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2013
Results of initial low-dose computed tomographic screening for Results of initial low-dose computed tomographic screening for
lung cancer lung cancer
Timothy R. Church
University of Minnesota School of Public Health
William C. Black
Darmouth-Hitchcock Medical Center
Denise R. Aberle
University of California - Los Angeles
Christine D. Berg
National Cancer Institute
Kathy L. Clingan
Westat, Rockville
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Recommended Citation Recommended Citation
Church, Timothy R.; Black, William C.; Aberle, Denise R.; Berg, Christine D.; Clingan, Kathy L.; Duan,
Fenghai; Fagerstrom, Richard M.; Gareen, Ilana F.; Gierada, David S.; Jones, Gordon C.; Mahon, Irene;
Marcus, Pamela M.; Sicks, JoRean D.; Jain, Amanda; and Baum, Sarah, ,"Results of initial low-dose
computed tomographic screening for lung cancer." The New England Journal of Medicine. 368,21.
1980-1991. (2013).
https://digitalcommons.wustl.edu/open_access_pubs/2480
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Authors Authors
Timothy R. Church, William C. Black, Denise R. Aberle, Christine D. Berg, Kathy L. Clingan, Fenghai Duan,
Richard M. Fagerstrom, Ilana F. Gareen, David S. Gierada, Gordon C. Jones, Irene Mahon, Pamela M.
Marcus, JoRean D. Sicks, Amanda Jain, and Sarah Baum
This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/
open_access_pubs/2480
original article
The
new engl a nd jour nal
o f
medicine
n engl j med 368;21 nejm.org may 23, 2013
1980
Results of Initial Low-Dose Computed
Tomographic Screening for Lung Cancer
The National Lung Screening Trial Research Team*
The members of the writing team (who
are listed in the Appendix) assume re-
sponsibility for the integrity of the article.
Address reprint requests to Dr. Timothy
R. Church at the Division of Environmen-
tal Health Sciences, University of Minne-
sota School of Public Health, 200 Oak St.
SE, Suite 350, Minneapolis, MN 55455, or
at trc@cccs.umn.edu.
* A complete list of members of the Na-
tional Lung Screening Trial Research
Team is provided in the Supplementary
Appendix, available at NEJM.org.
N Engl J Med 2013;368:1980-91.
DOI: 10.1056/NEJMoa1209120
Copyright © 2013 Massachusetts Medical Society.
ABSTR ACT
Background
Lung cancer is the largest contributor to mortality from cancer. The National Lung
Screening Trial (NLST) showed that screening with low-dose helical computed to-
mography (CT) rather than with chest radiography reduced mortality from lung
cancer. We describe the screening, diagnosis, and limited treatment results from
the initial round of screening in the NLST to inform and improve lung-cancer–
screening programs.
Methods
At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptom-
atic participants, 55 to 74 years of age, with a history of at least 30 pack-years of
smoking. The participants were randomly assigned to undergo annual screening,
with the use of either low-dose CT or chest radiography, for 3 years. Nodules or
other suspicious findings were classified as positive results. This article reports
findings from the initial screening examination.
Results
A total of 53,439 eligible participants were randomly assigned to a study group
(26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants
(98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 par-
ticipants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography
group had a positive screening result; in the respective groups, 6369 participants
(90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, includ-
ing imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121
(5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT
group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants
and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4%
for low-dose CT and 73.5% and 91.3% for chest radiography, respectively.
Conclusions
The NLST initial screening results are consistent with the existing literature on
screening by means of low-dose CT and chest radiography, suggesting that a reduc-
tion in mortality from lung cancer is achievable at U.S. screening centers that have
staff experienced in chest CT. (Funded by the National Cancer Institute; NLST
ClinicalTrials.gov number, NCT00047385.)
The New England Journal of Medicine
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Low-Dose ct Screening for Lung Cancer
n engl j med 368;21 nejm.org may 23, 2013
1981
L
ung cancer is the largest single
cause of deaths from cancer in the world
1-3
and is expected to account for more than
160,000 deaths in the United States during 2013.
4
Most patients with lung cancer have smoked
cigarettes.
5
Of 94 million U.S. smokers, half are
former smokers whose risk remains elevated de-
cades after cessation.
6
In the National Lung Screening Trial (NLST)
of screening for lung cancer in older persons who
were heavy smokers,
7
mortality from lung can-
cer was lower with the use of 3 years of annual
screening with low-dose helical computed to-
mography (CT) than with the use of chest radi-
ography.
8
In addition, the Prostate, Lung, Colorec-
tal, and Ovarian Cancer Screening Trial (PLCO)
9
showed that among approximately 30,000 par-
ticipants with baseline characteristics that were
similar to those of the NLST participants, mor-
tality from lung cancer did not differ signifi-
cantly between participants undergoing screen-
ing by means of chest radiography and those
receiving usual care,
10
confirming the results of
previous randomized trials of screening with the
use of chest radiography.
11-13
The NLST, a joint effort of the Lung Screen-
ing Study (LSS) and the American College of Ra-
diology Imaging Network (ACRIN), both funded
by the National Cancer Institute (NCI), began
randomly assigning participants in August 2002
to annual screening for 3 years with the use of
either low-dose CT or chest radiography. Details
of the study design
7
and the rationale for choos-
ing chest radiography as the control procedure
14
have been published previously. A better under-
standing of the screening process, including the
frequency and management of positive screening
results, can inform the implementation of lung-
cancer screening programs as well as efforts to
improve them. Here, we describe the screening,
diagnosis, and limited treatment results from
the initial round of screening in the NLST.
Methods
Study Participants and Study Conduct
At 33 screening centers, we recruited asymptom-
atic men and women, 55 to 74 years of age, who
had a history of at least 30 pack-years of cigarette
smoking and who were either current smokers or
had been smokers within the previous 15 years.
Participants were randomly assigned to undergo
annual screening for 3 years with the use of ei-
ther low-dose CT or chest radiography. The study
was approved by the institutional review board at
each study center, and all participants provided
written informed consent before undergoing ran-
domization. Details of recruitment and random-
ization methods have been published previously.
7
Screening Equipment and Procedures
Low-dose CT was performed on multidetector
helical CT scanners of four or more channels.
Single-view posteroanterior chest radiographs
were obtained with the use of conventional film
or digital radiographic systems. Technical stan-
dards and acquisition variables for both low-dose
CT and chest radiographic screening have been
published previously.
7,15-17
Image Interpretation
Results were recorded on forms developed for
the study. The screening image was classified as
diagnostic, limited but diagnostic, or nondiagnos-
tic, with the reasons documented.
For low-dose CT, all noncalcified nodules with
long-axis diameters of 4 mm or greater in the
axial plane were considered to be positive for
potential lung cancer. For all positive nodules,
the anatomical location (lobe), longest axial, per-
pendicular diameters, margin characteristics, at-
tenuation, and representative slice number were
recorded.
For chest radiography, the results were read
on original film or digital image. All noncalci-
fied nodules and masses were considered to be
potentially positive for lung cancer, and for all
positive nodules, the anatomical location, longest
perpendicular diameters, and margin character-
istics were recorded.
The interpreting radiologist judged whether
the screening results were positive on the basis
of findings such as noncalcified hilar or medi-
astinal adenopathy, atelectasis, and pleural dis-
ease. Available historical images were reviewed,
and all results and recommendations were re-
corded. Screening results were classified as posi-
tive, negative with clinically significant abnor-
malities, negative with minor abnormalities, or
negative with no abnormality. Participants with-
out diagnostic results were considered to be
unscreened. Although the NLST had guidelines
for the follow-up of positive screening results,
radiologists could make diagnostic recommen-
The New England Journal of Medicine
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The
new engl a nd jour nal
o f
medicine
n engl j med 368;21 nejm.org may 23, 2013
1982
dations as they saw fit. Screening results were
reported to the participant and the participant’s
designated health care provider, by mail, within
4 weeks.
Follow-up of Study Participants
All participants were mailed annual question-
naires (for the LSS participants) or semiannual
questionnaires (for the ACRIN participants) as-
certaining vital status and interim cancer diag-
noses. Among participants with positive screen-
ing results or with a diagnosis of lung cancer, all
related diagnostic procedures, complications (not
reported here), and results were abstracted by
certified medical-record abstractors.
For cases of diagnosed lung cancer, the his-
tologic type and grade, tumor stage,
18
and initial
treatment were documented. To augment the
ascertainment of deaths from questionnaires, the
National Death Index was also searched through
December 31, 2007. Determination of the cause
of death led to the discovery of some previously
unreported cases of lung cancer, which were
also abstracted.
Here, we describe the results of the first
round of screening and diagnostic evaluations
that were initiated on the basis of positive find-
ings at the screening visit, as well as all cancers
diagnosed and treatments initiated at any time
after randomization until the second screening,
if applicable, or until 1 year after the first screen-
ing. A diagnostic evaluation consisted of a se-
ries of diagnostic procedures with no more than
12 months between consecutive procedures, in-
cluding the first screening.
Statistical Analysis
We compared the two screening groups with re-
spect to adherence of the participants to the test-
ing protocol, image quality, types of diagnostic
procedures, and results (positive or negative
screening result, ultimate diagnosis, and initial
treatment information). The results were strati-
fied according to group and, in some cases, age,
sex, race, educational level, and smoking history.
All tabulations were performed with the use of
SAS/STAT software, version 9.1 of the SAS Sys-
tem for Unix or version 9.2 for PC (SAS Institute).
Each screening result was judged to be posi-
tive or negative, and a strict algorithm was used
to ascertain whether lung cancer was present at
the time of screening (see details in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). Confidence intervals
were calculated by means of bootstrapping.
19
Results
Recruitment and Randomization
From August 2002 through April 2004, a total of
53,454 participants were enrolled at 33 sites
across the United States; 26,722 were randomly
assigned to low-dose CT and 26,732 to chest ra-
diography. Figure 1 shows the follow-up of par-
ticipants during the trial.
20
A total of 8 partici-
pants had lung cancer and 7 died before the first
scheduled screening. Of the remaining 53,439
participants, 26,715 were in the low-dose CT
group and 26,724 were in the radiography group.
Screening
The first scheduled screening examination was
performed in 98.0% of the participants (52,344
of 53,439) — specifically, in 98.5% of the partici-
pants in the low-dose CT group (26,309 of 26,715)
and in 97.4% of those in the chest radiography
group (26,035 of 26,724) (Table 1). Compliance
did not differ significantly according to sex, age,
race or ethnic group, smoking status, or educa-
tional level (Table 1, and Table 1 in the Supple-
mentary Appendix). Four participants undergo-
ing low-dose CT and 13 participants undergoing
chest radiography had nondiagnostic results,
none of whom received a diagnosis of lung can-
cer during the follow-up period. The proportion
of participants with positive screening results
was higher in the low-dose CT group (7191 of
26,309 participants [27.3%]) than in the radiog-
raphy group (2387 of 26,035 [9.2%]). Rates of
positivity increased slightly with older age and a
larger number of pack-years of smoking in both
screening groups.
The proportion of all screened participants
who had negative screening results but poten-
tially clinically significant, noncancerous abnor-
malities was higher in the low-dose CT group
(2695 of 26,309 [10.2%]) than in the radiography
group (785 of 26,035 [3.0%]).
Screening Accuracy
During the baseline follow-up period, lung can-
cer was diagnosed in 292 of the 26,309 partici-
pants (1.1%) who underwent low-dose CT screen-
ing versus 190 of the 26,035 participants (0.7%)
The New England Journal of Medicine
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