This year, lung cancer will kill
approximately 157,200 of the
171,900 people diagnosed with
this disease in the United States
alone. According to recent Centers
for Disease Control and Prevention
data, lung cancer deaths have for the
first time outstripped coronary artery
disease deaths as the leading type of
smoking-related death. Despite
new laws in many states imposing
public smoking bans and higher taxes
on cigarettes, young people-especially
women-continue to start
smoking at an alarming rate, and
smoking remains the leading cause of
premature death in our society.
Lung Cancer, Smoking,
and Public Health
Lung cancer will continue to grow
as a public health problem despite
success with tobacco control because
in contrast to the risk of cardiac disease,
which decreases rapidly after
smoking cessation, the risk of lung
cancer in former smokers remains persistently
elevated. Close to 50 million
former smokers in the United
States remain at elevated risk for developing
lung cancer. At Harvard
and other major cancer centers, half
of the new cases of lung cancer are
diagnosed in former smokers.
Moreover, 10% to 15% of all lung
cancer cases occur in never-smokers.[
6-8] Therefore, the number of
lung cancer deaths in former and nevnever-
smokers represents a solid majority
of newly diagnosed lung cancers,
resulting in over 90,000 deaths.
Thus, sole dependence on tobacco
control is an insufficient public health
response for lung cancer, because this
policy will in no way benefit most
people with lung cancer. As lung cancer
deaths in former and never-smokers
exceeds the number of deaths due
to colon and breast cancer combined,
renewed efforts to improve lung cancer
outcomes are clearly essential.
Another major reason for concern
about tobacco-related diseases is that
the care of these diseases accounts for
the majority of health-care costs in
our society. With our aging demographics,
the expected number of lung
cancer cases in our society will continue
to increase, exacerbating the current
unsatisfactory state of affairs.
While it is essential to maintain tobacco
control efforts, additional measures
are required to address the
health-care needs of the many people
who have already stopped smoking.
Most smokers become addicted in
childhood. The implications of this fact
have been highlighted in a landmark
Surgeon General's report. Today,
former smokers are at high risk of developing
lung cancer, and when that
occurs, their 5-year survival rate is 15%.
Lethality of Lung Cancer
Given that there is no validated
test for early lung cancer detection,
the current standard approach to lung
cancer detection is to wait for signs or
symptoms to develop. In that setting,
newly detected lung cancer is generally
rapidly fatal. The lethality of lung
cancer is attributable to the high frequency
of metastatic spread at the time
of initial diagnosis.
As recently discussed by Carney,
there has been only modest objective
improvement in outcomes related to
treating advanced lung cancer.
This situation is particularly unfortunate
at the current time, when women
in the United States have the highest
death rate in the world from lung cancer,
with 27.2 deaths per 100,000
women. A recent report has suggested
that women may be inherently
more susceptible to developing lung
cancer than men. Female cohorts
in this study exhibited a prevalence-
odds ratio of 2.7 vs male cohorts
matched for age and smoking history.
While it may be premature to definitively
conclude that women are at inherently
higher risk for developing
lung cancer, a recent surgeon general
report also pointed out a disproportionate
rise in the incidence of lung
cancer in women. Clearly, this
topic warrants further investigation.
The only form of lung cancer that is
likely to be curable is localized lung
cancer. In other epithelial cancers with
much more favorable 5-year survival,
including cervical, colon, and breast
cancer, techniques exist to routinely
detect these diseases prior to metastatic
spread. The 5-year survival rate for patients
with completely resected stage I
lung cancer is approximately
60%.[1,14,15] Finding a more effective
way to diagnose premetastatic lung
cancer would be a crucial step toward
an improved lung cancer-related mortality
rate. Based on studies of breast
cancer screening, we know that achieving
optimal benefit from early cancer
detection also involves defining the
most effective, efficient, and safest approach
to the clinical management of
screen-identified lung cancer.
In this review, we will consider
how to build on the successes of other
cancer screening efforts to detect and
manage early lung cancer. This
involves outlining the specific elements
for lung cancer that could make
a screening program safe, affordable,
and effective. We will also explore
the current standards of lung cancer
management and target areas where
potential pitfalls and opportunities for
Why Screen for Lung Cancer?
Lung cancer treatment is currently
managed on a case-by-case basis in
our society, as are other sporadic cancers.
When a patient presents to a
physician's office with symptoms, a
diagnostic work-up is performed at
the discretion of the primary physician
according to local standards of
care. Given that presymptomatic tobacco-
related illness in a screening
setting will involve a vast number of
at-risk individuals, defining how to
achieve the best outcomes at the lowest
cost is a major challenge. However,
in a clinical environment, this more
structured approach to managing early
lung cancer would constitute a
significant paradigm shift. Also, significant
clinical research will clearly
be required to define the appropriate
clinical management that would
achieve an optimal balance of risks
and benefits in this new area of lung
Recent efforts based on clinical trials
in advanced lung cancer have suggested
that better outcomes can be
achieved by following practice guidelines-
for example, those of the National
Network-but gaining broad adherence
to such recommendations is
slow. The best precedent in this regard
emerges from experience in the
clinical management of breast cancer.
Many experts attribute the reduction
in breast cancer mortality
beginning in the early 1990s, at least
in part, to wide-based mammographic
screening for breast cancer.
Indeed, mammography provides a
noninvasive, safe, fast way to screen
women for breast cancer in advance of
clinical symptoms. Mammographic instruments
are also portable and can be
brought into the community and the
workplace to encourage screening compliance.
With the maturation of breast
cancer screening, it was recognized that
the best outcomes were seen in centers
that were dedicated to breast cancer
screening and its attendant downstream
clinical requirements. Furthermore,
it was found that disparities
in imaging technique and instrument
calibration could result in suboptimal
case detection rates. To guard against
these problems, measures were legislated
to govern the quality control of
Managing early lung cancer in an
asymptomatic, high-risk population is
likely to be an even more demanding
process than that with breast cancer.
It is therefore prudent to consider
whether these types of measures are
fundamental to success in managing
preinvasive lung cancer. The precedent
in a public health setting is that
certain formal criteria must be met
before disease screening is justified.
In reviewing such criteria as summarized
in Table 1, it is evident that
these are commonsense provisions,
and it is useful to consider their relevance
in lung cancer screening.
As already discussed, with lung
cancer being the most lethal of can-
cers, its public health significance is
indisputable. The question that emerges
is whether we can now detect lung
cancer at a point in time that improves
cancer-related mortality. With chest
x-ray screening, regional or distant
metastatic disease was still found in
most newly diagnosed lung cancer
cases. As a result of rapid refinements
in high-resolution spiral computed tomography
(CT) imaging, this situation
is changing and localized cancers
are being found more frequently.
That said, is this approach to lung
cancer care affordable? A key issue
in this regard is the cost of diagnostic
evaluations in the screening process.
Initial reports outlined significant
challenges with the frequency and cost
of CT screening.[20,21] A more recent
report of the screening experience
in Milan outlined a more
disciplined approach to work-up of
suspicious nodules. In that approach,
nodules that were smaller than 6 mm
were noted but only worked up the
following year if these nodules were
growing. Some of those nodules
did grow and were subsequently found
to be cancers, but in all cases, surgery
with curative intent could still be performed
and all of those resected cases
were still found to be stage I cancers.
This is an example in which improving
the downstream management of
screen-detected early lung cancer can
have a favorable impact on the overall
process. Moreover, it illustrates that
in population-based clinical management,
to do less (such as to do fewer
diagnostic work-ups with < 6-mm
nodules) is sometimes to achieve more
efficient overall outcomes.
Why Is Lung Cancer
Detected So Late?
A factor contributing to the difficulty
in imaging early lung cancer
relates to its location deep in the thoracic
cavity. In addition, the presence
of complex bony structures and the
cardiovascular system further exacerbate
the challenge of thoracic
imaging. In contrast, other organs
such as the breast and the cervix are
more easily accessible for diagnostic
Previous attempts at chest x-ray
screening for lung cancer were clearly
limited by the insensitivity of this
diagnostic tool. Even with repeat chest
x-rays performed every 4 months, as
in the Mayo Lung Project, only
30% of patients were found to have
stage I disease. As the majority of
patients were still diagnosed with advanced
lung cancer, there was no significant
reduction observed in that trial.
Subsequent reanalysis of aggregate
trial data by an international body of
screening experts found that the previously
completed randomized lung
cancer screening trials using chest
x-ray and sputum cytology did not
offer convincing evidence for or
against lung cancer screening.
The continued lethality of lung cancer,
the absence of informative screening
evidence, and the emergence of
more potent spiral CT imaging capabilities
has mandated the urgent
reevaluation of the benefit of lung
What Is Changing?
Specific technical refinements in CT
imaging were recently reviewed in detail.[
26,27] Briefly, improvement in instrument
design coupled with vastly
more capable microprocessor capabilities
allows a much more detailed thoracic
imaging study to be acquired much
more rapidly. Since the imaging interval
is so much shorter (seconds rather
than minutes), the confounding influence
of respiratory motion is eliminated.
Spatial relationships in the thorax
can be defined with much greater precision
than with early-generation CT
scanners. The greatest advantage of spiral
CT technology is the reliable detection
of very small nodules.
With state-of-the-art, high-resolution
spiral CT scanning, slice thickness
as thin as 0.6 mm can be acquired
through the entire chest volume in
less than 20 seconds, with radiation
exposure comparable to a normal chest
x-ray. Spiral CT scanners already exist
in most hospitals and free-standing imaging
centers in the developed world.
In contrast to some screening tests currently
done for other cancers (eg, mammography
and Pap smear), the CT scan
is neither painful nor invasive, making
this test more acceptable to the general
population. These factors along with
the rapidly decreasing cost of a CT
scan are making this tool even more
attractive for potential application in a
public health setting.
Small-Volume Primary Tumors
Conventional wisdom tells us that
early lung cancer, although seldom
found, can be associated with favorable
long-term survival. A recent
study has suggested that the small size
of lung cancer at the time of detection
by screening may not result in favorable
long-term outcomes. Patz et
al evaluated mortality outcomes
among patients with stage IA lung
cancer at a single institution over an
18-year interval. They concluded that
primary tumor size had no significant
impact on mortality; however, this
cohort had a favorable overall 5-year
survival of 80%. It is unclear
whether tumors were initially detected
by CT scan or by chest x-ray, but
as only 26 (of 510) subjects had a
subcentimeter nodule at the time of
detection, the suggestion that detection
of subcentimeter primary tumors
(in a screening setting) will not improve
survival seems premature.
Many investigators are excited
about the possible routine detection
of small-volume primary lung cancer,
including a much higher percentage
of subcentimeter primaries. To
attempt to generalize about potential
outcomes with spiral CT-detected
screening cases based on historical
experience from a single institution
retrospectively evaluating referral cases
is, at best, speculative.
The Metastatic Process
Several reports from radiologists
have suggested that lung cancer is
inherently metastatic from its inception.[
20,29] From an epidemiologic
perspective, it is known that the peak
incidence of lung cancer lags 2 decades
after high levels of cigarette
consumption. In this regard, the
natural history of lung cancer is similar
to that of typical colon or breast
epithelial cancers. Epithelial cancers
begin as a localized phenomenon.
Cancer progression involves many
discreet molecular steps to acquire the
biologic competence to permit a tumor
to grow in three dimensions. Additional
acquired steps in metastatic
competence may include factors such
as the ability of a cancer to degrade
matrix structures in the basement
membrane. This property allows metastatic
cells to escape in the vascular
or lymphatic system, where they can
"seed" the entire body.
Some authors contend that a significant
number of lung cancers can
remain latent for the entire life span
of the patient.[20,31] Other authors
have suggested that lung cancer may
in fact be more virulent than other
cancers, conferring the ability to metastasize
much earlier than other tumors
of similar size.[28,32] These
contentions are at odds with a large
body of clinical experience.[15,33,34]
How frequently will subcentimeter
lung cancers metastasize prior to
detection on screening? In the
Memorial Sloan-Kettering experience,
only about 10% of subcentimeter lung
cancers were found to involve distant
metastatic disease. Using the 2000
Surveillance, Epidemiology and End
Results (SEER) registry with regard
to the impact of tumor size on survival,
Wisnivesky et al reviewed data
from patients with stage I non-smallcell
lung cancer (NSCLC) diagnosed
since 1988 who had undergone curative
tumor resection. Among stage I
malignancies, 12-year survival was
inversely proportional to primary tumor
size (Figure 1).[34a] High curability
with smaller primary tumor size
is also evident from the decreased
number of deaths from breast cancer
and cervical cancer with the advent of
mammography and cervival cytomorphologic
In the recent published experience
from Milan, the size of screendetected
primaries on prevalence
screening averaged about 20 mm, with
the average primary size of incidence
cases being about 15 mm. In Table 2,
we summarize the salient characteristics
from recent spiral CT reports.[
22,35-38] It is apparent that the
average lesion size on initial evaluation
as well as on annual follow-up
represents much smaller-volume cancers
than clinicians are accustomed to
managing. In this situation, we not only
have challenges in defining the optimal
clinical care, but we also may not know
the natural history of such lesions.
Along with the Cornell group, the
early pioneers in this field were from
several institutions in Japan. Recently,
Ryutaro Kakinuma, an investigator
from the National Cancer Center,
Tokyo, presented the 27-year screening
experience of the Anti-Lung Cancer
Association. In the first
18 years of this effort, chest x-ray
and sputum cytology were used as
screening tools. During that time, the
Association performed over 26,000
screening evaluations, detecting
stage IA cancer in about 42% and
resulting in a 49% 5-year overall survival
rate. Over the past 9 years, the
Association has moved to the use of
spiral CT. In over 15,000 screening
evaluations during this interval, the
stage IA detection rate was 78%, and
those patients had a 5-year overall
survival rate of 78%. Additional details
of this experience are summarized
in Table 3.
Other centers in Japan have shown
comparable results, especially in regard
to the frequency of stage IA detection
in their screening efforts. While this
visionary Japanese experience is clearly
promising, it is still necessary to wait
for clinical trials evidence of improved
lung cancer-related mortality benefit
before drawing any conclusions about
the real benefit of lung cancer screening.
To that end, these data certainly
support the wisdom of expeditiously
conducting a large randomized trial of
lung cancer screening.
Indeed, based on the promising data
from the pilot screening trials at Cornell
and other sites, the National Cancer
Institute launched a major
randomized study called the National
Lung Screening Trial (NLST) to compare
spiral CT to chest x-ray in a highrisk
The trial will accrue 50,000 current
and former smokers at coordinating
centers throughout the country looking
for differences in lung cancer-related
mortality between the two arms. Study
accrual has been proceeding well ahead
of schedule. Depending on the outcome,
follow-up for as long as 10 years may
be needed to reliably evaluate the benefit
of spiral CT screening.
Costs of Lung Cancer Care
Lung cancer surgery is associated
with considerable morbidity and a
predictable rate of mortality, so the
process of defining less aggressive
approaches to surgical evaluation is
attractive. In the same vein, when
proposing to employ a populationbased
screening strategy, the cost of
clinical management becomes a critical
determinant. As there are approximately
100 million current and former
smokers in the United States, this issue
can become paralyzing. The cost of
starting and sustaining such a program
is predicted to be enormous and,
in and of itself, has been suggested
as a reason not to screen for lung
On the other hand, in the United
States we are already spending roughly
$50 billion on health care for tobaccorelated
disease. Despite this expenditure,
current treatments for these
tobacco-related diseases are suboptimal
and tobacco use remains the overwhelmingly
leading cause of premature
mortality in our society. Because
more than $50 billion in economic productivity
is also lost annually as a consequence
of tobacco-related diseases,
the true cost of our tobacco use is not
A premise for screening research
in lung cancer is that moving the focus
of care from late metastatic disease
to earlier disease may effect
improvements in health and economic
outcomes, as have been recently
described for cardiovascular disease
screening. With research progress,
could the cost of an effective, welldesigned
and implemented lung cancer
screening system be sustainable
within the envelope of resources currently
expended in lung cancer care?
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