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
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Keith: Lung Cancer Chemoprevention193