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Changing Rates of Adenocarcinoma of the Lung David M. Burns* Family and Preventive Medicine, UCSD School of Medicine, 1120 Solana Drive, Del Mar, California 92014, United States ABSTRACT: Over the past several decades, adenocarcinoma of the lung has been increasing as a fraction of all lung cancer. Examination of the available evidence led the 2014 Report of the Surgeon General to conclude that the increases in the rates of adenocarcinoma among smokers in the U.S. were a result of changes in cigarette design and composition over the past 6 decades. While a causal link to design and composition changes as a whole is clear, the changes that have been implemented over the past several decades are not uniformly applied across all cigarette brands in the current market, raising questions about differences in risks among users of different cigarette brands. Recognition of the increased risks resulting from design and composition changes offers a corollary opportunity to reduce current disease risks by identifying and regulating the specific compositional and design changes that produced the increase in risk.
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INTRODUCTION The proportion of all lung cancer that is adenocarcinoma has progressively increased over the past several decades, and adenocarcinoma is now the most common type of lung cancer in both males and females (Figure 1).1−3 Examination of the available evidence led the 2014 Report of the Surgeon General to conclude that the increases in the rates of adenocarcinoma among smokers in the U.S. were a result of changes in cigarette design and composition over the past 6 decades.3 While the causal link to design and composition changes as a whole is clear, the changes that have been implemented over the past several decades are not uniformly applied across all cigarette brands in the current market, and this raises the possibility that there may be differences in disease risks for smokers of different cigarette brands. In addition, the recognition that design and compositional changes over time have increased lung cancer risks offers a corollary opportunity to reduce current disease risks by identifying and regulating the specific compositional and design changes that produced the increase in risk. There are wide variations among currently marketed cigarettes in filter design, level of filter ventilation, toxicant composition of smoke produced, levels of tobacco-specific nitrosamines in the tobacco rod, amounts and types of additives used, and other characteristics.4,5 Many of these differences have been suggested to be factors contributing to the rise in adenocarcinoma of the lung.3,4,6,7 This perspective examines the evidence on which the Surgeon General’s conclusion is based and then explores what is known, and not known, about some of the factors that have been suggested to be causing the rise in adenocarcinoma of the lung. The hope is that such discussion will stimulate further investigation into ways that this very large and recently identified source of lung cancer risk might be reduced. © 2014 American Chemical Society
EVIDENCE ESTABLISHING THAT INCREASES IN ADENOCARCINOMA OF THE LUNG ARE A RESULT OF DESIGN AND COMPOSITIONAL CHANGES IN CIGARETTES OVER TIME Epidemiological investigation into changes in cigarette design over time initially focused on what was expected to be a substantial decline in lung cancer risk with the widespread adoption of filtered and “low-tar” cigarettes.5,8 Subsequent release of previously secret internal cigarette company documents describing the engineering and performance characteristics of new cigarette designs led to a recognition that smokers who switched to lower yield products changed their pattern of smoking in ways that returned the nicotine delivery of these purportedly lower delivery cigarettes to the level of nicotine (and carcinogenic tar) that the smoker had been receiving from their previous higher yield brand.3,5,9−11 In addition, large epidemiological studies examining the lung cancer risks of smoking across the time period when most smokers adopted filtered and low-tar cigarettes showed that lung cancer risk had increased instead of declining as expected.8,12,13 Reconsideration of the evidence in light of this new information resulted in a change in the public health recommendations on use of filtered and low-tar cigarettes,3,5,11,14 initially recognizing that they have not resulted in a reduction in disease risks, and more recently concluding that these changes have produced an increase in lung cancer risk. Large epidemiological studies covering a 50 year time span show that lung cancer risk among smokers has increased substantially, even for smokers of the same number of cigarettes per day or the same duration of smoking.8,12,13 Over the same time interval, lung cancer rates among never smokers were Received: May 1, 2014 Published: July 11, 2014 1330
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were never smokers. The increase in adenocarcinoma rates over time was limited to the cigarette smokers in the population. The modeling of changes in lung cancer rates expected to result from changes in smoking behaviors over several decades demonstrated that lung cancer risk measured in the 1960s progressively underestimated the observed lung cancer mortality as the calendar year advanced.5,19−21 The modeled estimates could be matched to the observed lung cancer mortality by adding a term that increased the risk of smoking with the advent of filtered and lower tar cigarettes.21 When the incidence of lung cancer by histological type was modeled and compared to the observed U.S. SEER data, smoking risks derived in the 1960s predicted the changes in squamous cell lung cancer over time quite well. However, adenocarcinoma rates required the addition of a term increasing the risk over time in order to adequately predict the changes in incidence.22 Changes since the 1950s in the composition and design of cigarettes and in the curing of tobacco have resulted in increases in the concentrations of tobacco-specific nitrosamines, notably, NNK, an organ-specific carcinogen for adenocarcinoma of the lung in animals.23 Biomarkers of NNK exposure are increased among smokers of cigarettes with higher levels of NNK in the tobacco rod24 and have been identified as an independent predictor of lung cancer risk even after the intensity of smoking is controlled in the analyses using cigarettes smoked per day or cotinine levels.25,26 When smokers switch to cigarettes with ventilated filters, they change their pattern of smoking, taking bigger puffs, increasing the number of cigarettes smoked per day, and inhaling more deeply in order to maintain their intake of nicotine.5,9,10 These changes may lead to increases in the deposition of smoke in the alveolar portions of the lung, where adenocarcinoma is thought to originate. This evidence led the 2014 Surgeon General’s report to conclude that changes in cigarette design and composition had resulted in an increased rate of adenocarcinoma and pointed to the rise in tobacco-specific nitrosamines and the ventilated filter as changes that likely played a role.3 In considering the Surgeon General’s conclusions, there are at least three large areas that would benefit from further exploration. First, the more intense pattern of smoking that results from the changes in design alters the composition of the smoke generated. Second, the compensation for reduced nicotine levels in the smoke can lead to deeper inhalation of smoke into the lung, resulting in greater exposure of alveolar cells that may be more vulnerable to such exposures. Third, changes in agricultural, curing, and manufacturing practices have led to increases in tobacco-specific nitrosamines, which are likely to play a role in rising adenocarcinoma rates, and this role may be enhanced if larger amounts of smoke are also being presented to alveolar cells. Changes in Smoke Composition. Because design and compositional changes in cigarettes are treated as trade secrets by cigarette manufacturers, only limited information is available on the actual variation in cigarette design and composition of cigarettes sold in the U.S. This absence of information led to an assumption, now invalidated by the recent Surgeon General’s review, that a quantum of cigarette smoke from one cigarette was similar to that from all other cigarettes for purposes of disease risk estimation. Yields of tar and nicotine per cigarette increase with the intensity with which a cigarette is smoked, and the machine measured yields are highest with the Canadian Intense
Figure 1. Standardized incidence of lung cancer by gender and histology (age adjusted to 2000 U.S. population), 1973−2010. Source: 2014 Report of the Surgeon General3 Figure 6.10, Surveillance, Epidemiology, and End Results (SEER) Program, public use data. Note: Other non-small-cell-lung carcinoma (NSCLC) includes code 8046 from the SEER registry as well as others. In the most recent years (2001−2010), most of the “other NSCLC” were coded 8046. Before 2001, most “other NSCLC” were coded as 8010 “carcinoma, NOS”. Around 2004, there were changes in how lung cancers were coded in the SEER registry data. There were also advances in diagnosis and treatment around 2004 (erlotinib or gefitinib for patients with EGFR mutations; bevacizumab for patients with non-squamous NSCLC) that make accurate histologic classification important
essentially unchanged,8,12,15,16 demonstrating that the change in lung cancer risk was confined to the smokers in the population. During this same time period, the fraction of all lung cancer that was adenocarcinoma increased substantially.1−3 This increase is presented in Figure 1. In the 1950s, when smoking was first identified as a cause of lung cancer, the relative risks of smoking for developing adenocarcinoma were so low that it caused some to question whether cigarette smoking was even a cause of adenocarcinoma. 17 As the absolute rate of adenocarcinoma and the fraction of lung cancer that was adenocarcinoma both rose, the relative risks due to cigarette smoking also rose dramatically.14,18 Examination of this increase by smoking status revealed a substantive increase in death rates from adenocarcinoma of the lung for male and female smokers over the 20 year interval between the two large American Cancer Society epidemiological studies (1960−66 and 1982−88).8 No increase was observed among those who 1331
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measurement protocol, lower with the Massachusetts protocol, and lowest with the International Organization for Standards/ Federal Trade Commission (ISO/FTC) protocol due to differences in the intensity of machine smoking across the three protocols.27 The parameters used in these testing regimens are presented in Table 1.
Table 2 presents the mean values of individual toxicants per milligram nicotine for all brands tested and compares the results derived from the three different machine testing protocols.29,30 As might be expected from the different conditions of combustion occurring with the different protocols, the mean values for some toxicants increase substantially, more than doubling per milligram of nicotine.
Table 1. Measurement Parameters for Different Machine Smoking Protocols smoking regime ISO/FTC Massachusetts Canadian Intense
puff volume (mL)
puff frequency (s)
puff duration (s)
ventilation blocking (%)
35 45 55
60 30 30
2 2 2
0 50 100
Table 2. Ratios of the Mean Levels of Individual Smoke Toxicants for the Same Brands of Cigarettes Measured under Different Machine Smoking Protocolsa measurement protocol
It has been suggested that differences in levels of individual chemical toxicants in smoke from different brands of cigarettes can be predicted from the differences in tar or nicotine yields.28 Underlying this approach is an assumption that the toxicant composition of smoke, and smoke toxicity, remains relatively uniform across different intensities of smoking when normalized per milligram of tar or per milligram of nicotine. However, the differences in machine smoking protocols presented in Table 1 include blocking different amounts of filter ventilation as well as differences in puff volume and flow rate. These differences will lead to differences in the conditions under which tobacco is burned using the different protocols. Differences in the design and composition across brands may lead the different brands to have different conditions for combustion even within a single machine testing protocol. The interplay of all of these differences creates the toxicant mix present in the resultant smoke. Linking overall changes in cigarette design and composition to increases in lung cancer risk creates an imperative to examine the impact of specific design and compositional changes on individual toxicant exposures and risks, and it raises serious questions about an assumption that all cigarette smoke is equally toxic per milligram of total particulate matter exposure to the smoker. It is hoped that the Food and Drug Administration will soon obtain and release a systematic evaluation of the smoke composition for U.S. cigarette brands using the FTC and Canadian Intense machine smoking protocols. In the interim, data do exist for single points in time for Canadian and Australian brands, for a set of brands reported to the State of Massachusetts, and for a selected sample of international Philip Morris Brands that use the American-style blended tobacco composition.29,30 These data have been used to examine the variation in the toxicant composition of smoke that exists across brands and across testing protocols.30,31 The amounts of toxicants present in smoke from different brands of cigarettes reported in these data sets vary meaningfully across cigarette brands.30 This variation persists even when the amounts are normalized per milligram of nicotine or per milligram of tar yield, a normalization of yields intended to reduce the effect of differences in dilution of the smoke due to filter ventilation.30,31 Although tar yields increase with increasing intensity of smoking across the three machine testing protocols, the yields of individual toxicants do not consistently follow the yields of tar.30
toxicant per milligram of nicotine
ISO
MASS
Canadian Intense
carbon monoxide acetaldehyde acetone acrolein butyraldehyde crotonaldehyde methyl ethyl ketone propionaldehyde formaldehyde acrylonitrite benzene 1,3-butadiene isoprene styrene toluene ammonia total hydrogen cyanide impinger hydrogen cyanide pad hydrogen cyanide nitric oxide nitrogen oxides aminonaphthalene 1 aminonaphthalene 2 aminobiphenyl-3 aminobiphenyl-4 benzoapyrene catechol m,p-cresol o-cresol hydroquinone phenol resorcinol pyridine quinoline NNN NNK NAT NAB mercury cadmium lead arsenic
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.07 1.05 0.96 1.11 1.04 1.39 1.27 1.03 0.94 1.07 0.87 0.98 0.89 1.39 1.02 1.05 1.50 1.81 1.15 1.04 1.05 0.83 0.82 0.87 0.86 0.82 0.98 1.04 1.11 0.99 1.14 0.85 1.67 1.32 0.82 0.90 0.83 0.72 0.82 1.11 0.88 1.09
1.20 1.23 1.04 1.37 1.11 1.68 1.42 1.14 1.31 1.27 0.82 1.02 0.98 1.61 1.03 1.04 1.93 2.35 1.44 0.91 0.97 0.64 0.63 0.74 0.73 0.80 0.88 0.82 0.85 0.98 0.83 0.77 2.11 0.91 0.77 0.80 0.75 0.62 0.73 1.09 0.81 0.98
a
The toxicant values were normalized per milligram of nicotine using the values for each brand in the tables, and then the mean value for all brands using each testing protocol was calculated and converted to a ratio of the mean value to the mean value for the FTC/ISO method. See Table 1 for testing parameters used for each machine testing protocol. Data adapted with permission from ref 29. Copyright 2005 Elsevier.
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Shifts in the Location of Toxicant Exposure in the Lung. One potential cause of an increase in lung cancer rates among smokers could be an increase in the average intensity of smoking among those who have not quit; however, there is little evidence that the residual population of smokers is composed of more intense smokers who would be expected to be at higher risk.32,33 In addition, the mean number of cigarettes smoked per day has fallen among smokers over time.34 Thus, consideration has focused on the effect of changes in the pattern of puffing and inhalation secondary to increased filter ventilation on differences in the relative amount of smoke exposure occurring in the alveolar spaces, as compared to the airways, of the lung. Much of the current understanding of the anatomic location of smoke deposition in the lung comes from the modeling of deposition based on particle size. That work acknowledges that the fraction of the smoke retained in the lung is not well predicted by the size of smoke particles measured as the smoke leaves the end of the cigarette filter.35 The small particle size of smoke would predict that most of the smoke inhaled would be exhaled rather than retained, and that is not what is observed. Increasing size of the particles due to humidification in the airway and aggregation of the particles due to their high density in smoke are suggested as reasons for this discrepancy.35 As smoke particles move down the airway, changes occur in their chemical composition: their pH moves toward that of the body (pH 7.40), constituents that are water-soluble are preferentially absorbed in the airways, and constituents reactive with proteins and other structures are removed as they interact with the airway walls. Little is known about the effect of these processes on the relative levels of toxicants that reach the alveoli in either the gas phase or the particulate phase of the smoke. Many of the toxicants may also move from the particulate phase to the gas phase as they are absorbed along the airway or in the alveoli, as it is thought that nicotine does. Changes in cigarette design that result in lower machine yields lead to increases in the size of the puff taken by the smoker. As the puff size increases, it is harder for the smoker to hold the puff in the mouth transiently before inhaling, and the smoke is often inhaled into the lung without a pause in the mouth. In addition, the lower level of nicotine in the smoke may lead the smoker to inhale more deeply following the puff, and the inhalation may be held for several seconds in order to absorb more nicotine.27,36,37 The increasing depth of inhalation and greater residence time in the lung is likely to lead to greater deposition and absorption of smoke constituents in the alveolar portions of lung. Gower and Hammond37 reviewed studies of the threedimensional location of particle deposition in the lung and suggest that greater depth of inhalation leads to greater deposition in the peripheral, as opposed to the central, parts of the lung. These locations of deposition studies do not clearly differentiate between deposition in the smaller peripheral airways as being separate from the alveoli, but it is reasonable to assume that if there were greater delivery of smoke to the peripheral airways there would also be greater delivery to the alveoli as well. Adenocarcinoma of the lung is felt to arise from type II pneumocytes that are very thin cells that help form the walls of the alveoli. The concern about greater depth of inhalation damaging these cells is 2-fold. First, a larger fraction of the total smoke inhaled may be adsorbed or absorbed in the alveoli, increasing the dose of exposure to these cells. Second, airways
Other toxicants decline by almost 40%, and some remain relatively unchanged. Clearly, the mix of toxicants shifts with different smoking patterns, suggesting that, even if the total amount of particulate matter inhaled by the smoker remains constant, the toxicity of that smoke may change. A similar wide variation in toxicant yields per milligram of tar or per milligram of nicotine is evident across individual cigarette brands even when using a single machine testing protocol.30 This demonstrates that design and compositional differences across cigarette brands can produce a different smoke composition even when machine smoked under identical conditions.30 In addition, when brand-specific toxicant levels per milligram of nicotine are examined using the different smoking protocols, not all brands follow the direction defined by the mean of all brands presented in Table 2.29,30 Some brands follow the trend defined by the mean of that constituent for all brands. However, yields from other individual brands move in a direction that appears to be the opposite of the mean for that constituent as the testing protocol changes.30 These discrepant trends across brands suggest that the effect of increasing the intensity of smoking cannot be assumed to be similar for all cigarette brands and that differences between brands in design and composition may be important in determining how the constituent mix of smoke changes with more intense smoking. The observation that design and compositional differences across brands result in differences in the toxicant mix of smoke raises serious questions about an assumption that “a cigarette is a cigarette” for purposes of risk estimation even when the intensity of smoking is controlled using measures of nicotine intake. Different smokers smoke the same brand differently, the same smokers may smoke the same brand differently at different times, and some design changes produce predictable differences in the pattern of smoking when smokers switch to them. Because these differences in smoking behavior are likely to expand the variability of toxicant yields measured by the three machine smoking protocols described above, a technical challenge exists to define the best approach for examining differences in smoke chemistry across brands. Using a single testing protocol, varying the testing protocol for the pattern of actual puffing observed among smokers for that brand, and changing the testing protocol based on differences in design characteristics such as filter ventilation all have strengths and weaknesses as approaches, but no single approach accounts for all of the meaningful differences across brands. Important gaps in our knowledge include how large the differences in toxicant yields are for different U.S. brands as they are actually smoked, whether differences in specific toxicant yields across brands produce differences in exposure to smokers who use them, and what level of difference in toxicant exposures is biologically meaningful for each toxicant or for the combination of toxicants in smoke. Projecting human exposures to individual constituents from cigarette design and composition characteristics remains a theoretical challenge rather than a practical tool. Biomarkers of toxicant exposure remain the only validated measures of human exposure at this time. Nevertheless, investigation of the effects of individual design and compositional changes on smoke chemistry may provide guidance as to which changes over the last 6 decades are likely to have increased adenocarcinoma risk and correspondingly could be regulated in an effort to reduce the future risks of smoking. 1333
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potential contributions of the many other carcinogens in smoke to lung cancer risk, and the potential interactions of those other carcinogens with TSNAs, will be needed as an important set of information for regulators.
have multiple protective barriers including mucocilliary clearance and a layer of epithelial cells protecting the basilar layer of cells that are dividing and are therefore susceptible to carcinogenic transformation. The alveoli lack these protective barriers. This lack of protection may make the alveolar cells more vulnerable to carcinogenesis even from modest levels of carcinogen exposure. Increasing Levels of Tobacco-Specific Nitrosamines in Smoke. The change in cigarette composition with the strongest evidentiary base to support regulation based on the increase in adenocarcinoma risk is the high levels of tobaccospecific nitrosamines (TSNAs) in U.S. cigarettes. Nitrosamines that are tobacco-specific are formed from the nicotine and other minor alkaloids in tobacco and are potent human carcinogens.23 They are organ-specific carcinogens for adenocarcinoma of the lung in rodents,23 and differences in levels of metabolites of NNK are independent predictors of lung cancer in humans, even after controlling for variations in total smoke exposure using cotinine levels.25,26 There are substantively different levels of TSNAs across different brands of U.S. style blended cigarettes,29,30 and cigarettes made utilizing only flue-cured tobacco have dramatically lower levels of TSNAs.30 Smokers who smoke these lower nitrosamine cigarettes have lower levels of biomarkers for TSNA exposure.24 Much of the higher level of TSNA’s in U.S. blended tobacco comes from the use of burley tobacco, but changes in agricultural practices have increased the nitrite concentration in tobacco, which combines with the nicotine and minor alkaloids to form TSNAs. In addition, use of reconstituted sheet tobacco (tobacco leaf components converted to paper to which flavorings, nicotine, and other substances can be added) has increased TSNA levels.4 Changes in the curing practices for flue-cured tobacco that exposed the tobacco to higher levels of oxides of nitrogen during curing also resulted in higher TSNA levels.38 Thus, U.S. cigarettes clearly have levels of TSNAs that are higher in some brands than in others and are much higher than that in cigarettes from several other countries, and technologies exist to reduce the levels of these potent carcinogens known to cause adenocarcinoma of the lung in animals and which have been associated with the rise of adenocarcinoma of the lung in U.S. smokers. The scientific case to support regulatory action dramatically reducing the levels of TSNAs in tobacco or in smoke is solid and sufficient for action. In the inevitably long interval between proposal of regulations by the FDA and those regulations taking effect, several areas of investigation are of high priority. First, the magnitude of the differences in biomarkers of TSNA exposure across smokers of different brands of U.S. cigarettes can be examined. The question of whether the existing differences in TSNA levels for U.S. brands translate into meaningful differences in human smoker exposures will be important to regulations limiting TSNAs in cigarettes and cigarette smoke. A better understanding of the changes in smoke composition as it moves down the airway, as well as measures that differentiate airway from alveolar exposure with different patterns of puffing, would be of value. It would be useful to have a better understanding of the relative contributions to increasing adenocarcinoma rates of increasing delivery of whole smoke to the alveolar spaces as compared to the differing concentrations of TSNAs in the smoke delivered, as this may be important for assessing the need to examine regulation of constituents other than the TSNAs. Finally, research on
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SUMMARY Adenocarcinoma of the lung has risen dramatically in the U.S. population due to changes in cigarette design and composition. This excess burden of lung cancer need not have occurred if cigarette design changes had been monitored for their potential to increase disease risks and had disclosure of the design changes been made public with careful surveillance of the subsequent disease risk. The damage that occurred in the past cannot be changed, but recognition that the design and compositional changes have created harm creates an opportunity for regulatory action to roll back those changes. It also creates a challenge to the scientific community to aid in identifying the specific changes that will have the greatest impact.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 858 794 8547. Fax: 858 794 8543. E-mail: dburns@ ucsd.edu. Notes
The authors declare the following competing financial interest(s): I have testified extensively against the tobacco companies in litigation.
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REFERENCES
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