for lung cancer indicate that in the United States, active smoking is responsible for 90% of lung cancer cases, occupational exposures to carcinogens account for approximately 9 to 15% of lung cancer cases, radon causes 10% of lung cancer cases,¹⁷ and outdoor air pollution accounts for perhaps 1 to 2% of lung cancer cases.⁴³ The precise contribution of nutritional factors remains to be determined, but dietary factors have been hypothesized to account for approximately 20% (range, 10 to 30%) of the lung cancer burden.⁴⁴

	Environmental and Occupational Agents

TOP Abstract Introduction Patterns of Occurrence The Etiology of Lung... Environmental and Occupational... Host Factors Conclusions References

 
Smoking
Overview:
A single etiologic agent, cigarette smoking, is by far the leading cause of lung cancer, accounting for approximately 90% of lung cancer cases in the United States and other countries where cigarette smoking is common.⁴⁵ Compared to never-smokers, smokers have about a 20-fold increase in lung cancer risk at present. Few exposures to environmental agents convey such risks for any disease. In general, trends of lung cancer occurrence closely reflect patterns of smoking, but rates of occurrence lag smoking rates by about 20 years. Analyses using statistical modeling techniques show a tight association between national mortality rates and smoking.⁴⁶ The unequivocal causal association of cigarette smoking with lung cancer is one of the most thoroughly documented causal relationships in biomedical research.^{7 47}

The burden of lung cancer that is attributable to smoking has been extensively documented. Using an attributable risk approach, the Centers for Disease Control and Prevention has documented the numbers of deaths caused in the United States by smoking-related lung cancer. For 1990, that number was 117,000.⁴⁸ Peto et al⁴⁵ have used a different attributable risk method to quantify the burden of smoking-related deaths from lung cancer in the major developed countries. For 1990, the US total was 127,000 deaths, which was the highest in the world, with country-specific estimates ranging down to 150 deaths for Tajikistan. The total number of smoking-related deaths for the developed countries was 457,371.⁴⁵ Peto and colleagues forecast a staggering future burden for China, which now has one third of the worlds smokers.⁴⁹ The numbers are predicted to reach several millions by mid-century.

Cigar smoking is also an established cause of lung cancer.⁵⁰ The lung cancer risks associated with cigar smoking are substantial, but are less than the risks observed for cigarette smoking due to differences in smoking frequency and depth of inhalation. The same pattern holds true for pipe smoking.⁵¹

Quantitative Risks:
The risk of lung cancer among cigarette smokers increases with the duration of smoking and the number of cigarettes smoked per day^{48 52} (Table 2 ). This observation has been made repeatedly in cohort and case-control studies. Risk models have been derived to quantitatively estimate how lung cancer risk varies with the number of cigarettes smoked, the duration of smoking, and age. Such models are useful for estimating the future burden of lung cancer under various scenarios of tobacco control. In one widely cited analysis, Doll and Peto⁵² proposed a quantitative model for lung cancer risk based on data from the cohort study of British physicians. This model predicted a stronger effect of duration of smoking than of 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 the duration of smoking was estimated to increase the lung cancer risk 100-fold.⁵³ These quantitative dimensions of the dose-response relationship between smoking and lung cancer have implications concerning the now widespread occurrence of smoking among youths. Those persons starting to smoke at younger ages have a greater likelihood of becoming heavier smokers and remaining smokers.⁵⁴ The exponential effect of the duration of smoking on lung cancer risk markedly increases the lifetime risk for those who become regular smokers in childhood. Thus, those who initiate smoking earlier in life are most likely to develop lung cancer and are most likely to do so at younger ages. Prevention approaches that delay the age of onset of smoking in a population could have a substantial impact on the incidence of lung cancer by shortening the duration of smoking. In considering the likelihood of lung cancer in a particular patient, clinicians should give more weight to the duration of smoking and less weight to actual age.

A concomitant shift toward lowered levels of tar and nicotine, as measured by a smoking machine, has occurred (Fig 4 ). Cigarette tar is the label given to the condensable residue of cigarette smoke (ie, the total particulate matter from cigarette smoke that is deposited on the filter machine’s less the moisture and nicotine). Tar is a complex mixture that includes many chemicals that are cancer initiators and/or promoters.⁵⁹ Tar and nicotine yields are measured with a smoking machine according to a standardized protocol established by the Federal Trade Commission (FTC) that specifies such details as puff volume, the frequency of puffing, and the length to which the cigarette is to be smoked.⁶⁰

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Sales-weighted average tar and nicotine deliveries, 1954 to 1993. Adapted from US Department of Health and Human Services.59

The gradual reduction in tar yield over recent decades would be expected to have reduced smokers’ exposures to carcinogens if the FTC test protocol were predictive of carcinogen doses that are delivered to the lung.⁵⁹ However, questions remain as to whether the FTC test method is informative with regard to lung cancer risk, or to the risks of smoking-caused diseases more generally.^{63 64} Epidemiologic studies have been carried out to assess whether the seemingly substantial changes in tar and nicotine yield, as measured by the FTC protocol, have resulted in parallel changes in the risk of smoking. Epidemiologic studies have been the key source of information, because they can provide direct evidence on the risks of smoking cigarettes as they are actually smoked during use, including any compensatory behavior.

For lung cancer, and for other diseases, two lines of epidemiologic data have been available on the changes in smoking products. The first line of data comes from case-control studies that compared the smoking history profiles of persons developing lung cancer over the several-year period of case accrual with those of concomitantly selected control subjects, and the second line of data comes from cohort studies that have tracked the risk of lung cancer over time, as the products being smoked changed. These studies have provided temporally cross-sectional assessments, but have not provided insights into the consequences of smoking one product or another across the full time period of smoking. In fact, smokers change the products that they smoke and the product characteristics continue to change over time as well. Consequently, researchers cannot compare the risks of smoking one type of cigarette across decades with that of smoking another. Because of these methodological issues, the epidemiologic data need to be interpreted cautiously.⁶³

Some epidemiologic data, coming primarily from case-control studies, suggest that filtered cigarettes and lower tar yields slightly reduce the risk of lung cancer associated with cigarette smoking compared to unfiltered cigarettes (Table 4 )^{52 53 54 55 56 57 58 59 60 61 62 65 66 67 68 69 70 71 72 73 74 75} or to higher tar yields (Table 5 ).^{69 74 75 76 77 78 79 80}

In a 1976 publication, Hammond and colleagues⁷⁹ compared the mortality risks from lung cancer and other diseases by the tar yield of products smoked by participants in the American Cancer Society Cancer Prevention Study (CPS) I participants. The follow-up interval spanned the years 1960 to 1972. Smokers were placed into the following three categories of cigarette products smoked: low yield, < 17.6 mg per cigarette; high yield, 25.8 to 35.7 mg per cigarette; and medium yield, intermediate. The standardized mortality rate for lung cancer in low-yield and medium-yield smokers was approximately 80% of the rate in high-yield smokers. A further analysis of tar yield using the same data set confirmed that the risk for lung cancer death increased with tar yield.^{81 82 83}

This study only provided a comparison of risks across the 12 years of follow-up from 1960 to 1972. Further insights have been gained by comparing the risks in the two CPS studies of the American Cancer Society. This comparison addressed whether the risks have changed, comparing smokers who developed the disease between 1960 and 1972 with a similar group who developed the disease during the initial follow-up of CPS II, from 1980 to 1986.^{84 85} If the risk for lung cancer that is associated with smoking is decreasing over time, the expectation would be that risks for smokers would be less in CPS II than in CPS I. In fact, the opposite was observed, with increasing lung cancer mortality in male and female smokers in CPS II compared with CPS I (Fig 5 ).⁸⁶ While differences in smoking patterns may partially explain the increased lung cancer mortality, comparing CPS I and CPS II, male smokers in CPS II had substantially higher lung cancer mortality rates than their counterparts in CPS I.⁸⁶

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Age-specific death rates from lung cancer among current cigarette smokers and lifelong never-smokers based on smoking status at enrollment in the CPS I or CPS II, according to attained age. Adapted from Thun et al.86

Several expert panels have recently reviewed the findings. Stratton et al⁸⁸ for the Institute of Medicine carried out a comprehensive review on various harm-reduction strategies for reducing the disease burden caused by smoking, including the smoking of lower yield cigarettes. There are also new products in various phases of development that are intended to deliver nicotine without the direct combustion of tobacco. The Institute of Medicine report concluded that smoking lower yield products had not been shown to benefit the health of smokers.

This topic was also addressed in the National Cancer Institute monograph, Risks Associated with Smoking Cigarettes with Low Machine-Measured Yields of Tar and Nicotine.⁶³ This monograph provides a comprehensive review of the topic as well as new analyses of the CPS I data. The report proposes that the net consequences of having lower yield products needs consideration, along with any change in the risk of disease to smokers. If some persons start smoking or continue to smoke because they view the smoking of lower yield cigarettes as having a more acceptable level of risk, then the success of tobacco control interventions may be lessened. The report also found that compensatory changes in smoking patterns reduce any theoretical benefit of lower yield products. Overall, the report concluded that changes in cigarette design and manufacturing over the last 50 years had not benefited public health.

Passive Smoking:
Passive smokers inhale a complex mixture of smoke that is now widely referred to as environmental tobacco smoke (ETS). 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. Hirayama⁸⁹ reported the findings from a cohort study in Japan, which showed that among nonsmoking women, those whose husbands smoked cigarettes were at higher risk for lung cancer than those whose husbands were nonsmokers. A case-control study in Athens reported by Trichopoulos and colleagues⁹⁰ shortly thereafter replicated this finding. Additional evidence rapidly accrued so that by 1986 two important summary reports were published. The National Research Council reviewed the epidemiologic evidence and concluded that nonsmoking spouses who were married to cigarette smokers were about 30% more likely to develop lung cancer than nonsmoking spouses who were married to nonsmokers, and that this relationship was biologically plausible.⁹¹ Almost one fourth of lung cancer cases among never-smokers were estimated to be attributed to exposure to passive smoking.⁹¹ The 1986 report of the Surgeon General also judged passive smoking to be a cause of lung cancer,¹⁴ an inference corroborated by the 1992 review¹⁵ of the evidence and risk assessment by the US Environmental Protection Agency, which classified ETS as a known human (class A) carcinogen. Estimates indicate that passive smoking accounts for approximately 3,000 lung cancer deaths per year in the United States.¹⁵

Since these conclusions were reached, several major studies have been carried out to further characterize 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 potentially confounding factors.^{92 93}

Passive smoking is more weakly associated with lung cancer than is active smoking, as would be expected given the generally lower doses of carcinogens that are received passively by the lung of the nonsmoker compared to the doses received by the active smoker. Because of broad societal implications, the conclusion that this association is causal has been controversial.^{94 95} Questions have been raised about the methodology of the epidemiologic studies, including confounding and the misclassification of exposures to environmental tobacco smoking. Review groups have concluded^{14 15 91} that the association between ETS and lung cancer cannot be attributed to the methodological limitations of epidemiologic data.

Studies have been directed at the specific venues where nonsmokers are exposed to tobacco smoke, including the home, workplaces, and public places. Much of the literature has focused on the increased risk associated with being married to a smoker, an exposure variable that can be readily ascertained. Meta-analyses have been conducted periodically to summarize the evidence from the epidemiologic studies. A 1997 meta-analysis by Law and colleagues⁹⁶ found an approximately 20% increased risk associated with marriage to a smoker. This excess risk appeared to be due to exposure to passive smoking since it could not be explained by confounding or misclassification.

Reynolds⁹⁷ summarized the evidence on workplace exposure to secondhand smoke and lung cancer risk. In general, the estimates have indicated the existence of an increased risk associated with exposure, although they are imprecise due to a limited numbers of cases. There is also coherence between model-based estimates derived by combining risk estimates from studies of exposure to smoking by husbands and monitoring data from workplaces.⁹⁸

The studies of passive smoking provide further evidence documenting the dose-response relationship between cigarette smoke and lung cancer. The doses extend to far lower levels than those of active smoking, and increased risk is observed, suggesting that there is no threshold for tobacco carcinogenesis.¹⁴

Lung Cancer Histopathology:
Lung cancer occurs in multiple histologic types as classified by conventional light microscopy. The four major types include squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell undifferentiated carcinoma. Together, these four types of lung cancer account for > 90% of lung cancer cases in the United States.⁹⁹ Despite extensive research, the mechanisms leading to these different types of lung cancer remain uncertain. Hypotheses have focused on the cells of origin of lung cancers and on the pathways of differentiation of malignant cells.^{17 99} Smoking has been shown to cause each of the major histologic types of lung cancer, although the dose-response relationship with the number of cigarettes smoked varies across the types and is steepest for small cell undifferentiated carcinoma.^{57 100 101} There are a few suggestive links of histologic type with occupational agents. Small cell lung cancer has been reported to be in excess in workers who have been exposed to chloromethyl ethers and in underground miners who have been exposed to radon progeny.^{17 99}

In the initial decades of the smoking-caused epidemic of lung cancer, squamous cell carcinoma was the most frequent type of lung cancer that was observed in the population among smokers, and small cell carcinoma was the next most frequent. In the late 1970s, the first evidence of a shift toward a predominance of adenocarcinoma was noted,^{99 102 103} and now adenocarcinoma of the lung is the most common histologic type of lung cancer.^{4 28} The decline in lung cancer rates has been more rapid for squamous cell and small cell carcinomas than for adenocarcinoma, which is just beginning to show a lower incidence rate (Fig 6 ).⁴ In women, the Surveillance, Epidemiology, and End Results program data from 1973 to 1996 indicate that the incidence rates of squamous cell, small cell, and large cell carcinomas have at least reached a plateau while the rate for adenocarcinoma is still rising.

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Surveillance, Epidemiology, and End Results incidence rates of cancer of the lung and bronchus by histologic type, sex, race, and ethnicity for all ages, 1973 to 1996. Adapted from Wingo et al.4

Hypotheses concerning the shift in histopathology have focused on the potential role of changes in the characteristics of cigarettes and the consequent changes in the doses of carcinogens inhaled.^{60 101 105} Puff volume likely has increased over recent decades with the possibility that patterns of deposition in the lung have changed, tending toward enhanced deposition of tobacco smoke in the peripheral airways and alveoli.¹⁰⁵ The levels of nitrate, which enhances the combustion of tobacco, also have increased in tobacco smoke. While more complete combustion decreases the concentrations of polycyclic aromatic hydrocarbons, the increased production of nitrogen oxides contributes to the increased formation of tobacco-specific nitrosamines. An increase in the dose of the potent tobacco-specific nitrosamine NNK has been postulated as one factor leading to the increase in adenocarcinoma.^{105 106} NNK induces lung carcinomas, predominantly adenomas and adenocarcinomas, in mice, regardless of the route of administration.¹⁰⁶

Few studies can provide data to test these hypotheses because of the need for longitudinal observation of lung cancer risk in relation to the characteristics of the cigarettes smoked over time. Thun et al¹⁰⁴ compared the risks for lung cancers of different histologic types among participants in CPS I and CPS II of the American Cancer Society. They found markedly rising risks for adenocarcinoma of the lung to be associated with smoking in both men and women over the approximately 20 years separating the two studies. Thun et al¹⁰⁴ concluded that "the increase in lung adenocarcinoma since the 1950s is more consistent with changes in smoking behavior and cigarette design than with diagnostic advances."

The hypothesis has been advanced that women may have a greater risk of lung cancer than men at the same level of smoking. Hypotheses have been based on possible hormonally related differences in response to carcinogens. The evidence is limited and mixed, and the 2001 Report of the Surgeon General¹⁰⁷ did not reach a conclusion on this issue.

Diet
Overview:
The dietary factors that have received greatest emphasis in studies of diet and lung cancer, namely fruits, vegetables, and specific antioxidant micronutrients, are the focus of this summary. These are the research areas that also presently appear to have the greatest implications for lung cancer prevention. Much of the research on diet and lung cancer has been motivated by the hypothesis that diets high in antioxidant nutrients may protect against oxidative DNA damage and thereby protect against cancer.¹⁰⁸

Within this limited range of topics, we have attempted to be comprehensive in our review. We omitted studies with lung cancer mortality as the end point, as different factors may be associated with survival of lung cancer than disease risk. We limited our consideration of specific micronutrients to retinol, total carotenoids, ß-carotene, and vitamin C. For these postulated relationships, there is no reason to suspect a threshold effect in the exposure-response relationship. Rather, a dietary factor that protects against lung cancer would theoretically be expected to confer greater protection when present in greater amounts. Consequently, dose-response trends are emphasized in this review, with the presence of a monotonic dose-response relationship considered to provide strong evidence favoring an association, and measures of association in the protective direction but with no dose-response gradient providing weak evidence in favor of an association.

The overwhelming contribution of cigarette smoking as a cause of lung cancer imposes challenges to detecting the role that other lifestyle factors, such as diet, may play in the etiology of lung cancer. Cigarette smoking is so closely associated with less healthful lifestyles, such as less healthful diets,^{109 110 111 112 113} that it is often difficult to discern whether the dietary factors of interest have truly been disentangled from the effects of smoking. Compounding this problem, even associations between dietary factors and lung cancer that truly exist are likely to be very weak in relation to smoking. Even for a dietary factor such as vegetable consumption (reviewed below), which is fairly consistently associated with a lower risk of lung cancer, the highest exposure category is usually associated with, at most, a halving in the risk of lung cancer. In many instances, the potential residual confounding effects of smoking could thus plausibly be strong enough to explain the observed associations between dietary factors and lung cancer.¹¹⁴ In the future, studies that control for cigarette smoking in the design are best suited to address the persistent concern about residual confounding by cigarette smoking. Examples are case-control studies, in which cases and control subjects are closely matched on cigarette smoking history, and studies limited to never-smokers.

Fruit and Vegetable Consumption:
In case-control studies, fruit consumption has been clearly protective in 4 studies,^{115 116 117 118} suggestive of a protective association in 4 other studies,^{119 120 121 122} and not protective in 10 studies.^{123 124 125 126 127 128 129 130 131 132} In prospective studies, fruit consumption has been clearly protective in three studies,^{133 134 135} suggestive of a protective association in two other studies,^{136 137} and not protective in two studies.^{138 139} The combined evidence for fruit consumption is far from consistent but hints at the possibility of a protective association.

The evidence favoring a protective association is more consistent for vegetable consumption. In case-control studies, 12 studies showed a decreased lung cancer risk as vegetable consumption increased,^{115 116 117 123 124 125 127 129 132 140 141 142} while 5 other studies showed a weak association in this direction.^{93 118 126 143 144} A protective association was absent in only six studies.^{119 120 121 128 131} In prospective studies, vegetable consumption was clearly protective in two studies,^{134 137} was suggestive of a protective association in two other studies,^{135 138} and was not protective in two studies.^{133 136}

Micronutrients:
Two different strategies used to evaluate the relationship of micronutrients to lung cancer are (1) using data summarized from food-frequency questionnaires to estimate micronutrient intake and (2) drawing blood samples from study participants and assaying the concentrations of micronutrients in circulation. The former approach provides a better average measure of micronutrient "exposure," whereas the latter approach has the advantage of measuring micronutrient concentrations closer to the cellular level where the postulated biological effect occurs. As mentioned above, we focused on vitamins A and C, total carotenoids, and ß-carotene.

Evidence consistent with higher dietary retinol intake being associated with a reduced risk of lung cancer in at least one subgroup has been observed in only 11 studies,^{122 145 146 147 148 149 150 151 152 153 154} with 17 studies not providing supportive evidence.^{118 121 124 125 126 129 132 133 140 143 155 156 157 158 159 160 161} Circulating retinol concentrations also have not been consistently associated with protective associations.^{162 163 164 165 166 167 168 169 170 171 172}

In contrast to the results for retinol, the results for total carotenoids, ß-carotene, and vitamin C are more supportive of a reduction in lung cancer risk. Higher dietary intake of total carotenoids were consistent with a protective association in 18 observational studies^{119 121 122 125 126 132 135 139 143 146 150 153 155 156 161 173 174 175} and were not supportive in 6 studies.^{124 129 133 137 157 166} Circulating concentrations of total carotenoids have been linked to a reduced risk of lung cancer.^{163 172} Similar protective associations have also consistently been observed for a specific carotenoid, ß-carotene. Data from 16 case-control and cohort studies^{93 118 122 125 126 129 135 137 139 140 148 154 160 176 177 178} of dietary ß-carotene intake were compatible with associations in the protective direction. In only five studies^{121 124 134 138 152} have null findings been observed. Further bolstering the evidence in favor of a protective association between ß-carotene and lung cancer are prospective studies in which ß-carotene is assayed from blood that has been collected from a population that was initially cancer-free and was subsequently followed-up for the occurrence of lung cancer.^{163 166 168 169 172 179 180} The preponderance of evidence from observational studies thus has demonstrated a protective association between carotene (specifically, ß-carotene) and lung cancer.

The evidence for the protective association of vitamin C is less abundant than for total carotenoids and ß-carotene but also is suggestive of a protective association. For vitamin C intake, six case-control or cohort studies^{133 150 155 156 157 178} were at least compatible with an inverse association with lung cancer risk, whereas three studies were not.^{93 124 176} A serologic study of ascorbic acid concentrations and lung cancer was also compatible with a protective association.¹⁷⁹

Chemoprevention Trials:
The experimental rationale for trials of ß-carotene and retinoids is offered in another article in this supplement. These data indicated a potential for prevention with these agents, as supported by observational data as well. However, a protective association between ß-carotene and lung cancer was not found in three randomized, double-blind, placebo-controlled chemoprevention trials^{181 182 183} of ß-carotene, which indicated that ß-carotene supplementation does not protect against lung cancer. In fact, ß-carotene supplementation was associated with an increased risk of lung cancer among the high-risk populations of heavy smokers in the -Tocopherol ß-Carotene Cancer Prevention Study¹⁸¹ and of smokers and asbestos-exposed workers in the Carotene and Retinol Efficacy Trial.¹⁸³

In summary, people who eat more vegetables are at lower risk of lung cancer than persons who consume fewer vegetables. The same may also apply to fruit consumption, but the evidence is less clear-cut. The specific constituents of vegetables that confer protection are not known. The results of the chemoprevention trials clearly suggest a more complex role than researchers had previously thought. These trials also emphasize that we do not know whether the associations present in observational studies are specific to the micronutrients or whether the micronutrient measurements are merely serving as a marker of the intake of other protective substances or even of more healthful dietary habits in general.

If the association is attributable to vegetable consumption, we need to determine whether this effect applies globally to vegetable consumption or to specific classes of vegetables or specific vegetables. For example, carrots^{115 137 140 144 146} and tomatoes^{118 119 137 140 146} are associated with a reduced risk of lung cancer, at least for the highest vs the lowest categories of consumption. Resolving this question also will help to clarify whether specific biochemical constituents that are present in vegetables confer protection against lung cancer or whether the complex mixture that comprises vegetables leads to the net protective effect. Reports from large-scale prospective cohort studies that considered overall fruit and vegetable consumption as well as classes of vegetables (eg, cruciferous, brassica) and also individual micronutrients^{138 138} exemplify the comprehensive approach that affords the greatest opportunity to pinpoint the specific foods and/or nutrients that may explain the apparent protective association with vegetable consumption.

Environmental Exposures
Occupational Exposures:
Investigations of occupational groups, who often are heavily exposed over a long time to workplace agents, have provided a substantial understanding of the carcinogenicity of a number of chemicals and physical agents. Among cancers that are associated with occupational exposures, cancer of the lung is the most common.¹⁸⁴ Estimates derived from case-control studies of the proportion of lung cancer that is contributed to by occupational exposures, via independent or shared causal pathways, have ranged widely, but most point estimates or ranges have included values from 9 to 15%.^{185 186 187 188 189 190 191} While disagreement persists concerning specific estimates,¹⁹² the following message is clear: in industrialized nations the contribution of occupational exposures to the lung cancer burden is small compared to that of cigarette smoking, but it is large compared to the contributions of most other exposure classes. Cigarette smoking potentiates the effect of many of the known occupational lung carcinogens.⁴²

Lung cancer has been observed to be associated with many workplace exposures. Workers exposed to tar and soot (which contains benzo[a]pyrene), such as coke oven workers,^{193 194} in concentrations exceeding those present in urban air¹⁹⁵ are at increased risk of lung cancer. Occupational exposures to a number of metals, including arsenic,^{196 197 198} chromium,^{199 200 201} and nickel,^{202 203 204} are also causes of lung cancer.^{205 206} For many persons in the worker groups that have been exposed to these agents, there were substantial increments in risk. However, in developed countries these hazards largely have been controlled.

For some other workplace agents, the evidence has been less clear. The results of numerous case-control and cohort studies²⁰⁷ are compatible with a weak association between exposure to diesel exhaust and the development of lung cancer. Although inadequate control of cigarette smoking limits the inferences that can be drawn from many of these studies, the exposure to diesel exhaust remains a likely explanation for these findings.²⁰⁷ This association remains a public health concern, as the public is exposed to diesel exhaust in urban areas, and in some European countries diesel vehicles are being used increasingly.⁴³

The question of whether silica dust is a risk factor for lung cancer has been controversial.^{208 209 210} A twofold increase in lung cancer risk was estimated from a meta-analysis²¹¹ of the relationship between silicosis and lung cancer mortality. Effects of smoking have not been well-controlled in most of the studies.²¹¹ The evidence on silica exposure, absent consideration of the presence of silicosis, is less clear.^{212 213} In 1997, IARC did classify crystalline silica as a human carcinogen²¹⁴ ; however some still continue to question its carcinogenicity²¹³ and the role of silica exposure vs that of fibrosis in persons with silicosis.²¹²

Asbestos:
Asbestos, a well-established occupational carcinogen, refers to several forms of fibrous, naturally occurring silicate minerals.²¹⁵ The epidemiologic evidence dates to the 1950s, although clinical case series had previously led to the hypothesis that asbestos causes lung cancer.^{216 217} In a retrospective cohort study published in 1955, Doll²¹⁸ observed that asbestos textile workers at a factory in the United Kingdom had a 10-fold elevation in lung cancer risk and that the risk was most heavily concentrated during the time frame before regulations had been implemented to limit asbestos dust in factories. A sevenfold excess of lung cancer was subsequently observed among insulation workers in the United States.^{219 220} The peak incidence occurred 30 to 35 years after the initial exposure to asbestos (Fig 7 ).²²¹ The risk of lung cancer has been noted to increase with increased exposure to asbestos²²² and to be associated with the principal commercial forms of asbestos.²²³ Whether asbestos acts directly as a carcinogen or through indirect mechanisms such as causing chronic inflammation that eventually leads to cancer development remains uncertain.^{224 225}

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 7. Frequency distribution of the number of lung cancer cases by time since asbestos exposure began among a cohort of asbestos insulation workers. Adapted from Selikoff.221

The following two types of radiation, which are classified by the rate of energy transfer to the tissue, are relevant to lung cancer: low linear energy transfer (LET) radiation (eg, x-rays and gamma rays); and high-LET radiation (eg, neutrons and radon). High-LET radiation produces ionization of a relatively higher density in tissues than does low-LET radiation, so in equivalent doses more biological damage is produced by high-LET than by low-LET radiation.²³⁰ For both types of radiation, the majority of the epidemiologic evidence comes from cohorts who have been exposed at levels substantially greater than those experienced by the general population. Risk assessment methods then are used to estimate the risks to the population.

High-LET Radiation (Radon):
Radon is an inert gas that is produced naturally from radium in the decay series of uranium. Two of the decay products of radon emit particles that can, by virtue of their high energy and mass, cause damage to the DNA of cells of the respiratory epithelium. Epidemiologic studies of underground miners of uranium and other ores have established exposure to radon daughters as a cause of lung cancer.^{17 231 232} In the miners who were exposed to radon in past centuries, very high lung cancer risks were observed. These risks fell for more recent workers, but some epidemiologic studies¹⁷ still show clear evidence of existing cancer risk. Cigarette smoking and radon decay products synergistically influence lung cancer risk in a manner that is supra-additive but submultiplicative.^{17 232}

Radon is of broader societal interest because it is a ubiquitous indoor air pollutant, entering buildings in soil gas. On average, indoor exposures to radon for the general population are much less than those received by occupational groups such as uranium miners. For example, even the lowest historical radon concentration in a uranium mine is roughly 50 to 100 times higher than in the average home.²³² Exposure to radon in indoor air also is assumed to cause lung cancer, but the magnitude of the risk is uncertain because of the assumptions underlying the extrapolation of findings from uranium miners to the generally lower exposures indoors. These assumptions relate to dose, dose-rate, and dosimetry, and also reflect the lack of information on risks of exposures of women and children. Strengthening biological evidence supports the assumption that a single hit to a cell by an particle causes permanent cellular change, an assumption leading to a nonthreshold dose-response relationship.

The assumptions made by the Environmental Protection Agency and the Biological Effects of Ionizing Radiation IV and VI Committees of the National Research Council have led to estimates that approximately 15,000 to 20,000 lung cancer deaths per year in the United States are caused by radon.²³³ Case-control studies concerning indoor exposure to radon as a risk factor for lung cancer, which were undertaken to directly assess risks, have produced findings that are generally consistent with downward extrapolation of risk models based on the underground miners.²³⁴ When combined with metaanalysis, there is a significant association between indoor radon and lung cancer in the general population that is quantitatively comparable with risk models derived from the underground miners. This coherence lends support to using extrapolation of the miner data to estimate the risk of indoor radon.

Low-LET Radiation (X-Rays and Gamma Rays):
Epidemiologic data relating low-LET radiation to lung cancer stem from the following three principal populations: the atomic bomb survivors in Japan²³⁵ ; patients with diseases such as ankylosing spondylitis²³⁶ or tuberculosis,^{237 238} who received multiple radiation treatments; and occupational groups in professions who are exposed to radiation.²³⁹ The single, high-dose exposure of the atomic bomb survivors was associated with a significant lung cancer risk.²³⁵ Regardless of their age when the atomic bombs were dropped, the excess of lung cancer did not occur until the survivors reached older ages when cancer usually occurs.²³⁵

The risks associated with exposure to lower doses of low-LET radiation have been estimated in two ways. Statistical models have been used to extrapolate from the data of the atomic bomb survivors to lower doses. Tuberculosis patients who received radiation therapy also have been studied. They were intermittently exposed to radiation. Such intermittent, low-dose exposures may be most pertinent for the general population because this exposure pattern is the most common in technologically advanced societies. Studies of tuberculosis patients have suggested that if there is any risk of lung cancer associated with this exposure pattern, it is small,^{237 238} implying that the assumptions on which the higher risk estimates obtained from the atomic bomb survivors data may in actual fact not hold.²³⁸

Low-LET radiation therefore appears to be associated with higher lung cancer risk when exposure occurs at a higher dose rate.²³⁸ These results contrast with those for high-LET radiation, suggesting that the two types of radiation have different dose-rate relationships.²³⁸

Air Pollution
During a typical day, the average adult inhales about 10,000 L air.²⁴⁰ Consequently, even the carcinogens that are present in the air at low concentrations are of concern as a risk factor for lung cancer. Extrapolation of the risks associated with occupational