Changing Rates of Adenocarcinoma of the Lung

Changing Rates of Adenocarcinoma of the LungDavid 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, adenocarcinomaof the lung has been increasing as a fraction of all lung cancer.Examination of the available evidence led the 2014 Report ofthe Surgeon General to conclude that the increases in the ratesof adenocarcinoma among smokers in the U.S. were a result ofchanges in cigarette design and composition over the past 6decades. While a causal link to design and compositionchanges as a whole is clear, the changes that have beenimplemented over the past several decades are not uniformlyapplied across all cigarette brands in the current market, raisingquestions about differences in risks among users of differentcigarette brands. Recognition of the increased risks resultingfrom design and composition changes offers a corollary opportunity to reduce current disease risks by identifying and regulatingthe specific compositional and design changes that produced the increase in risk.

■ INTRODUCTION

The proportion of all lung cancer that is adenocarcinoma hasprogressively increased over the past several decades, andadenocarcinoma is now the most common type of lung cancerin both males and females (Figure 1).1−3 Examination of theavailable evidence led the 2014 Report of the Surgeon Generalto conclude that the increases in the rates of adenocarcinomaamong smokers in the U.S. were a result of changes in cigarettedesign and composition over the past 6 decades.3

While the causal link to design and composition changes as awhole is clear, the changes that have been implemented overthe past several decades are not uniformly applied across allcigarette brands in the current market, and this raises thepossibility that there may be differences in disease risks forsmokers of different cigarette brands. In addition, therecognition that design and compositional changes over timehave increased lung cancer risks offers a corollary opportunityto reduce current disease risks by identifying and regulating thespecific compositional and design changes that produced theincrease in risk.There are wide variations among currently marketed

cigarettes in filter design, level of filter ventilation, toxicantcomposition of smoke produced, levels of tobacco-specificnitrosamines in the tobacco rod, amounts and types of additivesused, and other characteristics.4,5 Many of these differenceshave been suggested to be factors contributing to the rise inadenocarcinoma of the lung.3,4,6,7

This perspective examines the evidence on which theSurgeon General’s conclusion is based and then exploreswhat is known, and not known, about some of the factors thathave been suggested to be causing the rise in adenocarcinomaof the lung. The hope is that such discussion will stimulatefurther investigation into ways that this very large and recentlyidentified source of lung cancer risk might be reduced.

■ EVIDENCE ESTABLISHING THAT INCREASES INADENOCARCINOMA OF THE LUNG ARE A RESULTOF DESIGN AND COMPOSITIONAL CHANGES INCIGARETTES OVER TIME

Epidemiological investigation into changes in cigarette designover time initially focused on what was expected to be asubstantial decline in lung cancer risk with the widespreadadoption of filtered and “low-tar” cigarettes.5,8 Subsequentrelease of previously secret internal cigarette company docu-ments describing the engineering and performance character-istics of new cigarette designs led to a recognition that smokerswho switched to lower yield products changed their pattern ofsmoking in ways that returned the nicotine delivery of thesepurportedly lower delivery cigarettes to the level of nicotine(and carcinogenic tar) that the smoker had been receiving fromtheir previous higher yield brand.3,5,9−11 In addition, largeepidemiological studies examining the lung cancer risks ofsmoking across the time period when most smokers adoptedfiltered and low-tar cigarettes showed that lung cancer risk hadincreased instead of declining as expected.8,12,13 Reconsidera-tion of the evidence in light of this new information resulted ina change in the public health recommendations on use offiltered and low-tar cigarettes,3,5,11,14 initially recognizing thatthey have not resulted in a reduction in disease risks, and morerecently concluding that these changes have produced anincrease in lung cancer risk.Large epidemiological studies covering a 50 year time span

show that lung cancer risk among smokers has increasedsubstantially, even for smokers of the same number of cigarettesper day or the same duration of smoking.8,12,13 Over the sametime interval, lung cancer rates among never smokers were

Received: May 1, 2014Published: July 11, 2014

Perspective

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essentially unchanged,8,12,15,16 demonstrating that the change inlung 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 Thisincrease is presented in Figure 1. In the 1950s, when smokingwas first identified as a cause of lung cancer, the relative risks ofsmoking for developing adenocarcinoma were so low that itcaused some to question whether cigarette smoking was even acause of adenocarcinoma.17 As the absolute rate ofadenocarcinoma and the fraction of lung cancer that wasadenocarcinoma both rose, the relative risks due to cigarettesmoking also rose dramatically.14,18 Examination of thisincrease by smoking status revealed a substantive increase indeath rates from adenocarcinoma of the lung for male andfemale smokers over the 20 year interval between the two largeAmerican Cancer Society epidemiological studies (1960−66and 1982−88).8 No increase was observed among those who

were never smokers. The increase in adenocarcinoma rates overtime 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 decadesdemonstrated that lung cancer risk measured in the 1960sprogressively underestimated the observed lung cancer mortal-ity as the calendar year advanced.5,19−21 The modeled estimatescould be matched to the observed lung cancer mortality byadding a term that increased the risk of smoking with theadvent of filtered and lower tar cigarettes.21 When the incidenceof lung cancer by histological type was modeled and comparedto the observed U.S. SEER data, smoking risks derived in the1960s predicted the changes in squamous cell lung cancer overtime quite well. However, adenocarcinoma rates required theaddition of a term increasing the risk over time in order toadequately predict the changes in incidence.22

Changes since the 1950s in the composition and design ofcigarettes and in the curing of tobacco have resulted inincreases in the concentrations of tobacco-specific nitrosamines,notably, NNK, an organ-specific carcinogen for adenocarcino-ma of the lung in animals.23 Biomarkers of NNK exposure areincreased among smokers of cigarettes with higher levels ofNNK in the tobacco rod24 and have been identified as anindependent predictor of lung cancer risk even after theintensity of smoking is controlled in the analyses usingcigarettes 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, andinhaling more deeply in order to maintain their intake ofnicotine.5,9,10 These changes may lead to increases in thedeposition of smoke in the alveolar portions of the lung, whereadenocarcinoma is thought to originate.This evidence led the 2014 Surgeon General’s report to

conclude that changes in cigarette design and composition hadresulted in an increased rate of adenocarcinoma and pointed tothe rise in tobacco-specific nitrosamines and the ventilated filteras changes that likely played a role.3

In considering the Surgeon General’s conclusions, there areat least three large areas that would benefit from furtherexploration. First, the more intense pattern of smoking thatresults from the changes in design alters the composition of thesmoke generated. Second, the compensation for reducednicotine levels in the smoke can lead to deeper inhalation ofsmoke into the lung, resulting in greater exposure of alveolarcells that may be more vulnerable to such exposures. Third,changes in agricultural, curing, and manufacturing practiceshave led to increases in tobacco-specific nitrosamines, which arelikely to play a role in rising adenocarcinoma rates, and this rolemay be enhanced if larger amounts of smoke are also beingpresented to alveolar cells.

Changes in Smoke Composition. Because design andcompositional changes in cigarettes are treated as trade secretsby cigarette manufacturers, only limited information is availableon the actual variation in cigarette design and composition ofcigarettes sold in the U.S. This absence of information led to anassumption, now invalidated by the recent Surgeon General’sreview, that a quantum of cigarette smoke from one cigarettewas similar to that from all other cigarettes for purposes ofdisease risk estimation.Yields of tar and nicotine per cigarette increase with the

intensity with which a cigarette is smoked, and the machinemeasured yields are highest with the Canadian Intense

Figure 1. Standardized incidence of lung cancer by gender andhistology (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 code8046 from the SEER registry as well as others. In the most recent years(2001−2010), most of the “other NSCLC” were coded 8046. Before2001, most “other NSCLC” were coded as 8010 “carcinoma, NOS”.Around 2004, there were changes in how lung cancers were coded inthe SEER registry data. There were also advances in diagnosis andtreatment around 2004 (erlotinib or gefitinib for patients with EGFRmutations; bevacizumab for patients with non-squamous NSCLC) thatmake accurate histologic classification important

Chemical Research in Toxicology Perspective

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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 todifferences in the intensity of machine smoking across thethree protocols.27 The parameters used in these testingregimens are presented in Table 1.

It has been suggested that differences in levels of individualchemical toxicants in smoke from different brands of cigarettescan be predicted from the differences in tar or nicotine yields.28

Underlying this approach is an assumption that the toxicantcomposition of smoke, and smoke toxicity, remains relativelyuniform across different intensities of smoking whennormalized per milligram of tar or per milligram of nicotine.However, the differences in machine smoking protocolspresented in Table 1 include blocking different amounts offilter ventilation as well as differences in puff volume and flowrate. These differences will lead to differences in the conditionsunder which tobacco is burned using the different protocols.Differences in the design and composition across brands maylead the different brands to have different conditions forcombustion even within a single machine testing protocol. Theinterplay of all of these differences creates the toxicant mixpresent in the resultant smoke.Linking overall changes in cigarette design and composition

to increases in lung cancer risk creates an imperative to examinethe impact of specific design and compositional changes onindividual toxicant exposures and risks, and it raises seriousquestions about an assumption that all cigarette smoke isequally toxic per milligram of total particulate matter exposureto the smoker.It is hoped that the Food and Drug Administration will soon

obtain and release a systematic evaluation of the smokecomposition for U.S. cigarette brands using the FTC andCanadian Intense machine smoking protocols. In the interim,data do exist for single points in time for Canadian andAustralian brands, for a set of brands reported to the State ofMassachusetts, and for a selected sample of international PhilipMorris Brands that use the American-style blended tobaccocomposition.29,30 These data have been used to examine thevariation in the toxicant composition of smoke that exists acrossbrands and across testing protocols.30,31

The amounts of toxicants present in smoke from differentbrands of cigarettes reported in these data sets varymeaningfully across cigarette brands.30 This variation persistseven when the amounts are normalized per milligram ofnicotine or per milligram of tar yield, a normalization of yieldsintended to reduce the effect of differences in dilution of thesmoke due to filter ventilation.30,31 Although tar yields increasewith increasing intensity of smoking across the three machinetesting protocols, the yields of individual toxicants do notconsistently follow the yields of tar.30

Table 2 presents the mean values of individual toxicants permilligram nicotine for all brands tested and compares theresults derived from the three different machine testingprotocols.29,30 As might be expected from the differentconditions of combustion occurring with the differentprotocols, the mean values for some toxicants increasesubstantially, more than doubling per milligram of nicotine.

Table 1. Measurement Parameters for Different MachineSmoking Protocols

smoking regimepuff volume

(mL)

pufffrequency

(s)

puffduration

(s)ventilation

blocking (%)

ISO/FTC 35 60 2 0Massachusetts 45 30 2 50CanadianIntense

55 30 2 100

Table 2. Ratios of the Mean Levels of Individual SmokeToxicants for the Same Brands of Cigarettes Measuredunder Different Machine Smoking Protocolsa

measurement protocol

toxicant per milligram of nicotine ISO MASS Canadian Intense

carbon monoxide 1.00 1.07 1.20acetaldehyde 1.00 1.05 1.23acetone 1.00 0.96 1.04acrolein 1.00 1.11 1.37butyraldehyde 1.00 1.04 1.11crotonaldehyde 1.00 1.39 1.68methyl ethyl ketone 1.00 1.27 1.42propionaldehyde 1.00 1.03 1.14formaldehyde 1.00 0.94 1.31acrylonitrite 1.00 1.07 1.27benzene 1.00 0.87 0.821,3-butadiene 1.00 0.98 1.02isoprene 1.00 0.89 0.98styrene 1.00 1.39 1.61toluene 1.00 1.02 1.03ammonia 1.00 1.05 1.04total hydrogen cyanide 1.00 1.50 1.93impinger hydrogen cyanide 1.00 1.81 2.35pad hydrogen cyanide 1.00 1.15 1.44nitric oxide 1.00 1.04 0.91nitrogen oxides 1.00 1.05 0.97aminonaphthalene 1 1.00 0.83 0.64aminonaphthalene 2 1.00 0.82 0.63aminobiphenyl-3 1.00 0.87 0.74aminobiphenyl-4 1.00 0.86 0.73benzoapyrene 1.00 0.82 0.80catechol 1.00 0.98 0.88m,p-cresol 1.00 1.04 0.82o-cresol 1.00 1.11 0.85hydroquinone 1.00 0.99 0.98phenol 1.00 1.14 0.83resorcinol 1.00 0.85 0.77pyridine 1.00 1.67 2.11quinoline 1.00 1.32 0.91NNN 1.00 0.82 0.77NNK 1.00 0.90 0.80NAT 1.00 0.83 0.75NAB 1.00 0.72 0.62mercury 1.00 0.82 0.73cadmium 1.00 1.11 1.09lead 1.00 0.88 0.81arsenic 1.00 1.09 0.98

aThe toxicant values were normalized per milligram of nicotine usingthe values for each brand in the tables, and then the mean value for allbrands using each testing protocol was calculated and converted to aratio of the mean value to the mean value for the FTC/ISO method.See Table 1 for testing parameters used for each machine testingprotocol. Data adapted with permission from ref 29. Copyright 2005Elsevier.



Other toxicants decline by almost 40%, and some remainrelatively unchanged. Clearly, the mix of toxicants shifts withdifferent smoking patterns, suggesting that, even if the totalamount of particulate matter inhaled by the smoker remainsconstant, 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 individualcigarette brands even when using a single machine testingprotocol.30 This demonstrates that design and compositionaldifferences across cigarette brands can produce a differentsmoke composition even when machine smoked underidentical conditions.30 In addition, when brand-specific toxicantlevels per milligram of nicotine are examined using the differentsmoking protocols, not all brands follow the direction definedby the mean of all brands presented in Table 2.29,30 Somebrands follow the trend defined by the mean of that constituentfor all brands. However, yields from other individual brandsmove in a direction that appears to be the opposite of the meanfor that constituent as the testing protocol changes.30 Thesediscrepant trends across brands suggest that the effect ofincreasing the intensity of smoking cannot be assumed to besimilar for all cigarette brands and that differences betweenbrands in design and composition may be important indetermining how the constituent mix of smoke changes withmore intense smoking.The observation that design and compositional differences

across brands result in differences in the toxicant mix of smokeraises serious questions about an assumption that “a cigarette isa cigarette” for purposes of risk estimation even when theintensity of smoking is controlled using measures of nicotineintake. Different smokers smoke the same brand differently, thesame smokers may smoke the same brand differently atdifferent times, and some design changes produce predictabledifferences in the pattern of smoking when smokers switch tothem. Because these differences in smoking behavior are likelyto expand the variability of toxicant yields measured by thethree machine smoking protocols described above, a technicalchallenge exists to define the best approach for examiningdifferences in smoke chemistry across brands. Using a singletesting protocol, varying the testing protocol for the pattern ofactual puffing observed among smokers for that brand, andchanging the testing protocol based on differences in designcharacteristics such as filter ventilation all have strengths andweaknesses as approaches, but no single approach accounts forall of the meaningful differences across brands. Important gapsin our knowledge include how large the differences in toxicantyields are for different U.S. brands as they are actually smoked,whether differences in specific toxicant yields across brandsproduce differences in exposure to smokers who use them, andwhat level of difference in toxicant exposures is biologicallymeaningful for each toxicant or for the combination of toxicantsin smoke.Projecting human exposures to individual constituents from

cigarette design and composition characteristics remains atheoretical challenge rather than a practical tool. Biomarkers oftoxicant exposure remain the only validated measures of humanexposure at this time. Nevertheless, investigation of the effectsof individual design and compositional changes on smokechemistry may provide guidance as to which changes over thelast 6 decades are likely to have increased adenocarcinoma riskand correspondingly could be regulated in an effort to reducethe future risks of smoking.

Shifts in the Location of Toxicant Exposure in theLung. One potential cause of an increase in lung cancer ratesamong smokers could be an increase in the average intensity ofsmoking among those who have not quit; however, there islittle evidence that the residual population of smokers iscomposed of more intense smokers who would be expected tobe at higher risk.32,33 In addition, the mean number ofcigarettes smoked per day has fallen among smokers overtime.34 Thus, consideration has focused on the effect of changesin the pattern of puffing and inhalation secondary to increasedfilter ventilation on differences in the relative amount of smokeexposure occurring in the alveolar spaces, as compared to theairways, of the lung.Much of the current understanding of the anatomic location

of smoke deposition in the lung comes from the modeling ofdeposition based on particle size. That work acknowledges thatthe fraction of the smoke retained in the lung is not wellpredicted by the size of smoke particles measured as the smokeleaves the end of the cigarette filter.35 The small particle size ofsmoke would predict that most of the smoke inhaled would beexhaled rather than retained, and that is not what is observed.Increasing size of the particles due to humidification in theairway and aggregation of the particles due to their high densityin smoke are suggested as reasons for this discrepancy.35

As smoke particles move down the airway, changes occur intheir chemical composition: their pH moves toward that of thebody (pH 7.40), constituents that are water-soluble arepreferentially absorbed in the airways, and constituents reactivewith proteins and other structures are removed as they interactwith the airway walls. Little is known about the effect of theseprocesses on the relative levels of toxicants that reach thealveoli in either the gas phase or the particulate phase of thesmoke. Many of the toxicants may also move from theparticulate phase to the gas phase as they are absorbed alongthe 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 thesmoker. As the puff size increases, it is harder for the smoker tohold the puff in the mouth transiently before inhaling, and thesmoke is often inhaled into the lung without a pause in themouth. In addition, the lower level of nicotine in the smokemay lead the smoker to inhale more deeply following the puff,and the inhalation may be held for several seconds in order toabsorb more nicotine.27,36,37 The increasing depth of inhalationand greater residence time in the lung is likely to lead to greaterdeposition and absorption of smoke constituents in the alveolarportions of lung.Gower and Hammond37 reviewed studies of the three-

dimensional location of particle deposition in the lung andsuggest that greater depth of inhalation leads to greaterdeposition in the peripheral, as opposed to the central, parts ofthe lung. These locations of deposition studies do not clearlydifferentiate between deposition in the smaller peripheralairways as being separate from the alveoli, but it is reasonable toassume that if there were greater delivery of smoke to theperipheral airways there would also be greater delivery to thealveoli as well.Adenocarcinoma of the lung is felt to arise from type II

pneumocytes that are very thin cells that help form the walls ofthe alveoli. The concern about greater depth of inhalationdamaging these cells is 2-fold. First, a larger fraction of the totalsmoke inhaled may be adsorbed or absorbed in the alveoli,increasing the dose of exposure to these cells. Second, airways



have multiple protective barriers including mucocilliaryclearance and a layer of epithelial cells protecting the basilarlayer of cells that are dividing and are therefore susceptible tocarcinogenic transformation. The alveoli lack these protectivebarriers. This lack of protection may make the alveolar cellsmore vulnerable to carcinogenesis even from modest levels ofcarcinogen exposure.Increasing Levels of Tobacco-Specific Nitrosamines in

Smoke. The change in cigarette composition with thestrongest evidentiary base to support regulation based on theincrease in adenocarcinoma risk is the high levels of tobacco-specific nitrosamines (TSNAs) in U.S. cigarettes. Nitrosaminesthat are tobacco-specific are formed from the nicotine andother minor alkaloids in tobacco and are potent humancarcinogens.23 They are organ-specific carcinogens foradenocarcinoma of the lung in rodents,23 and differences inlevels of metabolites of NNK are independent predictors oflung cancer in humans, even after controlling for variations intotal smoke exposure using cotinine levels.25,26 There aresubstantively different levels of TSNAs across different brandsof U.S. style blended cigarettes,29,30 and cigarettes madeutilizing only flue-cured tobacco have dramatically lower levelsof TSNAs.30 Smokers who smoke these lower nitrosaminecigarettes have lower levels of biomarkers for TSNA exposure.24

Much of the higher level of TSNA’s in U.S. blended tobaccocomes from the use of burley tobacco, but changes inagricultural practices have increased the nitrite concentrationin tobacco, which combines with the nicotine and minoralkaloids to form TSNAs. In addition, use of reconstituted sheettobacco (tobacco leaf components converted to paper to whichflavorings, nicotine, and other substances can be added) hasincreased TSNA levels.4 Changes in the curing practices forflue-cured tobacco that exposed the tobacco to higher levels ofoxides of nitrogen during curing also resulted in higher TSNAlevels.38

Thus, U.S. cigarettes clearly have levels of TSNAs that arehigher in some brands than in others and are much higher thanthat in cigarettes from several other countries, and technologiesexist to reduce the levels of these potent carcinogens known tocause adenocarcinoma of the lung in animals and which havebeen associated with the rise of adenocarcinoma of the lung inU.S. smokers. The scientific case to support regulatory actiondramatically reducing the levels of TSNAs in tobacco or insmoke 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, themagnitude of the differences in biomarkers of TSNA exposureacross smokers of different brands of U.S. cigarettes can beexamined. The question of whether the existing differences inTSNA levels for U.S. brands translate into meaningfuldifferences in human smoker exposures will be important toregulations limiting TSNAs in cigarettes and cigarette smoke. Abetter understanding of the changes in smoke composition as itmoves down the airway, as well as measures that differentiateairway from alveolar exposure with different patterns of puffing,would be of value. It would be useful to have a betterunderstanding of the relative contributions to increasingadenocarcinoma rates of increasing delivery of whole smoketo the alveolar spaces as compared to the differingconcentrations of TSNAs in the smoke delivered, as this maybe important for assessing the need to examine regulation ofconstituents other than the TSNAs. Finally, research on

potential contributions of the many other carcinogens insmoke to lung cancer risk, and the potential interactions ofthose other carcinogens with TSNAs, will be needed as animportant set of information for regulators.

■ SUMMARYAdenocarcinoma 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 ifcigarette design changes had been monitored for their potentialto increase disease risks and had disclosure of the designchanges been made public with careful surveillance of thesubsequent disease risk. The damage that occurred in the pastcannot be changed, but recognition that the design andcompositional changes have created harm creates an oppor-tunity for regulatory action to roll back those changes. It alsocreates a challenge to the scientific community to aid inidentifying the specific changes that will have the greatestimpact.

■ AUTHOR INFORMATIONCorresponding Author*Phone: 858 794 8547. Fax: 858 794 8543. E-mail: [email protected] authors declare the following competing financialinterest(s): I have testified extensively against the tobaccocompanies in litigation.

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mailto:[email protected]

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Changing Rates of Adenocarcinoma of the Lung