TOBACCO AND LUNG CANCER

Tobacco and Lung Cancer: Risks, Trends, and Outcomes in

Patients with Cancer
Graham W. Warren, MD, PhD, and K. Michael Cummings, PhD

OVERVIEW

Tobacco use, primarily associated with cigarette smoking, is the largest preventable cause of cancer mortality, responsible for
approximately one-third of all cancer deaths. Approximately 85% of lung cancers result from smoking, with an additional fraction
caused by secondhand smoke exposure in nonsmokers. The risk of lung cancer is dose dependent, but can be dramatically reduced with
tobacco cessation, especially if the person discontinues smoking early in life. The increase in lung cancer incidence in different
countries around in the world parallels changes in cigarette consumption. Lung cancer risks are not reduced by switching to filters or
low-tar/low-nicotine cigarettes. In patients with cancer, continued tobacco use after diagnosis is associated with poor therapeutic
outcomes including increased treatment-related toxicity, increased risk of second primary cancer, decreased quality of life, and
decreased survival. Tobacco cessation in patients with cancer may improve cancer treatment outcomes, but cessation support is often
not provided by oncologists. Reducing the health related effects of tobacco requires coordinated efforts to reduce exposure to tobacco,
accurately assess tobacco use in clinical settings, and increase access to tobacco cessation support. Lung cancer screening and
coordinated international tobacco control efforts offer the promise to dramatically reduce lung cancer mortality in the coming decades.

T obacco use is the largest preventable cause of cancer and

cancer mortality, responsible for approximately one-
third of all cancer deaths annually.1 Suffıcient evidence has
been accumulated to infer a causal relationship between to-
bacco use and cancers of the lung, larynx, oral cavity, phar-
ynx, esophagus, pancreas, bladder, kidney, cervix, stomach,
and acute myeloid leukemia, with additional evidence sug-
gesting a causal relationship for colorectal and liver cancer.2
There are more than 60 known or suspected carcinogens in
cigarette smoke that form DNA adducts and mutations, lead-
ing to loss of normal growth control mechanisms. In addition
to substantial cancer risks, tobacco use also increases risk
for other life-threatening chronic illnesses, including cardio-
vascular disease, stroke, pulmonary disease, and adverse
health effects related to fertility, bone density, vision, and peptic
ulcer disease. The purpose of this article is to present the historic
and current trends of tobacco use as relates to lung cancer, dis-
cuss the effects of tobacco on outcomes in patients with lung
cancer, discuss the current status of tobacco assessment and
cessation in patients with cancer, and present potential
mechanisms to reduce the risks associated with tobacco use.
THE LUNG CANCER EPIDEMIC
In the United States in 2012, there were an estimated
226,000 new lung cancer cases diagnosed and 160,000 deaths
resulting from lung cancer, accounting for more cancer
deaths than prostate cancer, breast cancer, and colon/rectal
cancer combined.3 The situation was much different at the
beginning of the 20th century, when cigarettes were not the
predominate form of tobacco consumed and there just of a
few hundred cases of lung cancer diagnosed annually (Fig. 1).
The rapid increase in lung cancer deaths observed during the
20th century, fırst seen in male and then later in female smok-
ers, can be traced directly to the wide-scale adoption of com-
mercial cigarettes, which were engineered to make it easy to
inhale smoke into the lungs—speeding nicotine delivery to
the brain and making cigarette smoking highly addictive.4
The invention of machinery that allowed for the rapid pro-
duction of cigarettes, coupled with World War I, provided
the perfect opportunity to introduce cigarettes to large num-
bers of soldiers whose primary tobacco use up to that time
had been with cigars, pipe tobacco, and chewing tobacco.
Soldiers received a weekly ration of 50 cigarettes, and many
returned from Europe as addicted smokers.5 The early evi-
dence of the adverse health effects of cigarette smoking began
to appear about a decade later as lung cancer death rates
steadily increased. As the early cohorts of cigarette smokers
began to die as result of lung cancer in large numbers, it be-
came more diffıcult to persuade the American public that
cigarette smoking was not detrimental to health. Cigarette

From the Department of Radiation Oncology, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Psychiatry and Behavioral Sciences, Hollings Cancer
Center, Medical University of South Carolina, Charleston SC.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

Corresponding author: Graham W. Warren, MD, PhD, Department of Radiation Oncology, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center,
Medical University of South Carolina, 169 Ashley Ave., Charleston, SC 29425; email: warrengw@musc.edu

© 2013 by American Society of Clinical Oncology.

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WARREN AND CUMMINGS
FIG 1. Timeline of trends in tobacco use and lung cancer.
Abbreviations: US, United States; PCC, per capita consumption.
companies introduced fılters (which were essentially the
same cigarettes with tiny vent holes added to the fılter) and
lower-yield cigarettes to alleviate growing concerns about the
risks of smoking.6 Many people switched to fılters and
“lower-tar and -nicotine” cigarettes under the assumption
that these newer cigarettes were less risky than their unfıl-
tered predecessors. However, recent evidence indicates that
the relative risk of smoking and lung cancer actually in-
creased over time, suggesting that the switch to fıltered and
later lower–machine-measured–tar and -nicotine cigarettes
made smoking even more dangerous, perhaps because the
design alterations helped to promote deeper inhalation of
smoke into the airways.4
KEY POINTS
䡠 In the 20th century, lung cancer went from being a rare
disease to the dominant cause of cancer mortality because
of the increase in cigarette consumption.
䡠 Tobacco smoke contains more than 7,000 chemicals and
more than 60 known or suspected carcinogens. Repeated
exposure to tobacco smoke can overwhelm DNA repair
mechanisms and result in genetic alterations that disrupt
normal cellular growth and regulation, resulting in cancer.
䡠 In patients with cancer, exposure to tobacco smoke can
also alter tumor biology in ways that decrease the
effectiveness of cancer treatments, resulting in decreased
disease-free and overall survival.
䡠 Although evidence suggests that tobacco cessation
improves outcomes in patients with cancer, tobacco
cessation treatments are not routinely provided to patients
by oncologists.
䡠 National and international efforts are working to promote
early detection of lung cancer, but improved outcomes will
also require efforts to prevent use of tobacco and promote
tobacco cessation among current users.
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As a consequence of declining smoking prevalence, lung
cancer mortality rates have declined since the early 1990s.
Compared with those of 1964, smoking prevalence rates have
halved from 40% to 20%.6 A recent analysis of smoking and
lung cancer mortality trends in the period between 1975 and
2000 suggests that an estimated 800,000 lung cancer deaths
have been averted as a result of efforts by the public health
community to discourage smoking in the United States.7
However, this same study also observed that 70% of lung can-
cer deaths could have been prevented if cigarette companies
stopped marketing their products in response to the Surgeon
General’s 1964 report on smoking and health.
Fortunately, times have changed and so have public atti-
tudes about cigarette smoking. When the 1964 Surgeon Gen-
eral’s report was released, cigarette companies were major
sponsors of popular television shows on all three television
networks. It was common to see doctors, athletes, and movie
and television celebrities advertising different cigarette
brands, and smoking was permitted nearly everywhere with-
out restriction.5 Gradually, the public’s perception of smok-
ing shifted from a viewpoint of smoking as a minor health
concern to increasing acceptance that there was serious
health risks associated with smoking, which in turn made
smoking less acceptable as a social practice.8 In parallel, dur-
ing the same timeframe, people became increasingly aware
that smoking was a major cause of cancer. Fortunately, re-
ductions in tobacco use were followed by a reduction in lung
cancer incidence and mortality.
TOBACCO, TUMOR BIOLOGY, AND THE PATIENT
WITH CANCER
The 2010 Surgeon General’s report on smoking and health
describes the mechanisms by which tobacco use causes can-
cer and other diseases.2 Tobacco smoke contains more
than 7,000 chemicals and more than 60 known or suspected
carcinogens. Every puff on a cigarette causes DNA damage.
 TOBACCO AND LUNG CANCER

Repeated exposure to tobacco smoke can overwhelm DNA
repair mechanisms and result in genetic alterations that dis-
rupt normal cellular growth and regulation, resulting in can-
cer. The reason that people repeatedly expose themselves to
the toxins in tobacco smoke is not because of free choice, but
rather because of nicotine addiction. Those who experience
the vast majority of illnesses resulting from tobacco use are
those who are the most dependent on nicotine.
Although the etiology of smoking-related cancers has been
studied extensively, there is proportionately little informa-
tion on the adverse effects of tobacco use after a person is
diagnosed with cancer. Figure 2 illustrates how the biologic
mechanisms associated with tobacco use before diagnosis
likely work to produce continued damage to patients with
cancer who smoke after a cancer diagnosis. Clinically, several
studies show that tobacco use is associated with poor out-
comes in patients with cancer. An analysis of long-term out-
comes in patients with cancer demonstrates that current
smoking at diagnosis in patients with lung cancer increases
all-cause mortality and disease-specifıc mortality compared
with never-smokers, former smokers (who quit at least 12
months before diagnosis), and recent quitters (who quit
within 12 months of diagnosis).9 In the same study, current
tobacco use was associated with decreased overall and
disease-free survival for the entire cohort of patients with
cancers, including cancers from 13 different disease sites. In a
separate review of studies in early-stage lung cancer, smoking
increased risk of all-cause mortality, disease recurrence, and
risk for second primary cancer.10 Similar risks associated
with current smoking have also been noted for survival in
patients with advanced lung cancer.11 Smoking also increases
risk of surgical complication and noncancer comorbidity
that can increase mortality in patients with lung cancer.12-13
Quality of life is also decreased by smoking in patients with
lung cancer, as well as family members and caretakers of pa-
tients with lung cancer.14
In the assessment of tobacco use and outcomes for patients
with cancer, it is important to differentiate ever smoking
from current smoking, and to consider the method by which
tobacco use is defıned. For example, studies noted earlier
demonstrate that current smoking is associated with adverse
outcomes in patients with lung cancer.9-14 Ever smoking has
also been associated with poor outcomes in several cancer
disease sites, including lung cancer15; however, a recent re-
view of phase III studies in patients with advanced lung can-
cer demonstrates that ever smoking had no conclusive
relationship with outcome in patients with lung cancer.16 A
common theme to these and other studies is the limitation
that most studies rely on retrospective analyses or chart re-
views and do not include structured assessments of tobacco
use. In addition, there are very few data on tobacco use after
a cancer diagnosis. These limitations restrict the accurate as-
sessment of the effects of continued tobacco use on cancer
treatment.17 However, current smoking in lung cancer seems
to result in adverse health outcomes in patients with cancer,
suggesting that the continued use of tobacco after diagnosis
may confer a different risk from that conferred by former
tobacco use.
Molecular alterations in lung cancer are often associated
with different phenotypes and different responses to cancer
treatment compared with those associated with lung cancer
that develops in never-smokers. Although smoking may give
rise to a different form of lung cancer, these data suggest
that current smoking has an adverse effect on lung cancer

FIG 2. The continuum of tobacco and outcomes in patients with cancer. Dashed lines indicate biologic and
physiological mechanisms associated with continued tobacco use after a cancer diagnosis.

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WARREN AND CUMMINGS
treatment, perhaps as a result of alterations in response to
cancer treatment (Fig. 2).1 The authors are unaware of any
well-structured published data on the effects of cigarette
smoke on therapeutic response in lung cancer, but preclinical
data demonstrate that exposure to nicotine (a systemically
available component of tobacco and cigarette smoke) during
cancer treatment may decrease the effectiveness of radiother-
apy and/or chemotherapy in vitro and in vivo.18-19 Activation
of beta-adrenergic receptors and nicotinic acetylcholine re-
ceptors that are present on both cancerous and noncancer-
ous tissue leads to a more aggressive tumor phenotype that is
less responsive to cancer treatment.20 As a result, nicotine
may provide a mechanism by which tobacco may decrease
therapeutic response. However, removal of nicotine from
cigarette smoke does not appear to prevent the tumor-
promoting activities of tobacco, and nicotine has no signifı-
cant effect on the development of lung cancer in clinical
cohorts.21-22 The point of this discussion is to illustrate that
chemicals in tobacco may modulate therapeutic response,
leading to failure of cancer treatment, and not to suggest that
nicotine replacement should be avoided in patients with can-
cer. At this time, there is no evidence to support an adverse
effect of nicotine replacement in patients with lung cancer,
and nicotine replacement (or other nicotine receptor– based
cessation strategies) should still be considered a viable stan-
dard of care for tobacco cessation support in patients with
cancer. Moreover, nicotine replacement therapy is a proven
cessation aid that eliminates the diverse other chemicals in
tobacco smoke.2
TOBACCO CESSATION
The adverse effects of continued tobacco use have recently
been reported to result in a 10-year loss of life for current
smokers compared with former smokers, and smoking ces-
sation at any age reduced risks associated with tobacco
use.4,23 There are far fewer data in patients with cancer, but a
review of studies in patients with early-stage lung cancer sug-
gests that tobacco cessation after a diagnosis of lung cancer is
estimated to improve 5-year survival by approximately 34%
to 37%.10 There are well-established guidelines for tobacco
cessation for people without cancer, and the American Soci-
ety of Clinical Oncology (ASCO) has recently developed
guidelines for tobacco cessation in patients with cancer. Un-
fortunately, data suggest that whereas oncologists may ask
about tobacco use and encourage patients to quit using to-
bacco, most do not discuss medications or provide cessation
support.24 Dominant barriers to providing cessation support
include patient resistance to treatment and inability to get
patients to quit; however, approximately 60% of oncologists
do not provide structured cessation support.24 Furthermore,
a recent report of tobacco assessment in cooperative group
clinical trials demonstrates that only 29.4% of clinical trials
assess any form of tobacco use at patient enrollment, only
4.5% assess tobacco at follow-up, and none address tobacco
cessation.25 Collectively, these data show that tobacco cessa-
tion reduces the risk of developing lung cancer and other
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health effects, cessation may benefıt patients with cancer, and
that tobacco cessation is supported by national recommen-
dations based on well-established guidelines. However, these
data also show that most patients with cancer are not pro-
vided tobacco cessation support.
Accurately assessing tobacco use and providing wide-
spread access to tobacco cessation support using standard
clinical guidelines is critical to reduce the effects of tobacco in
both patients with cancer and individuals without cancer.1,17
Importantly, the traditional clinical schedule for most pa-
tients with cancer includes rigorous follow-up for 1 to 2 years
after diagnosis, which facilitates promoting repeated assess-
ments and cessation support. If clinicians are unable or un-
willing to provide tobacco cessation support, then patients
should be referred to dedicated tobacco cessation support
services such as national quit lines (1-800-QUIT-NOW).
Furthermore, national organizations should work together
to develop standard defınitions of tobacco use so future re-
search can more accurately analyze the effects of tobacco and
cessation on health risks. Health care facilities and insurance
organizations should facilitate these activities to assist in co-
ordinated efforts to reduce the health burden of tobacco use.
LUNG CANCER SCREENING AND TOBACCO CONTROL
IN THE FUTURE
In the United States and other high-income countries, to-
bacco use has become an increasingly marginalized behavior,
which suggests that lung cancer mortality rates will continue
to decline in the coming decades.26 Today, more than half of
all lung cancers are diagnosed in former smokers, suggesting
that an important future direction for public health may be
lung cancer screening. The National Lung Screening Trial
(NSLT) provides evidence to support the use of low-dose CT
scanning for high-risk current and former cigarette smokers
(older than age 55 with ⬎ 30 pack-year history of smoking) to
identify cancers in an early, treatable stage, thereby lowering
lung cancer mortality.27 The opportunity exists during the
next decade to dramatically change the prognosis of lung
cancer from one of death sentence to one in which cancer can
be detected early and cured or managed more effectively.
However, concerns about who will pay for the costs of
screening and disease management may delay efforts to real-
ize the potential of lung cancer screening for high-risk cur-
rent and former smokers. Governments can take a leading
role in this effort by raising cigarette taxes to prevent young
people from taking up smoking, earmarking tax dollars to
assist addicted smokers to quit, and covering the costs of
screening and disease management for those at risk of devel-
oping lung cancer.
Although future predictions for cigarette trends in United
States and other high-income countries around the world
have consumption dropping to near trivial levels in 50 years,
the trends in many middle- and low-income countries are
not so positive. In many parts of the world, cigarette con-
sumption is actually increasing as cigarette manufacturers
have shifted their focus to emerging economies.28 The global

effort to reduce the burden of tobacco use has been aided by
the World Health Organization’s Framework Convention on
Tobacco Control (WHO FCTC), which is the fırst global
health treaty.29 The WHO FCTC has been ratifıed by 176
countries, and obligates countries to implement a compre-
hensive set of policies including higher taxes, effective health
warning labels, and smoke-free policies.30 However, the to-
bacco industry has worked to counteract and delay imple-
mentation of WHO FCTC policies. Thus, it is critical that the
medical and public health communities adopt evidence-
based guidelines to ensure that governments implement pol-
icies and programs proven to reduce tobacco use.
CONCLUSION
The widespread adoption of cigarettes as the predominant
form of tobacco used during the 20th century resulted in a
rapid increase in lung cancer deaths. Approximately 85% of
lung cancers result from smoking, with an additional fraction
caused by secondhand smoke exposure in nonsmokers. The
Disclosures of Potential Conflicts of Interest
The author(s) indicated no potential conflicts of interest.
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TOBACCO AND LUNG CANCER
risk of lung cancer is dose dependent and not altered by
switching to fıltered cigarettes or cigarettes with low tar or
low nicotine. The dose-dependent risks of tobacco on lung
cancer are reduced by smoking cessation, particularly with
cessation early in life. In patients with cancer, tobacco use
after diagnosis increases toxicity, increases noncancer co-
morbidity, increases second primary cancers, decreases qual-
ity of life, and decreases survival. Tobacco cessation can
improve health outcomes for both patients with cancer and
individuals without cancer, but cessation support is often not
routinely provided by oncologists. Reducing the health-
related effects of tobacco requires coordinated efforts to reduce
exposure to tobacco, accurately assess tobacco use in clinical
settings, and increase access to tobacco cessation support.
Recent international tobacco control efforts and lung cancer
screening promise to reduce future lung cancer mortality.
ACKNOWLEDGMENT
This work was supported in part by funding from the Amer-
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