Early Lung Cancer Action Project: overall design and findings from baseline
||Henschke C, McCauley D, Yankelevitz D, Naidich D, McGuinness G,
Miettinen O, et al.
||Lancet 354:99-105. July 10, 1999.
||Cornell and Columbia and NYU medical centers, New York;
McGill University, Montreal, Canada.
||National Institutes of Health, USA; Eastman-Kodak Corporation;
General Electric Corporation.
Lung cancer is most frequently detected at a stage when it is too advanced to
be curable. Although 5-year survival for stage I cancer that has been
resected can be as high as 70%, the overall 5-year survival for lung cancer is
only about 12%. This implies that screening to detect early disease should
be able to improve prognosis. The main randomized trial which
looked at this question, the Mayo Lung Project, did not show a significant
benefit for screening by chest x-ray, however.
Because CT scanning should be able to detect lung cancer at an earlier stage
than conventional radiography, the current trial was designed to look at the
effect of low-dose, non-contrast screening CT scans on the ability to detect
small, stage I lung cancers.
The Early Lung Cancer Action Project (ELCAP) was not a randomized study, but was designed as a screening and
follow-up trial. 1000 participants at high risk for lung cancer were
offered baseline screening, starting in 1992, with annual re-screening.
The endpoints were the detection of non-calcified nodules and the clinical
outcomes for those patients with nodules, with a particular emphasis on outcome
by size and radiographic appearance of the nodules detected. This paper
reports on the results of baseline screening.
Patients were recruited for screening if they were over 60 years of age, had
smoked at least 10 pack-years, had no history of cancer, had no symptoms of lung
cancer and would be able to undergo thoracotomy. A total of 1000
volunteers were enrolled (at New York Hospital and NYU Medical Center).
Baseline information recorded included age, sex, race, smoking history and
Screening was performed at baseline (the subject of this report) and is to be repeated annually.
Baseline x-ray and CT scan
Standard PA and lateral chest x-rays were obtained. Helical low-dose CT
scanning of the lungs was performed in a single breath-hold (up to 20 secs), at
end inspiration after hyperventilation. The slice thickness was 10 mm;
images were reconstructed in overlapping 5 mm increments.
All x-rays were read by two radiologists who then discussed their findings
and came to a consensus reading; if no consensus could be reached, a third
radiologist was asked to adjudicate.
X-rays and CT scans were analyzed for the presence and absence of
nodules. Each nodule was characterized by its shape (round or not), edge
(smooth or not), size (length and width), location (lobe involved and central
and by the presence or absence of benign calcifications.
Studies were classified as positive if there were between one and six
non-calcified nodules (NCN). Studies were negative if there were no NCN,
and were judged to show diffuse disease if there were more than six NCN.
Patients with positive screening CT scans and/or x-rays were recommended to
have standard-dose diagnostic CT scans for better delineation of the
lesions. If the non-calcified nodules seen on screening were confirmed and
were non-calcified on the diagnostic CT, further work-up was recommended,
depending on the size (average of length and width) of the nodule:
- nodules 5 mm or less: follow up with high resolution CT scans at 3 mos, 6
mos, 12 mos and 24 mos as long as there was no growth.
- nodules 6-10 mm: if possible, CT guided fine needle aspiration biopsy or
thoracoscopic biopsy; if not biopsied, CT follow up as for the smaller
- nodules greater than 10 mm: biopsy by fine needle aspiration, bronchoscopy
The actual decisions about diagnostic and therapeutic procedures were left up
to the referring physician and patients. Whether or not the recommendations were
followed, the results of all diagnostic procedures and any surgery for
resectable tumors were recorded.
This paper presents the results of baseline screening (prevalence data) and
the stage of malignant nodules by nodule size. It is too early in the protocol
to present survival data and data on follow-up screening (incidence data).
Median age was 67; 54% were male; 91% were white. Median number of
pack-years smoked was 45. Asbestos exposure was present in14%.
The readers disagreed on the interpretation of the low-dose screening scans
in only 31 out of the 1000 scans. In 28 of these cases, both readers
identified abnormalities, but only one reader interpreted them as non-calcified
nodules. After adjucation, all were deemed NCN's. None of these nodules turned
out to be malignant.
On screening CT, a total of 559 nodules were detected, of which 35% had
benign calcifications. On standard x-ray, a total of 196 nodules were found, of
which 60% had benign calcifications.
CT scanning identified a total of 233 individuals with 1 to 6 non-calcified
nodules (23% of the study population). Only 33 of these individuals (14%) also
had positive findings on conventional x-rays. There were 68 individuals
with positive results on conventional x-rays; 33 had positive CT scans as
mentioned previously, the other 35 had "nodules" that were not
confirmed on CT scan (shadow confluence).
Among the 233 individuals with a positive CT screening test, 159 (68%) had
one nodule and 43 (18%) had two nodules. The remaining 14% had 3, 4, 5 or 6
nodules. The size of the largest nodule detected in these patients was 2-5 mm in
58%, 6-10 mm in 30%, 11-20 mm in 9% and greater than 20 mm in 2%. Among
the 33 patients whose nodules were also seen on standard x-rays, the sizes were
larger overall (2-5 mm - 33%; 6-10 mm - 42%; 11-20 mm - 16% and greater than 20
mm - 9%).
According to protocol, the 233 participants with positive screening scans
should have had high resolution CT scans. 50 participants did not, 14 for
"good" reasons (a previous CT scan was available or the nodules were
tiny and appeared benign), and 36 because the physician or insurance plan
declined or they were lost to follow up.
The remaining 183 participants underwent the high resolution CT scan. In 54
of these, the non-calcified nodules were not confirmed and in 9 the nodules were
so benign appearing that only CT follow-up in one year was recommended.
Among the remaining 120 patients requiring follow-up:
- biopsy was recommended immediately in 16, was performed in 14, and
revealed malignant disease in 13 cases.
- biopsy was recommended after growth was documented by subsequent scans in
14, and revealed malignant disease in all 14.
- there has been no growth in 90 participants, 36 of these have been
followed up for 2 years.
A total of 33 patients underwent biopsy, 30 recommended by protocol, as noted
above, and three for reasons not indicated by the protocol (all 3 turned out to
Of the 30 per-protocol biopsies, 27 were malignant. Thus, 27 out of 233
participants (12%) with positive screening tests turned out to have malignant
disease. Among the 68 patients with positive chest x-rays, 7 cases of
malignancy were detected (10%). All of these 7 cases were picked up by CT
screening. Thus CT screening identified 20 (out of 27) cases that would not
have been picked up on routine chest x-ray; the yield of CT screening was 4
times greater than that of conventional chest x-ray.
Screening CT also picked up a further 4 malignancies that were not picked up
by chest x-ray but were not NCN's (two endobronchial lesions and two mediastinal
lesions) and were thus not counted as positive screening results.
Treatment and stage
Diagnosis of malignancy was made by fine needle aspiration in 18 and
thoracoscopy in 9; all were judged to be operable. Of the 27 participants with
detected malignancies, 24 underwent lobectomy, one underwent mediastinoscopy
which revealed stage IIIB disease, one underwent radiosurgery and one declined
treatment. 18 of the 27 had adenocarcinoma, the remainder were a mix of
adenosquamous, bronchoalveolar, atypical carcinoid and squamous.
Of the 27 malignancies detected, 23 (85%) were stage I. Of the 7
malignancies detected by conventional x-ray, 4 were stage I. Thus CT
screening detected 6 times as many stage I tumors as conventional x-ray:
23 vs. 4.
The authors make a number of points about their study:
- Low-dose CT screening is much more sensitive than conventional x-ray for
detecting non-calcified nodules and small lung cancers. CT detected 3
times as many nodules, 4 times as many malignant tumors and 6 times as many
stage I tumors as conventional x-rays.
26 out of 27 patients with malignant disease were operable. In the Mayo Lung
Project study, which utilized conventional x-rays, only about 50% of tumors
detected at baseline were operable.
- A main objective of this study is to correlate cure rate with nodule
size, but follow-up is too short to give any data on this yet. However,
given the small size of tumors that were detected and prior historical data
on cure rates according to tumor size, the authors estimate that 5-year
survival should be 60%-80% for patients with tumors detected by low-dose
CT. This is much better than the usual 12% 5-year survival rate for
- Contrary to current beliefs, the data presented here demonstrate that the
presence of 2-6 non-calcified nodules detected on CT was almost as likely to
represent malignant disease (11% were malignant) as the presence of a
solitary nodule (12%).
- The finding of many cases of NCN's did not lead to a lot of unnecessary
biopsies. Unnecessary biopsies were avoided by the management
recommendations which required an increase in size before small nodules were
biopsied. If one disregards the three biopsies done which were not
recommended by the guidelines, only one out of the 30 recommended biopsies
was for a benign lesion.
- An argument that can be raised about a study like this one is that it
leads to overdiagnosis, i.e. that it leads to the excision of lesions that
would not have caused problems in the long run (very slow-growing
malignancies). The authors argue that, using precise measurements of
nodule size, the growth rate (doubling time) of the lesions that were
excised does not support this hypothesis.
- As data accumulates from this study, it will enable more targetted
diagnostic approaches to small nodules (based on the characteristics of
those nodules that turn out to be malignant) and the evaluation of novel
therapeutic approaches to these nodules.
- Detailed cost-effectiveness analyses will be conducted, but the authors
note that screening CT scans should be only slightly more expensive than
conventional x-rays and treatment of early lung cancer is cheaper than
treatment of more advanced disease.
This study, following 1000 participants at high risk for lung cancer with baseline and annual low-dose CT screening for non-calcified
nodules, clearly demonstrates the ability of CT scanning to detect small tumors
with much greater sensitivity than conventional radiography.
Will this ability translate into lives saved by early detection? ELCAP was not
a randomized trial and thus cannot answer this question directly, but the
authors argue that, given historical data linking cure rates to tumor size and
given the ability of CT scanning to identify much smaller tumors, it makes
perfect sense that screening should improve the cure rates for those cancers
It is important to note that this paper provides no actual data on survival
or cure rates. It only provides data on the number of tumors found and
their size. Any speculation on the effect of finding these smaller tumors
on cure rates remains -- speculation. Since further data from this study will be forthcoming, in
the future we will have hard data on the cure rates of those tumors detected by
As the authors themselves point out, one problem with this type of
non-comparative study is the issue of whether those cancers that were actually
detected would have caused problems for the patients in the long run, before
other illnesses intervene. Thus, the early discovery of a small lung cancer is of
little significance if the cancer thus detected and removed would have taken
years to become clinically significant and the patient dies from a different
illness before that time. The authors argue against this scenario based on
the doubling times of the tumors that they detected. Nevertheless, this is
an important point. Since the patients studied here were 67 years old on average and were
smokers, they would be expected to have a relatively high incidence
of cardiovascular diseases, so the detection of very small lung cancers would
have less impact on survival than might be apparent from the cure-rates alone.
Another issue is lead-time bias. Lead-time bias relates to the fact that tumors that are detected early will
have a proportionately longer survival time, just based on the fact that they
were detected early. Thus, for example, very small tumors that are
detected 2 years earlier than those detected after symptoms develop would have a
survival time even in the absence of any treatment that is 2 years
The improved detection of small non-calcified nodules comes at the price of a
high rate of detection of clinically insignificant nodules, which require
further work-up. Out of 1000 participants, 233 had positive screening
tests but only 27 had cancer. Thus, approximately 200 had false positive
test results (assuming that most of those who did not receive appropriate
follow-up had benign disease). Apart from the anxiety that positive
screening tests produce, most of these false positive tests will lead to at
least one and, for the majority, up to 5 high-resolution CT scans to confirm
benign disease. A false positivity rate of approximately 20% is quite high
-- one out of 5 patients who are screened. The authors do not even comment
on this issue.
This high rate of false positive screening examinations will adversely impact
on cost and cost-effectiveness. The authors state that
low-dose CT screening, which does not use contrast, is relatively cheap.
Indeed, I have been getting letters from local radiologists touting their
services and offering screening CT's at $300 each. However, the
performance of five high-resolution scans to rule out malignant disease will
cost substantially more, probably in the range of several thousand dollars.
Finally, the population studied here is at particularly high risk for lung
cancer (the asbestos exposure rate of 14% is particularly impressive). Even if it turns out that low-dose CT scanning is cost effective in
this population, its cost-effectiveness and its positive predictive
value will be markedly reduced in any population that is at lower risk for lung
cancer. Given the fear that lung cancer engenders in the population, it is
likely that this procedure will be demanded by many patients at much lower risk
of the disease. In this lower-risk population, a false positivity rate of
20% will cause a significant burden of anxiety and cost, without yielding many
cases of early lung cancer.
August 29, 1999
related to this article from the NLM's PubMed
October 11, 1999
to the editor about this article, from the October 2, 1999 Lancet.
Topics discussed include the sensitivity and specificity of the test,
cost-effectiveness and the risk of overdiagnosis of clinically insignificant
Date: November 12, 2000
There were 27 cases of malignant nodules reported. Of the 26 operated on, how
many are alive today which is past 5 years?
The authors state that they didn't yet have follow-up data, in terms of
survival. I don't believe this data has been published yet. It
will be important, but, since this was not a randomized trial, the survival
data can only be compared to historical controls. -- mj
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