Screening for Lung Cancer

WHY CONSIDER SCREENING
Lung cancer makes, at present, for quite a sad chapter in pulmonary
medicine. In the United States, some 170,000 cases
are diagnosed annually1; the average cost of care per patient is
about $50,0002–4; and yet, the annual number of deaths from
this disease is almost as high as the number of cases diagnosed,
some 160,000.1 This is to say that, despite the very costly care,
the case–fatality rate—the proportion of cases that are fatal—is
near 95%.
While the overall case–fatality rate remains dismal, cases
diagnosed in stage I—before clinically manifest metastases—are
quite commonly curable and, thus, nonfatal. Depending on the
size of the tumor at diagnosis, the curability rate ranges from
some 50% to more than 90%5–8 (see Chapters 30 and 32).
Thus, the problem with lung cancer now is that those stage I diagnoses
remain quite uncommon, representing only some 15%
of all diagnoses of lung cancer.9
The solution to this problem potentially is the pursuit of
early, latent-state diagnosis in persons at relatively high risk for
lung cancer; that is, screening high-risk people for lung cancer,
before any overt, clinical manifestations of the disease.
That some increase in stage I diagnoses can be achieved
by means of a suitable regimen of screening is obvious; but
the question is whether the attainable increase is substantial
enough to justify the screening, especially for people with only
moderately elevated risk for lung cancer. It is thus important
to know the magnitude of the stage shift, notably the increase
in the proportion of stage I diagnoses, and this in reference
to a well-thought-out, realistic regimen of the screening. For,
the attainable rate of curability is, to a close approximation,
the proportion of stage I diagnoses multiplied by the curability
rate of stage I cases, specifically such stage I cases that are
diagnosed in the context of the screening—asymptomatic and
with the tumor typically smaller than in stage I diagnoses in
the absence of screening.
Screening for lung cancer has been of interest not only
because of the generally dismal prognosis in the absence of
screening but also for two other reasons: highly discriminating
risk assessment is possible to identify those at high risk, and
the small, latent-state lung cancers tend to be relatively well
identifiable against the backdrop of the airy parenchyma of
the lungs in radiographic imaging, particularly in computed
tomography (CT) imaging.
Interest particularly heightened when several studies
demonstrated the considerable superiority of CT over traditional
radiography (chest x-ray [CXR]) in the identification of small
pulmonary nodules.10–13 What is more, research on CT screening
for lung cancer has already led to quite a well-established
regimen for it,14,15 and the research also has produced evidence
indicating the attainability of quite a high rate of curability of
this, thus far, near-uniformly fatal disease.16–18 Thus, the time
has come for physicians to consider CT screening for lung cancer
of persons at high risk for the disease or for persons who are asking
their doctors about it. These decisions should be made on a
case by case with the individual at issue suitably informed by his
or her doctor.
Research on Screening for Lung Cancer In the
early 1970s, the National Cancer Institute (NCI) funded a
screening trial for lung cancer.19 In this trial, sputum cytology
was the screening test and half of the 30,000 high-risk participants
were to be randomly assigned to the “intervention”
(sputum cytology every 4 months for 6 years) and half to the
“control” (no screening). All participants were to have annual
CXR. This study evolved into three separate ones, each having
about 10,000 participants: the Memorial Sloan-Kettering
Lung Project (MSKLP),20,21 the Johns Hopkins Lung Project
(JHLP),22,23 and the Mayo Lung Project (MLP).24,25 The
MSKLP and JHLP performed the study as planned for 6 years.
The MLP investigators, however, wanted to test both sputum
cytology and the CXR and thus developed a different protocol.
They first screened all of the 10,933 participants using both
sputum cytology and CXR, and then assigned 9211 people
with no evidence of cancer on the baseline round to either
receive sputum cytology and CXR every 4 months for 6 years
or to no screening; all received the usual Mayo Clinic advice of
having annual screening.
At the completion of these studies in the late 1970s,
none showed a reduction in lung cancer mortality because of
screening using sputum cytology. Beyond this, because of the
results of the MLP, CXR was also deemed not to be useful,
even though the investigators themselves26–28 as well as independent
experts29–31 judged the MLP to be inconclusive and
seriously flawed. Further, the International Union Against
Cancer (UICC) workshop on screening for cancer32 in 1984
concluded that “the effectiveness of annual CXR in reducing
lung cancer mortality was not evaluable in these trials. A
case-control study was proposed to attempt a relatively quick
evaluation, to be followed by a randomized trial if indicated.
A search for new screening procedures is warranted.”
Subsequently, in Japan where screening with CXR continued
as a matter of national policy, five case-control studies
were performed.33–37 These five studies considered the timing
of diagnosis with respect to the screening test, accumulated
many more lung cancers than have been found in the randomized
trials, and provided convincing evidence that deaths from
lung cancer were less common if the diagnosis was achieved
within 12 months of having CXR, but not when the delay
was longer.
Ultimately in the United States, the NCI funded another
screening trial to assess the benefit screening for prostate, lung,
colorectal, and ovarian cancer, known as the PLCO trial.38 For
lung cancer, participants were randomly assigned to receive the
“intervention” (baseline and two annual CXRs) or no screening.
It was started in 1993, but the conclusions of this trial
have not yet been reported.
Interestingly, at the same time as the lung cancer trial
was being planned in the early 1970s, the NCI also funded a
trial to assess the benefit of screening for colorectal cancer.39
This trial enrolled 45,000 participants, 15,000 received annual
screening, 15,000 biannual screening, and 15,000 no
screening, but even with the greater number of participants,
it did not show a mortality reduction after 5 years of screening
and further follow-up. But for this trial, different from the
lung cancer trials, the decision was made to provide another
5 years of screening and ultimately some 20 years after the
trial started, it demonstrated a significant mortality reduction,
improved survival rate, and a decrease in the incidence
of late-stage cancers due to screening.39,40 Since then, many
advances in screening for colon cancer have been introduced,
and they are accepted and reimbursed without any further
evidence from randomized trials.
Research in the CT Era In 1993, we initiated the
Early Lung Cancer Action Project (ELCAP) for research on
CT screening for lung cancer.10,11,41 To us, different from
the prior randomized trials, screening is not a single test nor
an intervention, rather it is a sequential process of pursuing
early, latent-stage diagnosis of the cancer in order to provide
for early treatment of it.42 From this vantage, we saw it necessary
to first endeavor to develop a justifiable regimen for the
diagnostic process; that is, a suitable definition of the initial
test, of its positive result, and of the workup that is to follow
that positive result, possibly leading to diagnosis of the
cancer.42 Thereupon, the principal concern was the diagnostic
performance properties of the regimen, and updating of this
regimen based on emerging evidence and new technologies.
Secondarily, there was going to be need for prognostic research,
focusing on the curability of screen-diagnosed cases of lung
cancer, stage I cases in particular.
Initially, the first version of the CT screening regimen
was compared with its CXR counterpart, applying both to
all participants in the study.11 Each regimen’s diagnostic
performance was addressed in terms of the proportion of
stage I diagnoses among all diagnoses and the proportion of
screen-diagnoses among all diagnoses. In the baseline round,
29 cases of lung cancer were diagnosed, 27 of them screendiagnosed,
two interim-diagnosed. Of the 29, 25 were in
clinical stage I, all of them screen diagnosed.11 CXR screening
identified only seven of the 27 cases of screen diagnosed
by the CT regimen, and only 4 of the 23 stage I cases.
Consequently, only CT was used in the 1184 repeat screenings.
41 In these repeat screenings, seven cases of lung cancer
were diagnosed, and there were no interim diagnoses. Of the
seven, six were in clinical stage I.
Subsequent studies of the expanded ELCAP in New York
State43 and then throughout the world44 showed that the
proportion of diagnoses in clinical stage I has remained high,
around 85%, for both baseline and annual repeat rounds of
screening, with rare interim diagnoses, confirming the initial
ELCAP results.
Prognostic research as to the curability of screendiagnosed
cases of lung cancer was provided after long term
follow-up of the diagnosed cases of lung cancer. This research
demonstrated an estimated curability rate of 80% for all those
diagnosed with lung cancer, regardless of stage and treatment.
If diagnosed in clinical stage I and promptly resected, the
estimated rate was 92%.44 The high curability rates are not
surprising as others previously had shown that when lung
cancer is diagnosed when it is still small and in stage I, it is
highly curable.5–8
The high proportion of stage I diagnoses and the high
estimated curability rate have raised the concern by some
that these may be due to “overdiagnosed” lung cancers,45
meaning that CT screening identifies slow-growing cancers
which, if not resected, would not lead to death. The I-ELCAP
protocol aims to minimize “overdiagnosis”15 by requiring
documentation of growth of small nodules prior to biopsy,
biopsy diagnosis prior to resection, review of the resected
specimens by a panel of expert pulmonary pathologists, and
by addressing the outcomes of patients diagnosed in stage I
but not treated. The review by pathologists who are experts
in pulmonary pathology has confirmed that all diagnosed
with lung cancer had genuine lung cancers whose pathologic
criteria met the World Health Organization (WHO) criteria
of malignancy,46 and patients diagnosed with stage I lung
cancer who had no treatment, all died of it.44
Other studies had also shown that if left untreated,
stage I lung cancers identified in the absence of screening,
are usually fatal47,48 and so are stage I cases diagnosed by
CXR screening.49–51 If, nevertheless, substantial concern
about overdiagnosis still exists, then a randomized trial
could ethically be performed by randomly assigning patients
diagnosed with potential overdiagnosed lung cancers to either
immediate treatment or delayed treatment. For early
prostate cancer, such a trial was performed and it demonstrated
that even for a cancer with a much lower fatality rate,
surgical resection was significantly better.52
Slower-growing cancers are proportionately more common
among cases diagnosed in the baseline round of screening,
a phenomenon that has been termed length bias.45 This
bias is reflected by the pathologic subtypes of cancers diagnosed
in the baseline round in which a higher proportion of
adenocarcinomas and lower proportion of squamous and small
cell carcinomas were identified as compared with the repeat
rounds.46 Further insight as to which cancers might be slower
growing was provided by the initial 1000 ELCAP participants
as we had identified a higher proportion of cancers manifesting
as subsolid (nonsolid and part-solid) nodules in the baseline
rounds than in the repeat rounds.53,54 The significance
of finding subsolid nodules, previously termed ground-glass
opacities, relative to lung cancer had not been fully appreciated
(see Chapter 33). Remarkably, the rate of malignancy was
significantly higher for part-solid nodules than for either solid
or nonsolid ones.53 We also found that the distribution by
type of malignancy was very different, with the malignancies
manifesting as subsolid nodules either being adenocarcinomas
with bronchioloalveolar features or adenocarcinomas-mixed
subtype, whereas malignancies manifesting as solid nodules included
the entire spectrum of the cell types of lung cancer with
the exception of adenocarcinoma with bronchioloalveolar features.
46 Analyses of the growth rates of adenocarcinomas has
allowed us to identify those manifesting as nonsolid nodules as
being slower growing lung cancers.54
The clinical concern about slowly growing malignancies
is to understand their course in the absence of treatment and
then to treat them appropriately. In the lung, typical carcinoid
tumors are a good example. Although considered to be benign
in the 1970s, this cell type was reclassified as a malignancy
in the 1980s when it was recognized that this was a neuroendocrine
tumor, albeit a slowly growing one. Faster-growing
neuroendocrine tumors are atypical carcinoids, and small cell
carcinomas. Clinical management has taken these differences
into account so that different treatment options are provided
for these different subtypes. Similarly, clinical management
and treatment might well be different for certain subtypes of
adenocarcinoma, particularly those manifesting as nonsolid
nodules.
It now is quite commonplace to think about overdiagnosis
as encompassing identification not only of slowly growing
cancers but also of genuinely life-threatening cancers in
persons who die of some other cause. In the former case,
the person is thus subjected to overtreatment, that is, treatment
of a screen-detected cancer when not at risk of dying of
the cancer, the cancer being effectively benign. Diagnosis of
the latter type occurs when screening is performed on wrong
indications (as for life expectancy) as the person has a genuine
life-threatening cancer but dies of another cause. We do
not view this latter type as an overdiagnosed cancer and have
addressed competing causes of death in the context of CT
screening separately.55
Important updates on the regimen of screening were
based on information obtained from the initial ELCAP and
its successors. With the technologic advances in CT scanners
markedly reducing the image thickness, the definition of a
positive result of the initial test at baseline needed to be updated
to avoid unnecessary diagnostic workup. From the accumulated
information on the very small noncalcified nodules
less than 5.0 mm in diameter, ever more frequently detected
at baseline, we found that such nodules only required a follow-
up CT scan 1 year later, at the time of the first annual
repeat screening.56 We also found that short-term follow-up
CT obviated the need for further evaluation of up to 75%
of the newly identified nodules on repeat screenings, as they
had either resolved or regressed.57 The usefulness of growth as
an indication for biospy of small nodules was tested58–62 and
was found to minimize unnecessary biopsies, so that for recommended
biopsies the malignancy rate was above 90%,43,44
while when not recommended but performed, the malignancy
rate was essentially zero. The workup following other findings
on the CT scans, such as mediastinal masses,63 cardiac calcifications,
64 and emphysema65 were formulated leading the way
to combined screening of the major tobacco-related diseases
in the chest, that is, lung cancer, emphysema, and coronary
artery disease.
Curability Gain and Mortality Reduction As should
be evident from the foregoing, screening for lung cancer is a
complex topic of diagnostic pursuit in clinical medicine, not
one of population-level intervention in community medicine.
The proximal aim of the screening is the attainment of early
diagnosis; the purpose of pursuing early diagnosis is to provide
for early treatment; and the purpose of seeking to provide
for early treatment is the ultimate one: to thereby enhance
the probability that treatment results in cure of the cancer in
the cared-for person. Were the screening to be provided in
the framework of community medicine—as “mass” screening
in the meaning of more or less indiscriminate application
of a single, simple test to members of the cared-for population—“
its ultimate purpose would be seen to be reduction in
the rate of lung cancer mortality in the cared-for population,
consequent the test-positives” referrals to clinical care—for
further diagnostic workup, ultimately leading to early diagnoses
of the cancer and their associated enhanced curability
in individual cases.
The consequence of screening on the rate of a cancer’s
curability can be studied through rates of surviving the cancer,
although only with attention to an important subtlety
in this. A misleading way, it is generally understood, is to
compare, say, 5-year survival rates between those whose
cancer is diagnosed in the framework of screening (screenand
interim-diagnosed cases combined) and those in whom
the cancer is diagnosed in the absence of screening. Most
of the cases diagnosed under screening are diagnosed with
a “lead time,” earlier than they would be diagnosed in the
absence of screening—pursuit of this lead time being the very
essence of screening. Consequent to this, assessment of the
curability gain from screening in terms of comparison of survival
rates can be marred by “lead time bias”: the, say, 5-year
survival rate following diagnosis among the screened is prone
to be higher than among the unscreened already on the basis
of the lead time peculiar to the screened, even if early treatment
is no more commonly curative than is treatment in the
absence of screening.
Study of a cancer’s curability requires a “survival analysis”
in which survival over a particular, rather short span of time
subsequent to diagnosis—5 years, say—is replaced by longterm
survival, in a particular meaning of this. The survival rate
naturally is a decreasing function of time since diagnosis; but
in the absence of deaths from other, “competing” causes, this
time function levels off and reaches its asymptote. This “causespecific”
asymptotic survival rate represents the rate with which
the cancer has been cured. By the same token, this survival
rate is the cancer’s curability rate provided that the most effective
treatment has been applied in all of the cases, without any
undue delays after their diagnoses. Competing causes of death
cannot be eliminated, of course; but elimination of their role
can be achieved statistically, so as to address the cause-specific
survival rate that refers to the cancer in the absence of other
causes of death.
In the I-ELCAP, we addressed the curability of lung cancer,
given its diagnosis in the framework of such screening as
had been applied in that program.44 Of all the diagnoses, 85%
had been achieved in clinical stage I; and for those in whom
stage I diagnosis had been followed by timely resection, the
10-year cause-specific survival rate—apparently representing
the survival function’s asymptote—was 92%. These results
suggested the overall curability rate of 0.85 (0.92) 78%.
This may, however, be an overestimate, on the basis not only
of involvement of some overdiagnosed cases but also of application
of the Kaplan-Meier estimation of the survival rate
to follow up well past the time of the last death from lung
cancer, with very few subjects contributing to the follow-up
beyond that time.
Insofar as overdiagnosis is perceived to be a possibility in
ELCAP-type screening for lung cancer, the need in practice
may be to refrain from routine early treatment of the types
of stage I cases that are most likely to be very slowly progressing,
to treat them only once follow-up shows definite further
growth at a substantial rate. The frequency with which this
provides for avoidance of overtreatment—of overdiagnosed
cases—has not yet been assessed in the I-ELCAP, nor elsewhere.
But the assessment is feasible, and it will be done, possibly
leading to downward adjustment of the curability-rate
estimate. Accrual of further experience with long-term survival
may have the same effect.
The curability gain can, in principle, be quantitatively
assessed through mortality reduction also. If the screening
of a cohort is continued long enough, there comes a period
of follow-up time in which the proportional gain in curability
is manifest in the same proportional reduction in the
cause-specific mortality rate. This, however, is not a practical
way of assessing the curability gain from CT screening for
lung cancer.
Now, there are those who take interest in quantification
of the mortality reduction associated with screening of for an
arbitrary, short duration, and without concern to focus on the
period of follow-up time in which the curability gain takes
its maximal manifestation in proportional reduction in the
cause-specific mortality—addressing, instead, the reduction
in the cumulative mortality from the cancer over the entire,
arbitrarily long duration of follow-up. This was the case in
the Mayo Lung Project originally,24 and also upon a subsequent
major extension of its duration of follow-up.66 There
is concern that the duration of screening and follow-up for
the ongoing National Lung Screening Trial (NLST)67 could be
impacted by its study design and could prematurely create the
impression that not much is gained from the screening—or,
even, that nothing is gained.68
Guidelines for Screening for Lung Cancer and
Needed Revisions Prior to the late 1970s, CXR had
been recommended by the American Cancer Society (ACS)
for people at high risk of lung cancer, that is, heavy smokers
and workers in asbestos industry.69 Subsequently, the ACS
adopted new guidelines for making the recommendations
that called for good evidence of “test efficacy” in that the
medical benefits were to outweigh the risks, the cost of the
testing was to be in reasonable proportion to the expected
benefits, and the test was to be practical and feasible. Largely
as a result of the randomized trials described previously, the
ACS changed its recommendation to be against screening for
lung cancer in 1980.69 Later in 2000, a nine-point protocol
was introduced which placed primary importance on the
results of randomized trials, less on nonrandomized studies
and even less on expert opinion.70 In 2001, the ACS clarified
its recommendation against screening for lung cancer, stating
that “The ACS does not recommend lung cancer screening
for asymptomatic individuals at risk for lung cancer,” but
pointed out that the ACS distinguishes between recommendations
concerning mass screening from those pertaining to
clinical decisions on or by individuals. Thus the recommendation
against screening expressly was not intended to discourage
early-detection tests on individuals, as it was stated
that “individual physicians and patients may decide that the
evidence is sufficient to warrant the use of these screening
tests on an individual basis.”71
The U.S. Public Health Service convened the U.S.
Preventive Services Task Force (USPSTF) in 1984 to provide
guidelines for screening. Later in 1998, this task force was
placed under the Agency for Healthcare Research and Quality
(AHRQ). The mission of the USPSTF was to evaluate the
benefit of preventive services with specificity to age, gender,
and risk factors for disease; to make recommendations about
which preventive services should be incorporated into primarycare
routines, for which populations, and to develop a research
agenda for clinical preventive care.72,73 It has subsumed screening
under preventive (rather than diagnostic) services. The
recommendations are graded according to the strength of the
evidence and the magnitude of the net benefit (benefits minus
harms) on a scale from a strong recommendation for to recommending
against, or to neither recommending for or against.
The quality of the evidence is graded as being good, fair, or
poor and randomized trials are considered to be superior to
“cohort and case-control” studies. In 1998, the USPSTF recommended
against screening for lung cancer, against use of
either CXR or sputum cytology as a screening test.73 In 2004,
the USPSTF changed its recommendation to the judgement
that there is insufficient evidence to recommend for or against
the screening with either CT, CXR, or sputum cytology.74
This change in recommendation by the USPSTF was stated
to be primarily based on five case-control studies performed in
Japan as previously reported, which demonstrated a benefit of
annual CXR screening.33–37
The practically exclusive reliance of both the ACS and
the USPSTF on randomized trials in evaluating screening for
lung cancer has persisted, despite two extensive reviews having
demonstrated that well-designed “cohort” and “case-control”
studies on screening show little evidence of overestimation of
the benefit.75,76 And it has persisted even when both agencies
have recommended screening for breast and colorectal cancers,
before there was any evidence from randomized trials, and despite
controversial results from these.
Both the ACS and USPSTF guidelines state that a person
interested in being screened for lung cancer discuss it with
his/her physician. Needed for such a discussion naturally is
information on the benefit from the screening specific to the
individual’s risk characteristics.
The benefit from screening needs to be addressed in
terms of individual’s probabilities of: (a) the screening if
now applied, resulting in the diagnosis of lung cancer;
(b) surviving all other potential causes of death over particular
periods of prospective time; and (c) cure resulting from
presymptomatic treatment of lung cancer.77 We addressed
the survival benefit specific to the baseline round of screening
for smokers 60 to 84 years of age. The estimated probability
of survival gain was 0.4% for a 60-year-old individual
with 10 pack-years of smoking who quit 20 years ago, 3.1%
for a 70-year-old current smoker with 100 pack-years, and
2.0% for an 85-year-old current smoker with 150 packyears.
Clearly, the benefit increases with increasing age up
to 70 years and ultimately decreases. We provided this information
both for current and former smokers. Thus, when
seeking counsel about initiation of screening for lung cancer,
an estimate of the probability of survival gain from the first
round of CT screening, specific to the person’s age and history
of smoking can be provided. Based on this information,
we believe there is sufficient evidence for it to be reasonable
for a person at high risk for lung cancer with a sufficient life
expectancy to pursue screening.
There is a growing body of evidence collected over the past
12 years that CT screening for lung cancer leads to a dramatic
increase in the proportion of early stage genuine (fatal in the
absence of early treatment) lung cancer relative to symptomprompted
diagnosis and a marked improvement in long-term
survival (Table 16.1). As lung cancer is the most common
cause of cancer death in both men and women in the industrialized
world, it is a major public health problem. We think
that the guidelines should be revised to recognize the following
points as has already been published by the Society of Thoracic
Radiology in the minority report82:
1. It is well-accepted that the curability of Stage I lung cancers
is very high relative to the curability of late-stage cancers;
and within Stage I, cancers less than 3 cm in diameter (Stage
IA) are more curable than those that are larger (Stage IB);
2. Studies on annual CT screening have established that the
lung cancers are much more commonly diagnosed at Stage
I and at smaller sizes than by chest radiography.
3. Based on the points above, it is knowable that annual CT
screening for lung cancer provides for prevention of death
from lung cancer by early intervention. Quantitative assessment
of the actual magnitude of this benefit is being pursued
by studies in the U.S. and elsewhere.
4. A person at high-risk for lung cancer yet free of suspicionraising
symptoms of it, who is interested in potentially
being screened, should be fully apprized of the implications
of screening and of the treatment that may result. In light
of this, it is reasonable for the individual to choose to be
screened by a suitably defined CT regimen.
Point 3 follows from points 1 and 2. Point 4 draws from
point 3 together with the principle of Patients’ Autonomy,
recently enunciated by a prestigious European–U.S. Joint
Commission