With the advent of helical computed tomography (CT), particularly multidetector-row helical CT, the possibility of accurate mass screening of populations at risk for lung cancer has been revisited. The authors extensively discuss the clinical, statistical, and financial criteria that must be evaluated to judge the feasibility of a screening tool for disease and review the available data on CT lung cancer screening.
is an Assistant Professor-In-Residence, Diagnostic Radiology and
Pulmonary/Critical Care Medicine, Director, Radiology Residency
Training Program, University of California, San Francisco,
Director, Body Imaging Practicum Program, Director, Thoracic
Imaging, San Francisco General Hospital, San Francisco, CA.
is a Professor, Diagnostic Radiology, Chief, Thoracic Imaging,
Department of Radiology, University of California, San Francisco,
Despite the recent attention in both the radiologic literature
and press, screening for lung cancer is not a new idea. Lung cancer
screening has been attempted as far back as the 1960s,
and four large lung cancer screening trials
were carried out in the 1970s. However, with the advent of helical
computed tomography (CT), particularly multidetector-row helical
CT, the possibility of accurate mass screening of at-risk
populations has been revisited.
Past lung cancer screening trials
Three major lung cancer screening studies sponsored by the
National Cancer Institute (NCI), have been performed in the United
States in the last 3 decades: Johns Hopkins trial,
The Mayo Lung Project (MLP),
and Memorial Sloan Kettering Cancer Institute trial.
The Mayo Clinic trial was specifically designed to assess the
utility of screening radiography for the detection of lung
carcinoma, whereas the other two trials were directed more at
evaluating the use of sputum cytology for the early detection of
Why screen patients for lung carcinoma?
According to Patz et al,
"The purpose of screening is to prevent, or delay, by means of
earlier detection, the development of advanced disease and its
adverse effects." The major reasons to screen populations for
diseases such as lung carcinoma are to improve the quality of
healthcare and to reduce heathcare costs. To implement such
objectives on a large scale, the disease being screened for should
be a worthy target for screening. Lung carcinoma certainly fits
that criterion. In 1999, approximately 175,000 new cases of lung
carcinoma were diagnosed in the United States; more than 150,000 of
these patients will die of lung carcinoma in the same year. More
than one million lung-cancerrelated deaths occurred worldwide in
The death rate from lung carcinoma exceeds that of breast, colon,
and prostate carcinomas combined.
Given the fact that screening programs for these latter three
diseases are in place, it certainly makes sense to examine the
utility of screening for lung carcinoma, particularly in light of
recent advances in helical CT technology.
What is required for a successful screening
There are numerous parameters that impact the effectiveness of
screening for disease, and these must be addressed before
significant resources are committed to a screening program.
These considerations were outlined elegantly by Obuchowski et al
in a recent article in the
American Journal of Roentgenology
. This article will discuss these parameters and the evidence for,
or against, the use of CT for lung cancer screening.
Is the disease being screened for serious?
Any screened-for disease should be capable of producing
significant morbidity and mortality, thus affecting patients from
an emotional and financial standpoint, as well as impacting society
in general from a productivity loss and general expense standpoint.
Lung carcinoma certainly fits this criterion. Lung carcinoma is the
leading cause of cancer-related deaths, and caring for cancer
patients contributes to enormous losses in productivity as well as
incredible healthcare costs. The 5- to 10-year mortality of
untreated stage I lung carcinoma is 80% to 100%,
which would tend to suggest that indolent lung carcinomas are
either incredibly rare or nonexistent (this controversy will be
discussed shortly). Because 50% to 60% of newly diagnosed lung
carcinomas are first detected when they are already stage IV, many
of the costs associated with caring for lung carcinoma patients are
accrued in the last few months or years of life.
Is the disease being screened for treatable?
Patient outcomes must be improved by whatever treatment exists
for the disease being screened for, otherwise there would be no
point in detecting the disease early. As mentioned above, the 5- to
10-year mortality rate of untreated stage I lung carcinoma is 80%
to 100%; however, surgery for stage I lung carcinoma improves
5-year survival to 50% to 70%.
Therefore, although lung cancer is certainly a deadly disease,
proper treatment markedly improves patient survival.
Does the population being screened have a high prevalence
of detectable preclinical disease?
The preclincal disease phase is defined as the period from the
point of onset of the illness being screened for to the time when
symptoms first appear. If this phase were extremely short, the
possibility of detecting disease early (before the patient would
have presented with symptoms anyway) would be remote, and screening
would simply cost money but could not improve patient outcomes.
Within the preclinical disease phase, the detectable preclinical
phase is the period of time when the disease is detectable, but
before the patient develops signs or symptoms and presents to
If the screened population has a low disease prevalence during
the detectable preclinical phase, screening will not be cost
effective. Additionally, if the disease prevalence is low, the
likelihood that a positive test will actually represent true
disease is also correspondingly low. This concept represents the
positive predictive value of a test. Unlike sensitivity and
specificity, predictive values are influenced by the prevalence of
disease. This would mean if the disease prevalence is low, most
patients who have positive results may not actually have lung
cancer, and would be subjected unnecessarily to additional (likely
expensive) diagnostic testing as well as the possibility of
How prevalent is lung carcinoma in at-risk populations during
the detectable preclinical phase? The answer to that question
depends on the definition of the at-risk population. Certainly lung
carcinoma screening programs will not be applied to just anyone;
rather, at-risk populations are targeted for screening based on
such criteria as age, history of smoking, and perhaps, as
exclusionary criteria, a history of prior lung carcinoma or
extrathoracic malignancy. Current estimates of the prevalence of
detectable preclincal lung carcinoma in at-risk populations range
from 2% to 4%.
An appropriate detectable preclinical lung carcinoma prevalence in
a screening population is 5%. This prevalence results in a positive
predictive value of 50% if the screening test is good (95%
sensitive and specific).
How is data regarding preclinical lung carcinoma prevalence
obtained? One way is to use information gained from prior lung
cancer screening trials that used chest radiography and sputum
cytology, or to analyze the prevalence of asymptomatic lung
carcinomas detected incidentally during lung transplantation for
pulmonary emphysema (nearly 5%). Also, several lung carcinoma CT
screening trials are currently well under way, and data from the
first year of prevalence scans obtained from these trials is
available (Table 1).
The detectable preclinical prevalence of lung carcinoma in the
at-risk populations in these trials is below the ideal, which will
result in a lower positive predictive value of CT scanning, as well
as potentially decreased cost effectiveness of screening. The
criteria for selecting patients for enrollment in lung cancer
screening studies are listed in Table 2.
Increasing the screening requirements (older patients, more
extensive smoking history), would increase the prevalence of lung
carcinoma and thereby make screening more specific and cost
effective, but at the risk of decreasing the sensitivity of the
screening test. It is known that the age-specific prevalence of
lung carcinoma rises abruptly at age 50 to 55, so this may be a
reasonable target age for lung cancer screening. Other reasonable
inclusion criteria for lung cancer screening programs is to require
that the patient be fit for surgical resection and that the
patients can hold their breath for the scan duration.
Does the screening test have a high accuracy for the
of disease during the detectable preclinical phase?
This question is somewhat difficult to answer directly for CT
scanning. The usual approach investigators take for answering this
question is to compare the ability of CT to detect lung carcinoma
with that of chest radiography, and CT is clearly better than chest
radiography for nodule/cancer detection.
Recent prevalence data from CT lung cancer screening trials,
compared with detection rates in chest radiography trials, confirm
this assertion: CT detected 27 cancers per 1000 high-risk screened
subjects versus 9.1 to 9.7 cancers detected by chest radiography
per 1000 screened subjects in the Early Lung Cancer Action Project
Compared with chest radiography, CT will detect lung carcinomas
at a significantly smaller size, and therefore (presumably) at a
more curable stage. The average sizes of lung carcinomas detected
with screening chest radiography in the major trials to date are
presented in Table 3.
CT clearly detects lung carcinoma at a smaller size and a
greater rate than chest radiography. Whether or not CT detects lung
carcinomas at a
small enough size
such that patient outcomes are improved with the use of CT
screening remains a question; there is no guarantee that smaller
size at detection will translate to decreased mortality. It is
already known that screening with chest radiography will result in
the detection of more lung cancers at an earlier stage, and this
appears to improve survival. In the Johns Hopkins chest radiograph
and sputum cytology study,
67% of the prevalence cancers detected in the screened group were
stage I (for cancers that present symptomatically, only 20% of
patients will present with stage I disease). However, survival is
not considered to be the proper end point for determining the
effectiveness of a screening program--mortality is the proper end
point for this purpose (see biases, below, for more discussion on
this point). In the Mayo Lung Project,
206 cancers were diagnosed in the intensive screening arm
("intervention arm," which consisted of chest radiography and
sputum every 4 months) versus 160 lung carcinomas diagnosed in the
less intensive arm ("usual care arm," consisting of yearly chest
radiography at the clinician's discretion). In the intervention
arm, 40% of the detected cancers were stage I, but only 25% of
cancers in the usual care arm were stage I.
Despite these encouraging results, no reduction in lung cancer
mortality was noted. Long-term data from the Mayo Lung Project has
shown that the lack of reduction in lung cancer mortality with
intensive chest radiographic screening has persisted.
A total of 337 lung cancer deaths were noted in the intervention
arm, whereas 303 lung cancer deaths were noted in the usual care
arm. This data translates to lung cancer mortality rates of 4.4 and
3.9 per 1000 person-years, respectively.
Part of the issue is that screening with chest radiography has
failed to provide a "stage shift": although screening has detected
more early stage cancers, radiographic screening did not detect
more advanced stage cancers. Comparing screened groups with control
groups, investigators found a similar number of advanced stage
cancers, indicating that screening detected the indolent cancers,
but had no impact on the more aggressive cancers. Because screening
detects more cancers compared with control groups, but does not
necessarily detect more advanced cancers, the possibility that
screening is detecting indolent cancers (perhaps even
inconsequential lesions) must be considered. However, data
regarding the impact of stage presentation on survival are subject
to biases (particularly lead-time bias), which will be discussed
Does the screening test detect the disease being screened
for at a point in the detectable preclinical phase when
treatment is effective?
For many serious diseases, especially malignancies, there is a
point during the disease history after which treatment is largely
ineffective; this point has been termed the "critical point."
For malignancies, this critical point usually occurs when the
cancer becomes metastatic. Therefore, for a screening test to be
effective, the screening test should be able to detect the disease
prior to the critical point. This issue is extremely important
because it reflects the biologic behavior of the tumors. The
question is, "Does screening detect more cancers because it detects
them at an earlier stage or because they are slow-growing and of
low biologic potential?" Answering this question is difficult.
Advocates of CT screening for lung carcinoma cite data that
patients screened with CT have a much greater prevalence of lower
stage tumors than do patients who present with lung carcinoma. The
stages of presentation of lung carcinomas detected in lung cancer
screening studies are given in Table 4.
The data presented in Table 4 certainly represent an improvement
compared to the historical lung carcinoma early stage presentation
rate of 10% to 20%. However, data regarding the stage of
presentation are subject to biases (particularly lead time bias)
will be discussed below.
There is compelling evidence that lung carcinomas are
heterogeneous lesions with significant variability in biologic
behavior. This implies that smaller tumors are not always
synonymous with early stage disease. In a recent study examining
this issue, in patients with lung carcinoma with what appeared to
be limited, local disease (T1N0M0), extrathoracic metastases were
found upon further work-up in 13% of cases.
In the remaining patients who were thought to be stage I, an
additional 11% of patients developed extrathoracic metastases 1
year later. Furthermore, no significant difference was found
between the prevalence of metastases at diagnosis and at 1-year
follow-up for tumors <2 cm and those >2 cm. Finally, as many
as 60% of patients with stage I disease die of lung carcinoma
within 5 years despite appropriate therapy.
Another way of examining this issue is to look at patient
outcomes with respect to tumor size. A recent investigation
examined the survival of patients with T1N0M0 lung carcinoma as a
function of the tumor sizes, and found that there was no difference
in survival among patients with tumors of various sizes <3 cm
The type of data presented in Table 5 has been noted previously.
For example, it had been demonstrated already that there is no
significant difference in survival among patients with stage I
Thus, patients with T1 disease (tumor <3 cm) all have about the
same 5-year survival. Given the assumption that chest radiography
is an ineffective screening method for lung carcinoma because no
mortality reduction has been noted, and the average size of tumors
detected in chest radiography screening programs was ¾3 cm in
several major chest radiography screening trials, the ability of CT
to detect smaller tumors may not necessarily translate to a
Does the screening test itself cause little morbidity?
The patient being screened presumably is asymptomatic and
therefore at little risk of dying from the disease being screened
for in the immediate future. Therefore, the screening test must not
have a significant frequency of adverse effects, or it may cause
more damage than it prevents. Does CT fit this criterion? No
intravenous contrast is required for lung cancer screening studies,
so there should be no contrast-associated risks. The major risk
related to lung cancer screening is the radiation dose associated
For this reason, screening lung cancer CT should be performed using
decreased tube current, thereby decreasing the radiation dose.
Because the target of lung cancer screening (a lung nodule)
presents as a soft-tissue density structure surrounded by
low-attenuation pulmonary parenchyma, there is an intrinsically
high signal-to-noise ratio between the target and background.
Therefore, tube currents may be decreased to one-fifth or one-sixth
of that used for routine studies without compromising diagnostic
accuracy for lung nodules.
It has been estimated that the risk of inducing a fatal cancer with
this technique is approximately 1 in 25,000.
Although CT scans may cause little morbidity themselves if
conducted properly, complications resulting from overdiagnosis and
additional CT scans required to follow nonspecific small nodules
will increase the morbidity and costs associated with CT for lung
Whether or not this effect is important depends on the rate at
which CT detects indeterminate, but ultimately benign, lung
nodules. Preliminary data suggest that this event may be common. A
recent study of prevalence data from 817 asymptomatic smokers found
noncalcified nodules in 43% of patients.
In the 1520 prevalence scans in the Mayo Clinic NCI trial, 51% of
patients had noncalcified lung nodules; more than 1300 nodules were
detected in these patients.
Is the screening affordable and widely available?
Helical CT is certainly widely available throughout the United
States, but the question of cost is a major consideration for the
widespread adoption of lung cancer screening protocols. The cost of
lung cancer screening depends on how much is charged for a CT scan,
how many false-positive results occur, and how the at-risk
population to be screened is defined. The National Cancer Institute
has estimated that a national lung cancer screening program for
current and former smokers aged 45 years or older would cost more
than $39 billion. Chest radiographic screening studies ($50 per
chest radiograph and $60 for sputum cytology) suggest that the cost
of screening the at-risk U.S. population once per year (in 1988)
would have cost $1.5 billion, not including the cost of
Obviously, such a cost is prohibitively expensive. However, is
the estimate accurate? One must also consider what an "appropriate"
amount of money spent per life saved may be. Some investigators
have asserted that $50,000 spent per life-year saved is an
appropriate return. For example, current estimates suggest that
screening for breast and colorectal carcinoma costs between $30,000
and $50,000 per life-year saved
; a similar target level may be appropriate for lung carcinoma.
Clearly the NCI estimate far exceeds this value, but not all
investigators agree that lung cancer screening with CT will be so
expensive. Estimates from the ELCAP group suggest that CT screening
for lung carcinoma may cost only $2000 per life-year saved.
Part of the discrepancy between these two estimates depends on
how they account for the additional costs incurred by CT lung
cancer screening. Although the first scan may be relatively
inexpensive (an average of approximately $300 per scan),
recommended follow-up scans may inflate the cost of screening
dramatically. CT--particularly narrow collimation multidetector
CT--commonly detects small nodules of unknown significance; these
nodules are either followed, biopsied, or evaluated noninvasively.
If followed, follow-up regimens aim to establish 2-year stability
by scanning the nodule at doubling time intervals, beginning 6
weeks to 3 months after the prevalence scan. This regimen can
result in one screening CT examination leading to 5 or 6 CT studies
over the ensuing 2 years, with the obvious accompanying increases
in costs. How common would this scenario be? In the Mayo Clinic
trial, among 1520 patients undergoing prevalence scans over a year
period, more than 1300 noncalcified nodules (51% of patients) were
Only a few of these lesions were carcinomas, thus the rest either
must be followed, biopsied, or evaluated with other noninvasive
methods, such as positron emission tomography (PET) scanning or
repeat CT. In the ELCAP study,
1 to 6 noncalcified nodules were detected in 233 patients among the
1000 patients scanned. Only 27 cancers were found among these 233
patients, implying that the remainder of the nodules required some
sort of evaluation (with associated costs) to exclude carcinoma. In
addition to these costs, the costs of surgery for false-positive CT
examinations (such cases will be inevitable) and costs associated
with losses in productivity for patients with false-positive
results must be considered.
One cost-effectiveness analysis of CT lung cancer screening has
Cost effectiveness is defined as the cost of screening divided by
the effect of screening (in terms of life-years saved). This
cost-effectiveness analysis assumes that screening results in a
stage shift (more carcinomas detected at an earlier stage,
resulting in fewer later stage carcinomas), and that this
down-staging will result in decreased mortality. It is also assumed
that no biases (see below) complicate the analysis. Variables
assumed for this analysis include a cost of $291 for a screening
CT, a diagnostic CT cost of about $340 to $416, lung biopsy costs
ranging from $507 to $5071 (depending on method used and
complications), a prevalence rate for abnormal CT screening studies
of 25% to 50%, a prevalence of carcinoma in the at-risk screened
population of 1.2% and 2.7%, and a carcinoma incidence rate of 0.7%
to 1.2% in the screened population. If CT screening for lung cancer
results in 20% of the detected lesions identified at stage I, then
no benefit will be derived because that is roughly the percentage
of patients that will present at stage I once symptoms develop
(this is where we are without screening). If CT screening finds 30%
of the lung carcinomas while still localized, then the cost per
life-years saved (assuming the above variables) is $90,022. If CT
detects 50% of the carcinomas while still localized, then the cost
for screening the at-risk population in terms of life-years saved
is $48,357. If CT detects 70% of lung carcinomas while still
localized, the cost of screening is $33,557. Current prevalence
data suggests that CT may be able to detect a significant number of
carcinomas at stage I (approximately 50%), indicating that
screening will cost <$50,000 per life-year saved. Compare that
with other screening programs in practice: cervical carcinoma
($15,600 per life-year saved), breast cancer screening with
mammography ($24,100 per life-year saved), colonoscopy ($127,700
per life-year saved), and chest radiograph and sputum cytology
screening for lung carcinoma (in Japan, $93,000 per life-year
Who will pay for lung cancer screening with CT? Most
investigators agree that the initial scan will be paid for by the
patient; insurance will not cover such scans. Abnormalities
detected on the prevalence scan are usually covered by insurance,
which means that society in general (including nonsmokers) will be
absorbing the costs associated with screening for a largely
self-induced illness. It remains to be seen if insurance companies
will "penalize" patients for screening themselves. It is possible
that insurance companies may try to deny payment for CT and other
costs incurred with lung cancer screening by claiming that the
detection of a lesion on a self-pay scan represents a pre-existing
Some investigators believe that screening for lung cancer will
still be cost-effective because the costs associated with caring
for late-stage lung carcinoma patients are so incredibly high.
Since the majority of patients with lung carcinoma present with
unresectable disease, most patients will incur costs related to
palliative care as well as losses in productivity. Potentially,
such costs could exceed the costs of screening for lung cancer with
Is treatment for lung carcinoma effective when disease is
detected in the preclinical phase?
Lung cancer treatment must be effective and/or less toxic when
applied during the detectable preclinical phase than when applied
during the symptomatic period. If the disease can be treated
successfully after symptoms are present, then there is no point to
Proving that treatment is effective during the preclinical phase
is difficult. Five-year, disease-specific survival and mortality
rates have been used as end points for determining the
effectiveness of treatment for carcinoma, and have also been used
to determine the effectiveness of screening programs. Although
5-year, disease-specific survival has been commonly employed to
demonstrate that screening programs detect carcinomas early, and
therefore lead to effective treatment at an earlier disease stage,
using 5-year, disease-specific survival as an end point results in
the introduction of bias.
The major biases that deserve consideration include lead-time bias,
length-time bias, and overdiagnosis bias.
For unscreened patients, disease-specific survival is defined as
the length of time from the clinical diagnosis of a disease to
death from the disease.
For screened patients, disease-specific survival is defined as the
time from the detection of the disease by the screening program to
the time of death from the disease.
Lead time is defined as the amount of time between the detection of
the disease by the screening test and the point at which the
disease first becomes symptomatic.
Because the screening test may detect disease before the disease
becomes symptomatic, the screening may create the impression that
it has detected the disease at an earlier and, therefore, more
curable stage. However, even if the disease is completely
untreatable, screening will create the impression that the patient
has survived longer, simply because the screening test detected the
disease before it became symptomatic.
Length-time bias occurs because of the heterogeneity of the
biologic behavior of diseases; disease in some patients will
progress at a slower rate than in others.
The probability that a carcinoma will be detected in a screening
program is directly proportional to the length of the asymptomatic
Indolent disease will progress at a slower rate than more
aggressive lesions, and thus may have a longer detectable
preclinical phase (hence the term "length-time" bias) than more
Because these more indolent lesions are easier to detect, they tend
to be over-represented in the screening cohort; this tends to make
the screening test appear more effective than it really is because
patients with more indolent lesions will appear to survive longer,
whether or not treatment is effective.
This longer survival is attributed inappropriately to the
effectiveness of early detection in the screening program.
For a lung cancer screening example, length-time bias may result
from the detection of relatively low-grade lesions such as some
bronchioloalveolar carcinomas (BAC). Because some BACs grow slowly
and behave more indolently compared to other bronchogenic
carcinomas, an over-representation of BACs in a screened population
would create the impression that screening prolongs survival.
Recent data analyzing the behavior of peripheral adenocarcinomas
supports this assertion.
Among small (<3 cm), peripheral, surgically resected lung
carcinomas, tumor volume doubling times ranged from 42 to 1486
days. If one considers that it will take 8 years for a tumor with a
doubling time of 365 days to increase in size from 5 mm to 3 cm,
the potential for length-time bias and overdiagnosis bias in CT
lung cancer screening regimens becomes clear.
Overdiagnosis bias refers to the possibility that some patients may
have extremely indolent forms of disease, or "pseudodisease." This
pseudodisease represents preclinical disease that would have never
become apparent clinically had it not been discovered by screening.
Because such pseudodisease does not have significant malignant
potential, when the patient "survives" for a long period after
disease detection, it appears that the screening test effectively
improves survival by early detection.
Less commonly, overdiagnosis bias can result from detection of a
lethal lung cancer in a screened subject, but the subject dies of
another process before they would have died of the detected lung
In essence, pseudodisease "dilutes" the screening disease detection
cohort with patients that would have survived anyway and makes the
screening test appear more effective.
For lung carcinoma, the detection of atypical adenomatous
hyperplasia (AAH) may represent an example of overdiagnosis bias.
Although this is controversial, AAH may represent a precancerous
lesion, and a significant number, but possibly not all, of AAH
lesions may never progress to frank carcinoma. If such a lesion is
detected on a lung cancer CT screening study (AAH often presents as
a small ground-glass nodule) and it is removed and cure is assumed,
that patient will be labeled as a "long-term survivor." An
over-representation of such patients in a screening cohort will
create the appearance of longer patient survival in the cohort, and
thus the appearance that screening is effective.
At first glance, it seems that overdiagnosis bias would be an
uncommon problem in lung cancer screening with CT. However, some
investigators have found clinically silent cases of lung carcinoma
implying that there may be some potential for overdiagnosis bias in
lung cancer screening.
Clinically silent lesions are certainly known in other organ
systems (especially prostate carcinoma), and some of the
information surrounding the concept of indolent carcinomas has been
discovered through mass screening programs.
Although the high fatality rate associated with untreated lung
carcinoma has often been cited as evidence that overdiagnosis bias
would not be a significant problem with lung cancer CT screening,
this fatality rate has been calculated based on lesions that
presented symptomatically, not those that are detected with
Furthermore, the disease- specific mortality of lung cancer, based
on chest radiographic screening studies, is about 2 to 5 per 1000
individuals. However, with prevalence data from CT screening
studies, it is clear that the number of cancers detected with CT
screening is much greater than would be expected to present
clinically in a 1- or 2-year period.
This suggests that CT may detect cancers that may not have
aggressive biologic potential. If lung carcinoma is rapidly
progressive and usually fatal (as lung carcinoma has traditionally
been considered to be), there should be no "backlog" of prevalence
cases waiting to be detected. Finally, if one considers that
overdiagnosis bias could lead to the false identification of lung
carcinoma and subsequent lobectomy, the potential for overdiagnosis
bias to harm patients is apparent.
To guard against any potential damage that could result from
overdiagnosis bias, investigators in the ELCAP group have suggested
that small lesions should be followed closely to first demonstrate
growth before proceeding to more invasive diagnostic procedures.
Therefore, because CT will be more sensitive for the detection of
small cancers and, therefore, presumably will detect small indolent
lesions (the source of overdiagnosis bias), short follow-up CTs to
demonstrate growth potential should allow for the distinction of
indolent lesions from small, but aggressive, lesions.
For this reason, some have advocated a mandatory observation period
for small nodules.
Because of these biases, using disease-specific survival is not
a valid end point to determine the effectiveness of a screening
Rather, disease-specific mortality is the most appropriate end
point to determine the effectiveness of screening examinations.
Disease-specific mortality is defined as the number of deaths due
to the disease in question divided by the number of patients at
risk. Disease-specific mortality is not a perfect measure because
it may require a very large number of patients to prove that a
screening program is actually effective in reducing mortality. For
example, a randomized, controlled trial in which the
disease-specific mortality is only 3 to 5 cases per year per 1000
individuals would require nearly 100,000 individuals in each study
arm to detect a small, but statistically significant, difference
between screened and control populations. Also, disease-specific
mortality will not be able to detect whether a treatment program or
screening program prolongs survival without preventing death.
Clearly, prolonging survival would be potentially meaningful to
Does the treatment have a high rate of significant adverse
If the disease being screened for has only toxic or highly risky
treatments available, then screening for the disease may be
problematic if the screening method has a significant
false-positive rate. In this case, the treatment may cause nearly
as much damage as the disease, or may be perceived as causing so
much damage that patients may not want treatment. Obviously both
situations would render screening useless. In the case of lung
carcinoma, treatment is thoracotomy with lobectomy or
pneumonectomy. Thoracotomy for lung carcinoma carries a 30-day
mortality of 2% to 4%,
with additional major and minor complications, and thus the
treatment is associated with significant potential for damage. This
means that the screening test must be very specific for carcinoma,
which CT is not. Therefore, additional costs will be incurred
because patients will need to undergo confirmatory procedures in
many cases, including PET scans, repeat CT, and biopsy. Given that
the target of lung cancer screening is a small nodule, these
additional methods (biopsy and PET) may have a significant
false-negative rate and costs associated with them as well.
How should lung cancer screening with CT be
There are several elements that should be considered in a lung
cancer CT screening regimen, including: patient selection, patient
consent, patient referral, scanning technique, image
interpretation, and communication and reporting of results. The
Society of Thoracic Radiology has developed a valuable consensus
statement regarding the use and implementation of helical CT lung
cancer screening protocols; anyone developing a lung cancer CT
screening regimen would be well-advised to read these
As discussed earlier, screening is more likely to be effective,
both in terms of cost and yield, if there is a substantial pre-test
probability of disease. A reasonable target disease prevalence is
5%. How does one achieve such a prevalence? The pre-test
probability of a CT scan discovering a lung carcinoma is increased
when the factors that influence the likelihood of carcinoma are
more prevalent. The two most important factors increasing the
likelihood of carcinoma are patient age and history of smoking.
Current lung cancer screening trials enroll patients 50 years old
or older, with at least a 10- to 20-pack per year history of
smoking. The Lung Screening Study, a randomized controlled trial
being conducted at 6 medical centers in the United States, is
enrolling men or women aged 55 to 74 years with at least a 30-pack
per year history of smoking. If less stringent criteria are used,
the prevalence of carcinoma will be lower, and it will become more
likely that nodules discovered will represent false-positive cases.
This situation will result in increased costs and increased
complication rates. Many trials have an upper age limit because the
benefit of screening takes years to be realized. After a certain
age, it becomes as likely or more likely that a patient will die of
something else even if they have a lung cancer.
Most trials to date have excluded patients with extrathoracic
Including such patients clearly would affect survival statistics,
but potentially such patients could be screened in routine
practice. If such patients are scanned, the detection of a nodule
is a very serious matter. There is evidence to suggest that the
prevalence of malignancy within a nodule in a patient with a known
extrathoracic malignancy exceeds 40%, and may range as high as 80%,
even for very small lesions.
Of course, for the study to be truly a screening study, the
patient should be asymptomatic.
Some investigators have excluded patients with recent febrile
illness in an effort to decrease false-positive studies.
The potential for misconceptions regarding the utility of lung
cancer screening with CT makes discussion of the risks and benefits
of such screening a prudent idea.
This is particularly true now that numerous radiology groups are
advertising the benefits of CT screening, as well as the fact that
the lay press has run stories that cast a favorable light on CT
lung cancer screening,
although the utility of CT lung cancer screening is far from
proven. This situation results in one of the most common reasons
patients will sue: false expectations. Patients may elect to
undergo a CT screening study under the assumption that a negative
CT represents a "clean bill of health," only to develop advanced
stage pulmonary carcinoma sometime in the future. Alternatively, a
patient may undergo a CT screening study that is interpreted as
positive, only to suffer a complication during the course of
evaluation of the discovered nodule. If that nodule is proven
ultimately not to represent carcinoma, the patient may sue for
damages. Whether or not such lawsuits will be successful remains to
be seen, but the potential for litigation is certainly real. The
misperceptions that could result in such litigation may be
dispelled with a realistic discussion of the potential risks
(false-positive studies, radiation, complications incurred in the
work-up of lesions discovered on CT, etc.) and benefits of CT lung
Patients should be made aware that CT is an unproven technology
for screening for lung carcinoma; and that it is therefore possible
that a patient could have a negative CT screening study and still
develop lung cancer and die from it. Furthermore, patients should
understand that radiologists are fallible, and despite best
efforts, small carcinomas will be missed. Finally, patients should
understand that, given the nature of CT, lung cancer screening with
CT targets small peripheral cancers (Figure 1). We fully expect to
miss some centrally located lesions.
Also, the target of lung cancer screening is primarily small
peripheral adenocarcinomas, which happen to be the cell type least
associated with smoking. In fact, the cell type most associated
with smoking, small-cell carcinoma, usually presents as a central
lesion and may frequently be missed on most CT screening studies.
This type of information will alter (appropriately) patient's
expectations, and some patients may forego the test altogether in
light of such information.
Anyone establishing a lung cancer screening regimen must decide
whether or not they will accept self-referred patients.
Self-referred patients should probably sign informed consent forms
(as above), but, more importantly, a radiologist that accepts
self-referred patients essentially establishes a doctor-patient
relationship with that patient. This means that the radiologist
will assume the responsibility of being certain that the results of
the study are communicated to the patient,
and, more importantly, the radiologist will assume the
responsibility of explaining the significance of the results,
discussing the proposed treatment plan, and ensuring that the
patient follows up appropriately. Such consultations may become the
ethical standard for self-referred patients, and may even become
commonplace for physician-referred patients. Therefore, if the
patient has a positive study, it may become the radiologist's
responsibility to remind the patient to report for follow-up
studies at the assigned intervals, and the radiologist will have to
assume the responsibility of counseling the patient regarding
findings and further evaluation. This situation is analogous to
mammography registries, and has already become the standard in
several of the large screening trials.
The scanning technique used depends on the available equipment.
Single-detector helical CT studies may be conducted with 5-mm
collimation and a pitch of 2, with mA 20% of routine.
Narrower collimation may be employed, but it is important to obtain
the study in a single breath hold to avoid slice misregistration.
Multidetector CT studies are currently being conducted with very
narrow collimation (2.5 mm) and decreased (40 to 50) mA.
Using multidetector CT, patients may also be scanned with narrow
collimation with the images reconstructed at wider increments to
facilitate more rapid review. This method has the advantage that
the images can be reconstructed at the narrow collimation should a
nodule be discovered. Narrow collimation provides improved spatial
resolution, which is essential for the detection of small nodules.
However, the narrower the collimation, the more a vessel in cross
section may simulate a nodule. Therefore, these studies must be
interpreted very cautiously. Some investigators have used sliding
thick-slab maximum intensity projection images to assist in nodule
detection (see below).
It is critically important to know the target of lung cancer
screening with CT--the peripheral nodule. Central lesions,
particularly endobronchial lesions, may be missed easily. Before
embarking on a lung cancer screening regimen, it is useful to
review the results of studies examining spiral CT lung cancer
The overall detection failure rate is low, but lesions that are
missed may have one or more of the following features: 1) are
located in an area of scarring; 2) are located in an endobronchial
location; 3) have faint high attenuation, suggesting calcification;
4) are very small nodules; 5) are nodules immediately adjacent to
vessels; 6) are central lesions (Figure 2).
Accurate diagnosis is facilitated with workstation review. The
ability to display the images sequentially in rapid format and the
ability to rapidly switch back and forth between different windows
are invaluable advantages, and should be considered essential for
the review of lung cancer screening studies.
As mentioned above, sliding thin-slab maximum intensity
projection images (MIPs) are useful for demonstrating small
nodules. MIPs can make nodules more apparent while simultaneously
rendering the appearance of vessels more obvious. In a recent
study, when using 3.75 mm collimation MDCT images (reconstructed at
3-mm intervals), Gruden et al
found that 10-mm MIPs detected more small nodules than did review
of the axial data alone. Eventually, computer-aided diagnosis may
play a significant role in lung cancer screening studies.
How should small nodules discovered during the course of a
routine lung cancer screening study be addressed?
While there is no definite consensus, the management schemes of
the investigators currently conducting lung cancer screening trials
may provide a management guide
The following represents a combination of the algorithms used by
the ELCAP group and the Mayo Clinic trial, as well as a recent
survey of the nodule management schemes used by members of the
Society of Thoracic Radiology.
Nodules that are clearly benign (fat or benign pattern of
calcification) or negative CT studies result in annual follow-up
(not following the nodule, but having the patient return for repeat
annual screening). If the nodule is ¾3 to 4 mm, thin-section CT is
performed to further characterize the nodule's morphology. Some
investigators may perform thin-section imaging at the time of
nodule detection, while others may perform the thin-section CT at
the time of the first follow-up study, which is usually
approximately 3 months after the nodule was detected initially. If
the nodule remains stable, it is followed with CT at successive
intervals: 3 months, 6 months, 12 months, and 24 months. If the
nodule remains stable for more than 2 years, it is generally
considered benign. Any growth raises concern for malignancy, and
prompts investigation. Obviously, great care must be taken to
measure the nodule accurately to detect even slight growth. While
some investigators have employed sophisticated segmentation
algorithms for this purpose, such methods are not available
routinely to most practitioners. Instead, repeat thin-section
imaging, using identical scan parameters, with very careful
comparison to (multiple) priors scans, must be performed.
If the detected nodule has no benign features and ranges in size
from 5 to 10 mm, it may be resected by video-assisted thoracoscopic
surgery (VATS); it may be biopsied; or, if it is in a dangerous or
inaccessible location, it may be followed closely for interval
growth. PET scanning may play a limited role for nodules of this
size. If the nodule shows no evidence of benign characteristics and
is >=10 mm in size, most investigators suggest that the lesion
be biopsied or resected (via VATS or thoracotomy). The Mayo Clinic
regimen suggests that 8- to 20-mm indeterminate nodules should be
worked up immediately with thin-section CT to detect benign
features. If the nodule remains indeterminate, the nodule may be
evaluated with a CT nodule enhancement protocol. PET scanning could
be used in this case, particularly if the nodule is in an
inaccessible location (rendering biopsy dangerous or impossible),
if the patient cannot cooperate with biopsy, or if VATS resection
cannot be performed.
Communication and reporting of results
Standard reporting methods may suffice if patients are
physician-referred. A call to the referring physician and some
discussion of the risks and benefits of lung cancer screening may
be advisable. However, as discussed above, self-referred patients
must be handled directly by the radiologist. This involves patient
informed consent, with discussion of risks and benefits; reporting
of the results of the study to the patient, including the
implication of the results; and discussion of recommendations for
management (Naidich DP, personal communication, January 2001).
If follow-up studies are recommended, then it may be the
responsibility of the radiologist to contact the patient to remind
him/her of future CT appointments. This responsibility will require
the maintenance of records, perhaps in the form of an electronic
The accuracy of helical CT for the detection of small lung
nodules has prompted the use of helical CT for lung cancer
screening programs. While lung cancer is a common, and often fatal,
disease, the issues surrounding the use of helical CT for lung
cancer screening are complex and are hotly debated. Although there
are numerous points of contention between proponents and opponents
of the use of CT for lung cancer screening, the debate primarily
centers around whether or not a randomized, controlled trial is
needed (or would be useful) to prove the efficacy of lung cancer
screening with CT. Currently, most academic radiology societies
have suggested that CT screening for lung cancer be reserved for
patients enrolled in clinical trials. Nevertheless, the use of CT
for screening purposes has been popularized by the press as well as
some entrepreneurial radiologists, so it is likely that many
radiology practices will eventually encounter patients interested
in screening CT studies. Familiarity with the issues surrounding
the debate on lung cancer screening, as well as an understanding of
the implementation of proper lung cancer screening protocols, image
interpretation, and the logistics of instituting a CT screening
program are therefore very important.