Chemoprevention of Lung Cancer
Robert L. Keith1
1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, VA Eastern Colorado Healthcare System, University of
Colorado at Denver Health Sciences Center, Denver, Colorado
and the majority of diagnoses are made in former smokers. While
avoidance of tobacco abuse and smoking cessation clearly will have
the greatest impact on lung cancer development, effective chemo-
prevention could prove to be more effective than treatment of
established disease. Chemoprevention is the use of dietary or
and has been successfully applied to common malignancies other
failing to identify effective agents, our ability to determine higher
risk populations and the understanding of lung tumor and pre-
malignant biology continues to advance. Additional biomarkers of
risk continue to be investigated and validated. The World Health
classification for lung cancer now recognizes distinct histologic le-
starts with normal epithelium and progresses through hyperplasia,
metaplasia, dysplasia, and carcinoma in situ to invasive squamous
cell cancer. Similar precursor lesions exist for adenocarcinoma, and
these pre-malignant lesions are targeted by chemopreventive
agents in current and future trials. At this time, chemopreventive
agents can only be recommended as part of well-designed clinical
trials, and multiple trials are currently in progress and additional
trials are in the planning stages. This review will discuss the prin-
ciples of chemoprevention, summarize the completed trials, and
discuss ongoing and potential future trials with a focus on targeted
Keywords: lung cancer; chemoprevention; premalignancy
Lung cancer is now the leading cause of cancer death in both
men and women in the United States, as well as being the
leading cause of cancer death worldwide (1). The current 5-year
survival rate in the United States for lung cancer is a discour-
aging 15%, and while there has been an interval improvement
in survival over the last several decades, the survival advances
seen in other common malignancies have not been realized in
lung cancer. One reason for the discouraging survival statistics
is that the majority of lung cancer subjects present with late-
stage disease and are not curable by current therapies. With the
advent of new biologically targeted therapeutic agents, treat-
ment of advanced lung cancer should continue to improve
(2), but effective chemopreventive agents are sorely needed.
Approximately 90% of lung cancer cases are attributable to
tobacco smoking. Recent decreases in smoking have led to
a downturn in lung cancer death rates in the United States, but
smoking rates continue to increase worldwide. It is well known
that the incidence of lung cancer decreases only slowly after
smoking cessation, ensuring that the lung cancer epidemic will
continue for many years. Smoking cessation is clearly the most
effective intervention to reduce lung cancer risk, but ex-
smokers still carry a significant risk and, in the United States,
the majority of lung cancers are diagnosed in former smokers
(3). Additional strategies to reduce the burden of lung cancer in
former smokers are needed, and because the large majority of
lung cancers are non–small cell lung cancer (NSCLC), chemo-
preventive efforts have chosen to focus on these histologic types
of lung cancer.
Similar to many solid organ tumors, lung tumorigenesis
results from a series of genetic and epigenetic alterations in
pulmonary epithelial cells. The World Health Organization/
International Association for the Study of Lung Cancer classi-
fication for lung cancer now recognizes distinct histologic
lesions that can be reproducibly graded as precursors of NSCLC
(4). By reproducibly identifying and focusing therapy on pre-
malignant stages of the disease, rather than the current focus on
invasive lung cancer, effective treatment and improved survival
may become a more attainable goal (5). Our understanding of
lung cancer biology continues to improve, and this has led to
a proliferation of targeted therapies that may prove to be
important chemotherapeutic and chemopreventive agents. Clin-
ical experience has also illustrated that chemopreventive agents
may have dramatically different results in current and former
smokers (6) and many trials either exclude current smokers or
analyze these subjects separately.
Chemoprevention is defined as the use of dietary or pharma-
ceutical interventions to slow or reverse the progression of
validated as effective in selected groups at high risk for breast
for lung cancer (8–10). Many of the principles that have proven
effective in chemoprevention of other common malignancies are
likely applicable to lung cancer, and therapeutic advances may
target pathways that are altered in pre-malignant stages of
PRINCIPLES OF CHEMOPREVENTION
The term ‘‘chemoprevention’’ was coined by Sporn and cow-
orkers in 1976 to describe either pharmacologic or dietary
interventions that would interfere in the carcinogenic process,
resulting in a decreased cancer risk (7). Lung carcinogenesis can
involve 20 to 30 years, and more recent studies have appropri-
ately chosen to evaluate the effects of treatment on pre-
malignant lesions or inhibition of the carcinogenic progression.
Chemoprevention studies can be further subdivided into three
distinct areas (primary, secondary, and tertiary), and current
investigations in each area should advance the field. Primary
chemoprevention measures the development of cancer in
a high-risk population (for instance, current or former smokers
who have airflow limitation on spirometry), while secondary
chemopreventive studies examine the development of cancer in
subjects with precursor lesions (for example, severe dysplasia on
an endobronchial biopsy or atypical adenomatous hyperplasia
[AAH] on a transthoracic needle biopsy). Tertiary chemo-
prevention studies examine the development of lung cancer in
subjects with a previous cancer.
(Received in original form July 9, 2008; accepted in final form November 20, 2008)
Supported by the Department of Veterans Affairs Merit Review Program; NIH
(Colorado SPORE in Lung Cancer)
Correspondence and requests for reprints should be addressed to Robert L. Keith,
M.D., VA ECHCS, 1055 Clermont St., Box 111A, Denver, CO 80220. E-mail:
Proc Am Thorac Soc
Internet address: www.atsjournals.org
Vol 6. pp 187–193, 2009
Development of agents follows the standard progression of
phased clinical trials. Phase I trials focus on safety, pharmacoki-
netics, and pharmacodynamics, with particular emphasis on drug
effects. Phase II trials begin to evaluate efficacy and are random-
evaluation of biomarkers and other potential surrogate endpoint
biomarkers for cancer prevention. A biomarker is defined as
a characteristic that is objectively measured or evaluated as an
indicator of a pathogenic process or a response to a therapeutic
intervention. The development and validation of biomarkers is
particularly important for lung cancer prevention studies, as
invasive cancer progresses over many years and longitudinal
studies with the development of lung cancer as an endpoint can
take decades to complete. Phase III trials are large, randomized,
blinded, placebo-controlled trials with the goal of delaying the
development of cancer, and continuing to evaluate efficacy and
toxicity. The NCI and FDA have developed general strategies
for developing chemopreventive agents. This typically involves
the initial in vitro studies, progressing to animal tumorigenesis
studies, and then concluding with phased human trials. Animal
testing that should result in only the most promising agents
progressing to human trials. Murine adenocarcinoma models
have many similarities to human adenocarcinoma in terms of
histology, mutations, and gene expression patterns (11), and
agents currently employed in the majority of trials have proven
efficacious in animal testing.
Chemoprevention has been applied with some early success
to individuals at high risk for breast, prostate, and colon cancer,
but there is no currently available chemoprevention for lung
cancer. In fact, certain agents (b-carotene, n-acetyl cysteine)
have been shown to increase cancer risk in current smokers (12,
13). Retinoids have received the most attention in the past as
potential lung cancer chemopreventive agents (14). A large
body of epidemiologic, genetic, and cell biology data suggested
that supplementation with b-carotene would be protective,
although preclinical animal studies were not very supportive.
No one would have predicted that the two large trials (the
ATBC and CARET trials) conducted in the 1990s would each
show a statistically significant increase in lung cancer incidence
(z 20%) associated with b-carotene supplementation (particu-
larly in current smokers) (6, 15). While a disappointing result,
b-carotene supplementation applied on a large scale without the
foresight of a clinical trial would have been disastrous.
At present, there are four major approaches to choosing
promising agents for study in lung cancer chemoprevention
trials: observational studies, analysis of the effects of drugs or
targeted agents on cancer or dysplastic cell biology, preclinical
animal models of lung carcinogenesis, and intermediate end-
point trials in humans. Since we currently have no validated
lung cancer chemoprevention agents, none of these strategies is
a reliable predictor.
Definition of High-Risk Groups
Three requirements must be met for clinically effective chemo-
prevention. First, an adequately high-risk population must be
readily identifiable (and historically this has proven challenging
for lung cancer). Second, effective agents with a tolerable side
agents must be minimal, given that annual risk for cancer
development is small. Subjects enrolled in tertiary chemopre-
vention trials have a previous history of cancer, and therefore
more toxicity may be tolerated in chronically administered
chemopreventive agents. This is a particularly important group
after resection can be as high as 1 to 2% per year (16). Third,
endpoints to the clinical trials must be identified, defined, and
validated in terms of demonstrating reduction in cancer de-
velopment. For tertiary trials this can be cancer incidence, but
for secondary prevention trials intermediate biomarkers must be
present and have an acceptable risk of progression. For lung
cancer, one could argue that there is no current gold standard
biomarker, and that histology is used in a similar paradigm to the
development of other epithelial cancers. Histologic changes may
not prove to be the best biomarker, and advances in genomics,
proteomics, and molecular imaging studies may increase our
understanding and better refine endpoints.
epidemiologic studies have been able to more accurately identify
high-risk populations. The development of COPD (as evidenced
by airflow obstruction on spirometry) and lung cancer have
a common genetic basis, as current and former smokers with
airflow obstruction have a significant increase in lung cancer
incidence (18, 19). Bach and colleagues developed and validated
a model of lung cancer risk based on age, sex, and tobacco smoke
that significant variation in risk within smokers is evident, with
in the upper quartile is up to 1.5% per year (20). A model similar
to that described by Bach that incorporates airflow obstruction
into the calculation of risk for lung cancer would be a significant
advance. The University of Colorado SPORE in Lung Cancer
recruited and followed a cohort of high-risk current and ex-
lung cancer in this group was 1.85 per 100 person-years, or six
times that required for tamoxifen chemoprevention of breast
cancer (0.3% per year) (22, 23). Therefore, high-risk groups for
lung cancer can easily be identified on the basis of age, smoking
history, exposure to asbestos, pulmonary function, and family
history. A very recent published report also showed an associa-
tion of spiral computed tomography (CT) detected emphysema
and risk of developing lung cancer (odds ratio [OR], 3.56; 95%
confidence interval [CI], 2.21–5.73) (24). This association was
maintained after controlling for airflow limitation. Ongoing
genetic testing should further clarify and aid in better defining
lung cancer risk in the near future and improve the ability to
identify even higher risk subpopulations. For example, a com-
prehensive study of somatic mutations in 188 human lung
adenocarcinomas identified 26 genes mutated at significantly
high frequencies and provided information on new signaling
new chemopreventive and chemotherapeutic targets (25).
Similar to other common cancers, lung cancer develops as the
result of predictable histologic and genetic abnormalities. The
development of squamous cell lung cancer in the central bron-
chial epithelium starts with normal epithelium and progresses
through hyperplasia, metaplasia, dysplasia, carcinoma in situ to
invasive squamous cell lung cancer. The term ‘‘intraepithelial
neoplasia’’ (IEN) has been used to describe the precursor lesions
(most often moderate to severe dysplasia) that precede the
development of carcinoma in situ and invasive cancer (26, 27).
The presence of IEN, which is most reliably detected with
fluorescence bronchoscopy (28, 29), can then be used to define
high-risk cohorts, and the genetic abnormalities present in IEN
can be used to define cancer risk and assist in the selection of
agents for trials. The natural history of endobronchial dysplastic
lesions is difficult to predict, as some of them may be completely
removedatthe timeof biopsy.Published reportshavestatedthat
37% of severe dysplasias persist or progress (30), and 50% of
188PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 62009
cancer (31). Most importantly, these severely dysplastic lesions
can be targets of chemopreventive trials and, because they
typically contain fewer genetic derangements and signaling
abnormalities, they may be more amenable to treatment.
The premalignant lesions for adenocarcinomas (BAC and
invasive adenocarcinomas) are microscopic proliferations of
atypical pneumocytes that are termed atypical adenomatous
hyperplasias (AAH) (32, 33). These lesions may be detected on
high-resolution CT as ground glass opacities. AAH contain
many of the genetic alterations seen in invasive adenocarcinoma
(including Kras mutations, p53 mutations, epidermal growth
factor receptor mutations , and loss of heterozygosity on
chromosomes 3p, 9p, 17p, and 16q) (32). Promoter hyper-
methylation has also been observed in AAH, and advanced
histologic grade was associated with more hypermethylation of
tumor suppressor genes (35, 36). It is not known at what
frequency AAH progress and how these can be reliably
modeled for preclinical testing. This may be better determined
as the number of AAH lesions undergoing longitudinal clinical
evaluation increases coinciding with improved thoracic imaging
modalities employed in screening trials.
No agents have been validated as effective for lung cancer
chemoprevention (37). The only intervention that has been
shown to be effective in reducing risk of lung cancer is smoking
cessation, most impressively demonstrated prospectively in the
Lung Health Study. In this large study smokers were assigned to
smoking cessation intervention programs or no smoking cessa-
tion intervention, with a resultant 55% reduction in lung cancer
risk observed in successful quitters (38). Early lung cancer
chemoprevention trials were based on epidemiologic data which
suggested that diets high in vitamin A reduced risk (39). Several
large randomized primary and secondary prevention trials were
conducted. Three large trials in primary prevention evaluated
b-carotene plus retinol, b-carotene and/or a-tocopherol, or
b-carotene alone. Three other trials investigated secondary
prevention strategies by administering retinyl palmitate, retinyl
palmitate and/or N-acetylcysteine (NAC), or 13-cis retinoic acid
(6, 12, 13, 37). Unfortunately, the results from these trials were
also disappointing. No protective effect against lung cancer was
observed, and two trials suggested that these agents could
increase the risk of lung cancer in current smokers (12, 13).
Only smoking cessation correlated with a significant reduction
in squamous metaplasia (40). In addition, a recent meta-analysis
of the large b-carotene trials (ATBC, CARET, Physician’s
Health, and Women’s Health) found an increased risk of lung
cancer in current, not former, smokers who received b-carotene
(OR, 1.21; 95% CI, 1.09–1.34) (41). Thus, high doses of a single
antioxidant vitamin do not appear to be a viable chemopre-
ventive strategy. In addition, these trials were based only on
epidemiologic data and required thousands of participants and
considerable resources to complete.
Phase III chemoprevention trials evaluating isoretinoin or
vitamin A/NAC in patients with a prior lung or head and neck
patients, but none have shown a reduction in lung cancer in-
cidence (13, 42). A number of preclinical studies have demon-
strated that corticosteroids, either administered systemically or
by inhalation, can decrease chemical carcinogen induced pulmo-
yielded negative results. Other completed trials that have failed
to yield positive results include the findings that (1) anethole
dithiolethione (an organosulfur compound that increases gluta-
thione-S-transferase and additional phase II enzymes) did not
reverse bronchial dysplasia (44), and (2) inhaled budesonide in
smokers with dysplasia did not induce histologic regression (45).
Phase II intermediate endpoint trials are currently being
conducted, and these trials have emerged as one strategy for
prioritizing agents for longer and more expensive phase III
chemoprevention trials containing a lung cancer endpoint. As
discussed above, there are no established intermediate bio-
markers for lung cancer prevention trials, although IEN or
dysplasia has been proposed as an endpoint for studies of
squamous cell carcinoma (5) and AAH lesions may also exhibit
a spectrum that would allow for progression to be monitored
(46). Validation of intermediate endpoint biomarkers will rely
on a proven chemoprevention treatment, and even then uncer-
tainties remain as to whether they will be predictive of outcome
(47, 48). However, given the difficulties in choosing agents for
phase III chemoprevention trials, modulation of biologically
plausible intermediate endpoint biomarkers is one rational
factor, among others, in prioritizing agents for more thorough
testing. Metaplasia index and sputum cytologic atypia have
been used in some trials, but they have also not been validated
(40, 49, 50). Metaplasia has been criticized, as it can occur as
a response to injury and is less specific for tobacco smoke
exposure than dysplasia. The histologic grading of dysplastic
endobronchial lesions was used in several recent trials, but the
best scoring methodology for assessing changes in bronchial
histology has not been established (44, 45, 51), although many
of the current trials are attempting to use similar criteria. The
use of more advanced biological and molecular markers
remains an area of active investigation (26), and many current
trials are providing biological samples for advanced testing.
One area of definitive advancement in chemoprevention is in
preclinical testing. Historical chemoprevention studies would
have benefited from animal studies. Mice develop pulmonary
adenomas that progress to adenocarcinomas in response to
a number of agents, including ethyl carbamate, nicotine-derived
carcinogens, or tobacco smoke exposure (52, 53). In addition,
investigators have developed a number of transgenic models in
which viral oncogenes or transforming ras mutants are selec-
tively and conditionally expressed in lung tissue (54). The
murine tumors developed in these models have many similar-
ities to human adenocarcinoma, ranging from specific markers
to gene expression patterns (52, 55). Models of squamous cell
lung cancer have also been developed, and some models (for
example, NTCU) also results in dysplastic lesions that are
similar to those found during bronchoscopy and can therefore
studies (56, 57). More recent chemoprevention trials rely on
preclinical testing in animals and this should allow for improved
screening of potential agents prior to clinical trials.
There are a number of chemoprevention trials currently being
conducted, and the majority of these are phase II trials based on
epidemiologic and preclinical studies. The ongoing studies
summarized below are based on molecular pathways and were
identified as ‘‘actively recruiting’’ on the NIH-sponsored clinical
trial website (http://clinicaltrials.gov).
Alterations in eicosanoid production have been associated with
many types of cancer, including lung cancer. Inhibition of
Keith: Lung Cancer Chemoprevention 189
cyclooxygenase (COX-1 and COX-2, PGH2synthase) activity
decreases eicosanoid production and prevents lung cancer in
animal models (58). A large number of COX-2–dependent
genes are involved in lung tumorigenesis (reviewed in Refer-
ence 59), and COX-2 can be up-regulated in IEN and many
NSCLC. Therefore, studies evaluating the role of COX-2
inhibition (celecoxib) are currently enrolling, but preliminary
results are not available. A separate Phase II trial evaluating the
effects of nonspecific COX inhibitor sulindac on endobronchial
histology has also been initiated.
PGI2is a PGH2metabolite with antiinflammatory, antiprolifer-
ative, and potent antimetastatic properties. Preclinical studies in
transgenic mice with selective pulmonary prostacyclin synthase
overexpression showed significantly reduced lung tumor multi-
plicity and incidence in response to either chemical carcinogens
or exposure to tobacco smoke (60, 61). Iloprost, a long-lasting
oral prostacyclin analog, also inhibits lung tumorigenesis in wild-
type mice. These studies formed the basis of an NCI-sponsored
double-blind, placebo-controlled clinical chemoprevention trial
in which subjects at high risk for lung cancer are being treated
with iloprost or placebo. The primary endpoint for the trial is
endobronchial histology, and subjects have fluorescence bron-
choscopy performed at study entry and after 6 months of
treatment. Enrollment has been completed and results should
be available in 2009.
Tobacco carcinogens can increase 5-lipoxygenase (5-LO), leu-
kotriene B4, and COX-2. 5-LO expression increases in lung
cancer, and 5-HETE (one product of 5-LO) augments the
growth of lung cancer cell lines (62). Inhibition of 5-LO and
5-LO–activating protein (FLAP) inhibits lung tumorigenesis in
murine studies (63), and a chemoprevention trial with the 5-LO
inhibitor zileuton has been initiated.
The use of selenium for cancer prevention has been an area of
considerable interest, as it improves cellular defense against
oxidative stress (64). The Nutritional Prevention of Cancer trial
tested selenium for the prevention of nonmelanoma skin cancer,
and while it did not prevent skin cancer, the subjects in the trial
exhibited a 44% decrease in lung cancer incidence (64). Further
analysis of the trial determined that selenium supplementation
baseline plasma selenium levels (65). The ongoing SELECT
(Selenium and Vitamin E Cancer Prevention Trial) trial for
prostate cancer chemoprevention has established lung cancer
as a secondary endpoint. SELECT trial participants were re-
cently suspended from taking supplements due to a lack of
efficacy in preventing prostate cancer and concerns about long
Green Tea and Broccoli Sprout Extracts
Green tea extract contains multiple polyphenols (including poly-
phenol E), and the protective effects in cancer chemoprevention
arise from the inhibition of cytochrome p450 (thereby blocking
the bioactivation of carcinogens) and the activation of phase II
detoxifying enzymes via the MAPK pathway (66). Broccoli
sprout extract contains phytochemicals that also activate phase
II detoxifying enzymes and protect against oxidative stress–
induced DNA damage. Trials of oral supplementation with both
agents are also currently being conducted, particularly in pre-
malignant lesions with specific genetic alterations.
FUTURE TRIALS AND ENDPOINT BIOMARKERS
Advances in our understanding of the early events in lung
tumorigenesis naturally has led to the discovery of important
pathways that can be targeted by potential chemopreventive
agents. Future trials must build upon the results of the current
trials, and it remains vitally important to identify and validate
intermediate endpoint biomarkers to allow for a more rapid
be targeted is contained in Table 1, and below are a couple of
examples of classes of agents that may be evaluated in the future.
Pathway targeted chemotherapeutic agents may also play an
Future trials will also need to be based on improved bio-
markers of both risk and response. Validated intermediate
endpoints will allow for shorter trials that do not have cancer
as an endpoint, but these intermediate biomarkers need to meet
the following requirements: expression correlates with disease
course; expression is different between normal and pre-malignant
tissue; and evaluation must be reproducible. Examples of bio-
markers being evaluated are Ki67, p53, EGFR expression, and
gene methylation. These biomarkers must ultimately be validated
in prospective clinical trials.
Prostacyclin analogs like iloprost selectively increases PPARg
agents, or by molecular overexpression, strongly inhibits trans-
formed growth, as assessed by colony formation in soft agar (67,
68). In addition, NSCLC cells overexpressing PPARg exhibit
significantly less invasiveness and metastasis compared with
control cells both in vitro and in a rat orthotopic lung xenograft
model (67). The thiazolidinediones (TZDs) are oral PPARg
agonists, and lung cancer incidence in diabetics on PPARg
agonists was decreased 33% when compared with diabetics on
shown to induce 15-hydroxyprostaglandin dehydrogenase (15-
PGDH), the enzyme that inactivates the anti-apoptotic and
immunosuppressive PGE2by conversion to 15-keto prostaglan-
dins (70).Arecentreport hasshown thatPPARgoverexpression
chemoprevents murine lung cancer (71). This class of agents will
likely be employed in future chemoprevention trials.
Mammalian Target of Rapamycin Inhibitors
Mammalian target of rapamycin (mTOR) is a serine/threonine
kinase that mediates the akt signaling pathway. Human lung
TABLE 1. CURRENT AND POTENTIAL FUTURE TARGETS FOR
LUNG CANCER CHEMOPREVENTION STUDIES
Prostacyclin analogs (75)
COX inhibitors (76)
PPARg agonists (71)
mTOR inhibitors (74, 77)
Corticosteroids (78, 79)
Farnesyltransferase inhibitors (80)
EGFR inhibitors (81)
Ras inhibitors (83)
Fatty acid synthase inhibitors (84)
Demethylating agents (85)
Angiogenesis inhibitors (86)
Definition of abbreviations: COX 5 cyclooxygenase; EGFR 5 epidermal growth
factor receptor; mTOR 5 mammalian target of rapamycin.
190 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 62009
cancers, as well as dysplastic endobronchial lesions (72), have
been shown to exhibit activation of the akt/mTOR pathway.
Tobacco-specific carcinogens also activate this pathway (73, 74)
and mTOR inhibitors (rapamycin and sirolimus) can success-
fully induce cell cycle arrest. Phase I studies evaluating the
mTOR inhibitors are in the planning stage.
Due to the potentially large number of genetic and metabolic
derangements in pre-malignant lesions, combinations of agents
may prove to the most effective route to chemoprevention. This
could largely be directed by genetic or proteomic abnormalities
detected in the dysplastic lesions, and similar to personalized
lung cancer chemotherapy, chemoprevention may also be di-
rected on the basis of specific ‘‘signatures’’ (gene expression,
proteomics, etc.) being present in biopsy specimens from high-
risk individuals. The most effective chemoprevention may de-
pend on abnormalities found in biological specimens.
needfor effectivelungcancer chemopreventionbeyondsmoking
cessation. The understanding of molecular changes present in
pre-malignant lesions continues to progress and this has resulted
in more targeted single-agent prevention studies. In addition,
higher-risk subjects can now be identified (including tobacco
history, occupational history, airflow limitation, and family
history), and trials can be enriched for these subjects. The lung
chemoprevention field still needs validated secondary endpoint
biomarkers, and the current trials are evaluating histology from
lung biopsy specimens, along with targeted markers in specific
pathways. Eventually, phase III trials with lung cancer as the
be recommended for widespread use in high-risk populations.
These trials are difficult, expensive, and time-consuming, and the
above-outlined strategies should assist in prioritizing agents for
Phase III trials. Information from epidemiology, cell biology,
preclinical models, and phase II intermediate endpoint trials all
may be useful to inform choices of agents for definitive phase III
chemoprevention trials. It is clear that we must continue to
promote successful smoking cessation and tobacco control. Lung
cancer chemoprevention research will advance more quickly as
the number of subjects involved in clinical trials increases, and at
the current time subjects should only be encouraged to use
chemopreventive agents in the context of a clinical trial.
Conflict of Interest Statement: R.L.K. and other investigators have a patent
application on the use of prostacyclin analogues for cancer chemoprevention.
1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics,
2007. CA Cancer J Clin 2007;57:43–66.
2. Lynch TJ, Adjei AA, Bunn PA Jr, Eisen TG, Engelman J, Goss GD,
Haber DA, Heymach JV, Janne PA, Johnson BE, et al. Summary
statement: novel agents in the treatment of lung cancer: advances in
epidermal growth factor receptor-targeted agents. Clin Cancer Res
3. Tong L, Spitz MR, Fueger JJ, Amos CA. Lung carcinoma in former
smokers. Cancer 1996;78:1004–1010.
4. NicholsonAG, PerryLJ,CuryPM,JacksonP,McCormick CM,CorrinB,
invasive squamous lesions of the bronchus: a study of inter-observer
and intra-observer variation. Histopathology 2001;38:202–208.
5. O’Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ, Hong
WK, Fabian CJ, Sigman CC, Bertagnolli MM, Stratton SP, Lam S,
et al. Treatment and prevention of intraepithelial neoplasia: an
important target for accelerated new agent development. Clin Cancer
6. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR,
Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, et al.
Effects of a combination of beta carotene and vitamin A on lung
cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.
7. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical
carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed
8. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford
LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, et al. The
influence of finasteride on the development of prostate cancer. N Engl
J Med 2003;349:215–224.
9. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon
GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, et al. The
effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adeno-
matous polyposis. N Engl J Med 2000;342:1946–1952.
10. Kinsinger LS, Harris R, Woolf SH, Sox HC, Lohr KN. Chemoprevention
of breast cancer: a summary of the evidence for the US Preventive
Services Task Force. Ann Intern Med 2002;137:59–69.
11. Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA Jr,
Johnson GL, Hirsch FR, Merrick DT, Franklin WA, et al. Analysis of
orthologous gene expression between human pulmonary adenocarci-
noma and a carcinogen-induced murine model. Am J Pathol 2005;167:
12. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook
NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, et al. Lack of
effect of long-term supplementation with beta carotene on the
incidence of malignant neoplasms and cardiovascular disease. N Engl
J Med 1996;334:1145–1149.
13. van Zandwijk N, Dalesio O, Pastorino U, de Vries N, van Tinteren H.
EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in
patients with head and neck cancer or lung cancer. For the EUropean
Organization for Research and Treatment of Cancer Head and Neck
14. Omenn GS. Chemoprevention of lung cancer: the rise and demise of
beta-carotene. Annu Rev Public Health 1998;19:73–99.
15. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group.
The effect of vitamin E and beta carotene on the incidence of lung
cancer and other cancers in male smokers. N Engl J Med 1994;330:
16. Johnson BE. Second lung cancers in patients after treatment for an
initial lung cancer. J Natl Cancer Inst 1998;90:1335–1345.
17. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death
in the United States, 1970–2002. JAMA 2005;294:1255–1259.
18. Tockman MS, Anthonisen NR, Wright EC, Donithan MG. Airways
obstruction and the risk for lung cancer. Ann Intern Med 1987;106:
19. Islam SS, Schottenfeld D. Declining FEV1 and chronic productive cough
in cigarette smokers: a 25-year prospective study of lung cancer
incidence in Tecumseh, Michigan. Cancer Epidemiol Biomarkers Prev
20. Bach PB, Kelley MJ, Tate RC, McCrory DC. Screening for lung cancer:
a review of the current literature. Chest 2003;123:72S–82S.
21. Kennedy TC, Proudfoot SP, Franklin WA, Merrick TA, Saccomanno G,
Corkill ME, Mumma DL, Sirgi KE, Miller YE, Archer PG, et al.
Cytopathological analysis of sputum in patients with airflow ob-
struction and significant smoking histories. Cancer Res 1996;56:
22. Prindiville SA, Byers T, Hirsch FR, Franklin WA, Miller YE, Vu KO,
Wolf HJ, Baron AE, Shroyer KR, Zeng C, et al. Sputum cytological
atypia as a predictor of incident lung cancer in a cohort of heavy
smokers with airflow obstruction. Cancer Epidemiol Biomarkers Prev
23. Early Breast Cancer Trialists’ Colloborative Group (EBCTCG). Effects
of chemotherapy and hormonal therapy for early breast cancer on
recurrence and 15-year survival: an overview of the randomised trials.
24. Wilson DO, Weissfeld JL, Balkan A, Schragin JG, Fuhrman CR, Fisher
SN, Wilson J, Leader JK, Siegfried J, Shapiro SD, et al. Association of
radiographic emphysema and airflow obstruction with lung cancer.
Am J Respir Crit Care Med 2008;178:738–744.
25. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K,
Sougnez C, Greulich H, Muzny DM, Morgan MB, et al. Somatic
mutations affect key pathways in lung adenocarcinoma. Nature 2008;
Keith: Lung Cancer Chemoprevention191
26. Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CC, Pearce HL, Reid
BJ, Szabo E, Jordan VC, Spitz MR, Mills GB, et al. Progress in
chemoprevention drug development: the promise of molecular bio-
markers for prevention of intraepithelial neoplasia and cancer–a plan
to move forward. Clin Cancer Res 2006;12:3661–3697.
27. Kelloff GJ, Sigman CC. Assessing intraepithelial neoplasia and drug
safety in cancer-preventive drug development. Nat Rev Cancer 2007;
28. Lam S, Kennedy T, Unger M, Miller YE, Gelmont D, Rusch V, Gipe B,
Howard D, LeRiche JC, Coldman A, et al. Localization of bronchial
intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest
29. Lam S, Macaulay C, LeRiche JC, Palcic B. Detection and localization of
early lung cancer by fluorescence bronchoscopy. Cancer 2000;89:
30. Bota S, Auliac JB, Paris C, Metayer J, Sesboue R, Nouvet G, Thiberville
L. Follow-up of bronchial precancerous lesions and carcinoma in situ
using fluorescence endoscopy. Am J Respir Crit Care Med 2001;164:
31. Venmans BJ, Van Boxem TJ, Smit EF, Postmus PE, Sutedja TG.
Outcome of bronchial carcinoma in situ. Chest 2000;117:1572–1576.
32. Westra WH. Early glandular neoplasia of the lung. Respir Res 2000;1:
33. Beasley MB, Brambilla E, Travis WD. The 2004 World Health
Organization classification of lung tumors. Semin Roentgenol 2005;
34. Ikeda K, Nomori H, Ohba Y, Shibata H, Mori T, Honda Y, Iyama K,
Kobayashi T. Epidermal growth factor receptor mutations in multi-
centric lung adenocarcinomas and atypical adenomatous hyperpla-
sias. J Thorac Oncol 2008;3:467–471.
35. Licchesi JD, Westra WH, Hooker CM, Herman JG. Promoter hyper-
methylation of hallmark cancer genes in atypical adenomatous
hyperplasia of the lung. Clin Cancer Res 2008;14:2570–2578.
36. Licchesi JD, Westra WH, Hooker CM, Machida EO, Baylin SB,
Herman JG. Epigenetic alteration of Wnt pathway antagonists in
progressive glandular neoplasia of the lung. Carcinogenesis 2008;29:
37. Omenn GS. Chemoprevention of lung cancer is proving difficult and
frustrating, requiring new approaches. J Natl Cancer Inst 2000;92:959–
JE. The effects of a smoking cessation intervention on 14.5-year
mortality: a randomized clinical trial. Ann Intern Med 2005;142:233–
39. McLaughlin JK,Hrubec Z, Blot WJ,FraumeniJF Jr. Smokingand cancer
mortality among US veterans: a 26-year follow-up. Int J Cancer 1995;
40. Kurie JM, Lee JS, Khuri FR, Mao L, Morice RC, Lee JJ, Walsh GL,
Broxson A, Lippman SM, Ro JY, et al. N-(4-hydroxyphenyl)retina-
mide in the chemoprevention of squamous metaplasia and dysplasia
of the bronchial epithelium. Clin Cancer Res 2000;6:2973–2979.
41. Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the
possible risk of lung cancer among smokers versus former smokers:
a meta-analysis and evaluation of national brands. Cancer 2008;113:
42. Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE,
Khuri FR, Marks R, Winn RJ, Fry W, et al. Randomized phase III
intergroup trial of isotretinoin to prevent second primary tumors in
stage I non-small-cell lung cancer. J Natl Cancer Inst 2001;93:605–618.
43. Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Steele
VE, Kelloff GJ. Chemoprevention of pulmonary carcinogenesis by
aerosolized budesonide in female A/J mice. Cancer Res 1997;57:5489–
44. Lam S, MacAulay C, Le Riche JC, Dyachkova Y, Coldman A, Guillaud
M, Hawk E, Christen MO, Gazdar AF. A randomized phase IIb trial
of anethole dithiolethione in smokers with bronchial dysplasia. J Natl
Cancer Inst 2002;94:1001–1009.
45. Lam S, leRiche JC, McWilliams A, MacAulay C, Dyachkova Y, Szabo
E, Mayo J, Schellenberg R, Coldman A, Hawk E, et al. A randomized
phase IIb trial of pulmicort turbuhaler (budesonide) in people with
dysplasia of the bronchial epithelium. Clin Cancer Res 2004;10:6502–
46. Dacic S. Pulmonary preneoplasia. Arch Pathol Lab Med 2008;132:1073–
47. Prentice RL. Surrogate endpoints in clinical trials: definition and
operational criteria. Stat Med 1989;8:431–440.
48. Berger VW. Does the Prentice criterion validate surrogate endpoints?
Stat Med 2004;23:1571–1578.
49. Saccomanno G, Moran PG, Schmidt R, Hartshorn DF, Brian DA,
Dreher WH, Sowada BJ. Effects of 13-CIS retinoids on premalignant
and malignant cells of lung origin. Acta Cytol 1982;26:78–85.
50. McLarty JW, Holiday DB, Girard WM, Yanagihara RH, Kummet TD,
Greenberg SD. Beta-Carotene, vitamin A, and lung cancer chemo-
prevention: results of an intermediate endpoint study. Am J Clin Nutr
51. van den Berg RM, van Tinteren H, van Zandwijk N, Visser C, Pasic A,
Kooi C, Sutedja TG, Baas P, Grunberg K, Mooi WJ, et al. The
influence of fluticasone inhalation on markers of carcinogenesis in
bronchial epithelium. Am J Respir Crit Care Med 2007;175:1061–1065.
52. Malkinson AM. Primary lung tumors in mice as an aid for understand-
ing, preventing, and treating human adenocarcinoma of the lung.
Lung Cancer 2001;32:265–279.
53. Witschi H, Espiritu I, Dance ST, Miller MS. A mouse lung tumor model
of tobacco smoke carcinogenesis. Toxicol Sci 2002;68:322–330.
54. Kim CF, Jackson EL, Kirsch DG, Grimm J, Shaw AT, Lane K, Kissil J,
Olive KP, Sweet-Cordero A, Weissleder R, et al. Mouse models of
human non-small-cell lung cancer: raising the bar. Cold Spring Harb
Symp Quant Biol 2005;70:241–250.
55. Sweet-Cordero A, Tseng GC, You H, Douglass M, Huey B, Albertson
D, Jacks T. Comparison of gene expression and DNA copy number
changes in a murine model of lung cancer. Genes Chromosomes
56. Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C, Lubet
R, You M. A chemically induced model for squamous cell carcinoma
of the lung in mice: histopathology and strain susceptibility. Cancer
57. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A.
Induction of small cell lung cancer by somatic inactivation of both
Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003;4:181–
58. Castonguay A, Rioux N. Inhibition of lung tumourigenesis by sulindac:
comparison of two experimental protocols. Carcinogenesis 1997;18:
59. Krysan K, Reckamp KL, Sharma S, Dubinett SM. The potential and
rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med
60. Keith RL, Miller YE, Hoshikawa Y, Moore MD, Gesell TL, Gao B,
Malkinson AM, Golpon HA, Nemenoff RA, Geraci MW. Manipu-
lation of pulmonary prostacyclin synthase expression prevents murine
lung cancer. Cancer Res 2002;62:734–740.
61. Keith RL, Miller YE, Hudish TM, Girod CE, Sotto-Santiago S, Franklin
WA, Nemenoff RA, March TH, Nana-Sinkam SP, Geraci MW. Pulmo-
nary prostacyclin synthase overexpression chemoprevents tobacco
smoke lung carcinogenesis in mice. Cancer Res 2004;64:5897–5904.
62. Tang DG, Chen YQ, Honn KV. Arachidonate lipoxygenases as essential
regulators of cell survival and apoptosis. Proc Natl Acad Sci USA
63. Gunning WT, Kramer PM, Steele VE, Pereira MA. Chemoprevention by
lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-
induced lung tumors in mice. Cancer Res 2002;62:4199–4201.
64. van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Dorant E,
Hermus RJ, Sturmans F. A prospective cohort study on selenium
status and the risk of lung cancer. Cancer Res 1993;53:4860–4865.
65. Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW, Clark LC,
Marshall JR. Selenium supplementation and lung cancer incidence:
an update of the nutritional prevention of cancer trial. Cancer
Epidemiol Biomarkers Prev 2002;11:1285–1291.
66. Yu R, Jiao JJ, Duh JL, Gudehithlu K, Tan TH, Kong AN. Activation of
mitogen-activated protein kinases by green tea polyphenols: potential
signaling pathways in the regulation of antioxidant-responsive ele-
ment-mediated phase II enzyme gene expression. Carcinogenesis
67. Bren-Mattison Y, Van Putten V, Chan D, Winn R, Geraci MW,
Nemenoff RA. Peroxisome proliferator-activated receptor-gamma
(PPAR(gamma)) inhibits tumorigenesis by reversing the undifferen-
tiated phenotype of metastatic non-small-cell lung cancer cells
(NSCLC). Oncogene 2005;24:1412–1422.
68. Wick M, Hurteau G, Dessev C, Chan D, Geraci MW, Winn RA, Heasley
LE, Nemenoff RA. Peroxisome proliferator-activated receptor-
gamma is a target of nonsteroidal anti-inflammatory drugs mediating
cyclooxygenase-independent inhibition of lung cancer cell growth.
Mol Pharmacol 2002;62:1207–1214.
192PROCEEDINGS OF THE AMERICAN THORACIC SOCIETYVOL 62009
69. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada
MV, Kim L, Kim PJ, Owens RJ, Lang NP. Thiazolidinediones and the
risk of lung, prostate, and colon cancer in patients with diabetes.
J Clin Oncol 2007;25:1476–1481.
70. Hazra S, Batra RK, Tai HH, Sharma S, Cui X, Dubinett SM.
Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-
small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin
dehydrogenase. Mol Pharmacol 2007;71:1715–1720.
71. Nemenoff RA, Hudish TM, Mozer AB, Snee A, Narumiya S, Stearman
RS, Winn RA, Geraci MW, Keith RL. Prostacyclin prevents murine
lung cancer independent of the membrane receptor by activation of
PPARa ˜. Cancer Prevention Research 2008;1:349–356.
72. Tsao AS, McDonnell T, Lam S, Putnam JB, Bekele N, Hong WK, Kurie
JM. Increased phospho-AKT (Ser(473)) expression in bronchial
dysplasia: implications for lung cancer prevention studies. Cancer
Epidemiol Biomarkers Prev 2003;12:660–664.
73. West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris
C, Belinsky S, Dennis PA. Rapid Akt activation by nicotine and
a tobacco carcinogen modulates the phenotype of normal human
airway epithelial cells. J Clin Invest 2003;111:81–90.
74. West KA, Linnoila IR, Belinsky SA, Harris CC, Dennis PA. Tobacco
carcinogen-induced cellular transformation increases activation of the
phosphatidylinositol 39-kinase/Akt pathway in vitro and in vivo.
Cancer Res 2004;64:446–451.
75. Keith RL, Geraci MW. Prostacyclin in lung cancer. J Thorac Oncol.
76. Mao JT, Cui X, Reckamp K, Liu M, Krysan K, Dalwadi H, Sharma S,
Hazra S, Strieter R, Gardner B, et al. Chemoprevention strategies
with cyclooxygenase-2 inhibitors for lung cancer. Clin Lung Cancer
77. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the
PI3K/Akt/mTOR pathway: effective combinations and clinical con-
siderations. Drug Resist Updat 2008;11:32–50.
78. WattenbergLW, WiedmannTS, EstensenRD, Zimmerman CL, Galbraith
AR, Steele VE, Kelloff GJ. Chemoprevention of pulmonary carcino-
dipropionate and by the combination of aerosolized budesonide and
dietary myo-inositol. Carcinogenesis 2000;21:179–182.
79. Parimon T, Chien JW, Bryson CL, McDonell MB, Udris EM, Au DH.
Inhaled corticosteroids and risk of lung cancer among patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
80. Zhang Z, Wang Y, Lantry LE, Kastens E, Liu G, Hamilton AD, Sebti
SM, Lubet RA, You M. Farnesyltransferase inhibitors are potent lung
cancer chemopreventive agents in A/J mice with a dominant-negative
p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 2003;22:
81. Merrick DT, Kittelson J, Winterhalder R, Kotantoulas G, Ingeberg S,
Keith RL, Kennedy TC, Miller YE, Franklin WA, Hirsch FR.
Analysis of c-ErbB1/epidermal growth factor receptor and c-ErbB2/
HER-2 expression in bronchial dysplasia: evaluation of potential
targets for chemoprevention of lung cancer. Clin Cancer Res 2006;12:
82. Liby K, Black CC, Royce DB, Williams CR, Risingsong R, Yore MM,
Liu X, Honda T, Gribble GW, Lamph WW, et al. The rexinoid
LG100268 and the synthetic triterpenoid CDDO-methyl amide are
more potent than erlotinib for prevention of mouse lung carcinogen-
esis. Mol Cancer Ther 2008;7:1251–1257.
83. Yang Y, Wislez M, Fujimoto N, Prudkin L, Izzo JG, Uno F, Ji L, Hanna
AE, Langley RR, Liu D, et al. A selective small molecule inhibitor of
c-Met, PHA-665752, reverses lung premalignancy induced by mutant
K-ras. Mol Cancer Ther 2008;7:952–960.
84. Orita H, Coulter J, Tully E, Kuhajda FP, Gabrielson E. Inhibiting fatty
acid synthase for chemoprevention of chemically induced lung
tumors. Clin Cancer Res 2008;14:2458–2464.
85. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in
neoplasia: pathophysiology and therapeutic implications. Ann Intern
86. Merrick DT, Haney J, Petrunich S, Sugita M, Miller YE, Keith RL,
Kennedy TC, Franklin WA. Overexpression of vascular endothelial
growth factor and its receptors in bronchial dypslasia demonstrated
by quantitative RT-PCR analysis. Lung Cancer 2005;48:31–45.
Keith: Lung Cancer Chemoprevention193