The Danish Randomized Lung Cancer CT Screening Trial—Overall Design and Results of the Prevalence Round

Department of Thoracic Surgery RT, Rigshospitalet, University of Copenhagen, Denmark.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 05/2009; 4(5):608-14. DOI: 10.1097/JTO.0b013e3181a0d98f
Source: PubMed

ABSTRACT

Lung cancer screening with low dose computed tomography (CT) has not yet been evaluated in randomized clinical trials, although several are underway.
In The Danish Lung Cancer Screening Trial, 4104 smokers and previous smokers from 2004 to 2006 were randomized to either screening with annual low dose CT scans for 5 years or no screening. A history of cigarette smoking of at least 20 pack years was required. All participants have annual lung function tests, and questionnaires regarding health status, psychosocial consequences of screening, smoking habits, and smoking cessation. Baseline CT scans were performed in 2052 participants. Pulmonary nodules were classified according to size and morphology: (1) Nodules smaller than 5 mm and calcified (benign) nodules were tabulated, (2) Noncalcified nodules between 5 and 15 mm were rescanned after 3 months. If the nodule increased in size or was larger than 15 mm the participant was referred for diagnostic workup.
At baseline 179 persons showed noncalcified nodules larger than 5 mm, and most were rescanned after 3 months: The rate of false-positive diagnoses was 7.9%, and 17 individuals (0.8%) turned out to have lung cancer. Ten of these had stage I disease. Eleven of 17 lung cancers at baseline were treated surgically, eight of these by video assisted thoracic surgery resection.
Screening may facilitate minimal invasive treatment and can be performed with a relatively low rate of false-positive screen results compared with previous studies on lung cancer screening.

Full-text

Available from: Jann Mortensen, Aug 07, 2015
ORIGINAL ARTICLE
The Danish Randomized Lung Cancer CT Screening Trial—
Overall Design and Results of the Prevalence Round
Jesper H. Pedersen, MD, DrMSci,* Haseem Ashraf, MD,† Asger Dirksen, DrMSci,†
Karen Bach, MD,‡ Hanne Hansen, MD,‡ Phillip Toennesen, DrMSci,† Hanne Thorsen, MD,§
John Brodersen, PhD,§ Birgit Guldhammer Skov, DrMSci, Martin Døssing, DrMSci,¶
Jann Mortensen, DrMSci,# Klaus Richter, PhD,**
Paul Clementsen, DrMSci,† and Niels Seersholm, DrMSci†
Introduction: Lung cancer screening with low dose computed
tomography (CT) has not yet been evaluated in randomized clinical
trials, although several are underway.
Methods: In The Danish Lung Cancer Screening Trial, 4104 smok-
ers and previous smokers from 2004 to 2006 were randomized to
either screening with annual low dose CT scans for 5 years or no
screening. A history of cigarette smoking of at least 20 pack years
was required. All participants have annual lung function tests, and
questionnaires regarding health status, psychosocial consequences
of screening, smoking habits, and smoking cessation.
Baseline CT scans were performed in 2052 participants.
Pulmonary nodules were classified according to size and morphol-
ogy: (1) Nodules smaller than 5 mm and calcified (benign) nodules
were tabulated, (2) Noncalcified nodules between 5 and 15 mm were
rescanned after 3 months. If the nodule increased in size or was
larger than 15 mm the participant was referred for diagnostic
workup.
Results: At baseline 179 persons showed noncalcified nodules
larger than 5 mm, and most were rescanned after 3 months: The rate
of false-positive diagnoses was 7.9%, and 17 individuals (0.8%)
turned out to have lung cancer. Ten of these had stage I disease.
Eleven of 17 lung cancers at baseline were treated surgically, eight
of these by video assisted thoracic surgery resection.
Conclusions: Screening may facilitate minimal invasive treatment and
can be performed with a relatively low rate of false-positive screen
results compared with previous studies on lung cancer screening.
Key Words: Lung cancer, Screening, Computed tomography, CT,
Randomized clinical trial.
(J Thorac Oncol. 2009;4: 608 –614)
D
uring the last decade the advent of low dose multislice
computed tomography (CT) scanning has generated a
widespread interest in lung cancer screening.
1
Early observa-
tional reports stated that lung cancer could be detected in
early stages in 85% of the cases
2
and subsequently a 10-year
survival rate of 88% for stage I lung cancer was estimated
after CT screening.
3
These reports have generated controver-
sy,
4–6
because data from other nonrandomized CT screening
trials have predicted that no reduction in lung cancer mortality
will be observed after screening and that harmful effects, over-
diagnosis and overtreatment may be substantial.
4–8
These con-
flicting results emphasize the need for randomized controlled
trials to demonstrate the effects, benefits and harms of CT
screening.
4
Therefore, randomized trials are now being per-
formed in the United States
9,10
and Europe.
11–13
In the United
States CT screening is compared with plain chest radiography,
9
whereas in the European studies CT screening is compared with
no screening in the control arm.
13,14
The aim of this article is to
present the design and results from the prevalence round of the
randomized Danish Lung Cancer Screening Trial (DLCST).
MATERIALS AND METHODS
Objective of the Study
Primary objective is to evaluate if annual low dose CT
screening can reduce lung cancer mortality by more than
25%. Major secondary end points are; overall mortality in
each study arm, numbers of lung cancer in each arm, 5-year
survival after diagnosis, stage of lung cancer at diagnosis
(stage distribution), surgical resection rate, effect on smoking
behavior, frequency of false-positive diagnoses, and psycho-
social consequences of these in addition to health economic
evaluations of the cost of CT screening in Denmark.
*Department of Thoracic Surgery RT, Rigshospitalet, University of Copen-
hagen; †Department of Respiratory Medicine, Gentofte University Hospi-
tal; ‡Department of Radiology, Gentofte University Hospital; §Institute of
Public Health, Dept. of General Practice, University of Copenhagen;
Department of Pathology, Herlev University Hospital (section Gentofte);
¶Department of Medicine, Frederikssund Hospital; #Department of Clinical
Physiology, Nuclear Medicine and PET, Rigshospitalet; and **Department
of Respiratory Medicine, Bispebjerg University Hospital, Denmark.
Disclosure: The Danish Lung Cancer Screening Trial is funded in full by a
governmental grant by the Danish Ministry of Health and Prevention.
Address for correspondence: Jesper Holst Pedersen, MD, DrMsci, Depart-
ment thoracic surgery RT-2152, Rigshospitalet, Blegdamsvej 9, DK-
2100 Copenhagen. E-mail: jesper.holst.pedersen@rh.regionh.dk
A brief review of the data were presented at 12th World Conference on Lung
Cancer in Seoul, 2007 and an abstract printed in Journal of Thoracic
Oncology, 2007, 2 (8), Supplement 4, S329 (A7-01).
Copyright © 2009 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/09/0405-0608
Journal of Thoracic Oncology Volume 4, Number 5, May 2009608
Page 1
The effect on lung cancer mortality will in the follow-
ing years be evaluated in collaboration with the NELSON
(Nederlands Leuvens Screening Onderzoek) CT screening
trial in Belgium and the Netherlands which has included
16,000 individuals.
12,14
The two trials combined are expected
to have sufficient power to detect a reduction in lung cancer
mortality of 25% 10 years after randomization.
12,14
Study Population
Individuals volunteered for the study in response to
advertisements in local and regional free newspapers and
weeklies that provided information regarding the general
outline of the study, the eligibility requirements for the study,
and the fact that the study was funded by a Governmental
grant and performed in collaboration with the NELSON trial.
Participants were men and women who were 50 to 70 years
of age and without lung cancer related symptoms. The sample
size was calculated on the assumption of a 1:1 randomization,
a power of 80%, significance level of 5%, 95% compliance in
the screen group, 5% contamination in the control group, and
10 years of follow-up after randomization.
12
From October 1, 2004, to March 31, 2006, 4104 par-
ticipants were enrolled and randomized at the initial visit after
receiving both oral and written information about the trial,
and signing the informed consent papers. A history of ciga-
rette smoking of at least 20 pack-years was necessary for
entrance into the study. Participants had to be current or
former smokers, and former smokers had to have quit after
the age of 50 years and less than 10 years ago. Participants
had to be able to climb 2 flights of stairs (36 steps) without
pausing. Spirometry is performed annually, and forced expi-
ratory volume in 1 second had to be at least 30% of predicted
normal at baseline to allow entry into the study.
Ineligible were those applicants with body weight
above 130 kg or previous treatment for lung cancer, breast
cancer, malignant melanoma, or hypernephroma. Individuals
with a history of any other cancer within 5 years or tubercu-
losis within 2 years or any serious illness that would shorten
life expectancy to less than 10 years were excluded, as was
the case if a prior CT scan of the chest had been performed
within the last year.
Design
The trial is performed in one institution: Gentofte
University Hospital in Copenhagen, Denmark. Participants
were randomized by a computer program (random permuted
blocks of 10 participants) to either annual screening by
low-dose CT (the screening group) or the control group who
were not offered CT screening. Prevalence CT scans were
performed within 1 month after randomization. The screening
is scheduled to last 5 years, i.e., an initial (prevalence)
screening round followed by 4 annual (incidence) screening
rounds (Figure 1). Follow-up is planned for 10 years after
randomization.
Questionnaires
At inclusion information on age, gender, educational
background, and occupational status has been collected for
each participant together with information on former and
present smoking habits including the Danish version of the
Fagerstroem scale.
15
In addition the participants completed a
questionnaire on their psychosocial status, the Consequences
Of Screening (COS) questionnaire.
16
This core-questionnaire,
which has been developed and validated in Denmark contains
questions relevant for participants in most cancer screening
programs.
17
After focus group interviews conducted during
the prevalence round questions especially relevant for partic-
ipants in lung cancer screening have been added to the COS.
This extended version of the COS, the COS-Lung Cancer will
be used during the next years to investigate especially psy-
chosocial consequences of having a false-positive screening
result.
Lung Function Test
Spirometry was performed annually on all participants
according to recommendations by the European Respiratory
Society using a computerized system (Spirotrac IV; Vitalo-
graph, Buckingham, UK), and expressed in absolute values
and as percent of predicted values according to European
reference equations.
18
Random.
4104
Control
2052
CT
screen
2052
Prevalence year 1 Year 2
Year 3
Year 4 Year 5
QOL+
Smok.
CT+QOL
+ Smok.
QOL+
Smok.
QOL+
Smok.
QOL+
Smok.
CT+QOL
+ Smok.
CT+QOL
+ Smok.
CT+QOL
+ Smok.
QOL
Smoke
Question
End points: Lung cancer incidence , stage, treatment, mortality.
Smoking habits, quality of Life
FIGURE 1. Design of the Danish lung cancer
screening trial (DLCST). QOL, quality of life ques-
tionnaires; Smok., questionnaires regarding smok-
ing habits; CT, low-dose multidetector computed
tomography.
Journal of Thoracic Oncology Volume 4, Number 5, May 2009 Danish Randomized Lung Cancer CT Screening Trial
Copyright © 2009 by the International Association for the Study of Lung Cancer 609
Page 2
Imaging and Image Review
All CT scans of the study were performed on a MDCT
scanner (16 rows Philips Mx 8000, Philips Medical Systems,
Eindhoven, The Netherlands). Scans were performed supine
after full inspiration with caudocranial scan direction includ-
ing the entire ribcage and upper abdomen with a low dose
technique, 120kV and 40 mAs. Scans were performed with
spiral data acquisition with the following acquisition param-
eters: Section collimation 16 0.75 mm, pitch 1.5, rotation
time 0.5 second. The obtained data were reconstructed in two
ways and parameters were as follows: Section width 3 mm/1
mm, reconstruction increment 1.5 mm/1 mm, with a soft and
hard algorithm, respectively. All image data were stored in
DICOM format on MOD and PACS. All scans were read by
two board certified radiologists (H.H. and K.S.B.) using
cine/slab-viewing supplied with Maximum Intensity Projec-
tion, and in case of disagreement consensus was obtained.
The location, size, demarcation and shape were registered,
and the density classified as solid, semisolid or pure GGO
lesions. The evaluation of size was based on linear measure-
ment of the maximal diameter in axial slices. In selected
cases volume of nodules were calculated by Philips nodule
evaluation semiautomated software.
Classification of Nodules
All nodules were classified into four categories accord-
ing to size and other characteristics: Nodules up to 15 mm in
maximal diameter with benign characteristics (for calcified
nodules up to 20 mm) (category 1) and nodules below 5 mm
(category 2) were tabulated and no further action taken.
Nodules with a diameter between 5 and 15 mm not classified
as benign were considered indeterminate and were rescanned
after 3 months (category 3). Nodules exceeding 15 mm
(category 4) and all growing nodules (category 5) were
referred for diagnostic investigation, in addition to nodules
with suspicious morphology. After repeat CT scan, nodules
were described as regressed, stable or growing by the radi-
ologists. Growth was defined as an increase in volume of at
least 25%.
Participants with nodules category 1 and 2 were re-
garded as screening test negative and those with nodules
category 3, 4, or 5 regarded as screening test positive.
Diagnostic Work-Up of Positive Findings
Referral of participants for diagnostic evaluation was
decided at weekly follow-up conferences between a pulmo-
nologist (A.D.) and the radiologists. Indeterminate nodules
were often evaluated using Fluorodeoxyglucose-positron
emission tomography-CT, but will be reported separately. CT
with contrast was performed before invasive procedures.
Depending on the results of these initial procedures an indi-
vidual diagnostic plan was made involving a variety of
invasive procedures such as bronchoscopy, transthoracic nee-
dle aspiration biopsy, endoscopic ultrasound, endobronchial
ultrasound and/or mediastinoscopy. In most cases video as-
sisted thoracic surgery (VATS) had to be performed to reach
a histologic diagnosis and staging of the disease. All diag-
nostic workup and treatment of participants with suspicious
nodules was taken care of by units specialized in lung cancer
and part of the public health service in Copenhagen.
Incidental findings on the CT scan outside the lungs or
bronchi judged to be of clinical significance for the partici-
pant, was revealed to the participant and referred to relevant
work up and treatment. The results are not reported here.
Surveillance of Vital Status and Occurrence of
Lung Cancer
The vital status of all participants is checked annually
in the Danish Civil Registration System which registers all
national deaths within 2 weeks. In case of death, information
was obtained from the Danish Causes of Death Register,
which is updated with a lag time of 1 to 2 years, and from
hospital and autopsy files when possible. Information on
occurrence of lung cancer for the whole study group is
obtained annually from the Danish Lung Cancer Register
which registers over 90% of all lung cancers in Denmark.
Both active participants and drop-outs will be followed for 10
years after randomization or until death. An international,
independent death review board will be established.
Treatment was performed in two centers specialized in
lung cancer treatment in Copenhagen. The indication for
surgical or oncological intervention was in all cases decided
at multi speciality conferences by board certified specialists
in pulmonary medicine, thoracic surgery, pathology, oncol-
ogy, and radiology. Pulmonary resection was in most cases
performed in the same procedure as the diagnostic VATS,
following frozen section pathology evaluation of the speci-
mens obtained by wedge resection. Definitive surgical treat-
ment was performed either by VATS or open thoracotomy
depending on the preference of the surgeon. Danish national
guidelines for lung cancer management were followed.
Morphologic Classification
Resected tumors and specimens were analyzed accord-
ing to the guidelines for screening-detected lung tumors from
the EU-US pathology panel
19
by one pathologist (B.G.S.) and
all lung cancers were verified by the panel. All tumors were
classified according to World Health Organization.
20
Ethical and Legal Approval
The DLCST was approved by the Ethical Committee of
Copenhagen County on January 31, 2003 and funded in full
by the Danish Ministry of Interior and Health on June 23,
2004. Approval of data management in the trial was obtained
from the Danish Data Protection Agency on February 11,
2005. The trial is registered in Clinical Trials.gov Protocol
Registration System (identification no. NCT00496977).
RESULTS
From October 2004 to March 2006, 5861 subjects
contacted the screening unit. Of these 1757 where excluded
either because they did not meet the eligibility criteria or
because they did not show up, and the remaining 4104
subjects (70%) were randomized to screening by CT (2052)
or no screening (2052) after signing the informed consent
form.
Pedersen et al. Journal of Thoracic Oncology Volume 4, Number 5, May 2009
Copyright © 2009 by the International Association for the Study of Lung Cancer610
Page 3
No statistically significant difference in age, sex, pul-
monary function, smoking status, tobacco consumption, or
duration of smoking cessation was seen between CT and
control group (Table 1). In addition no difference in social
status was found between the two groups (data not shown). In
the CT arm all except five participants were scanned at base
line (compliance 99.95%).
Radiologic and Clinical Findings
At baseline no nodules were found in 1458 participants
(71%) and in the remaining 594 participants (29%) a total of
897 lung nodules were identified (Table 2). Seven hundred
eight nodules did not require further diagnostic workup,
either because the nodules were calcified (337 category 1
nodules) or because the size was under 5 mm (371 category
2 nodules) (Table 2). This leaves 189 nodules of which 151
noncalcified nodules in 142 participants were between 5 mm
and 15 mm (category 3) and 38 nodules were larger than 15
mm (category 4) (Table 3). In 30 participants ground glass
opacities (GGO lesions) were found, three of these having
two GGO and three more than 2 GGO lesions (included in the
above).
Based on the radiologic appearance, three participants
with six category three nodules were referred for diagnostic
evaluation, and all three participants had a malignant nodule.
The remaining 145 category 3 nodules were rescanned after 3
months, where 29 (including 1 GGO) had regressed in size,
112 (including GGOs in 28 pts) were unchanged, and 4
showed growth and were removed. Of the growing nodules,
3 (including 1 GGO lesion) proved to be lung cancer, and one
was a granuloma.
The 38 nodules larger than 15 mm (category 4) were
found in 37 participants (Table 3). Five of these nodules were
judged benign by morphology and presence of calcifications
and no further action was taken except in one who had a 45
mm harmatoma removed by VATS due to the size. Seven
nodules were judged malignant, and in six of these a malig-
nant diagnosis was confirmed by further workup. The remain-
ing 26 nodules (mean maximum diameter: 29.8 mm) (range,
16 –93 mm) were rescanned after 3 months, 6 nodules re-
gressed in size, 18 were unchanged in size but 5 showed
changes in morphology and therefore sent for diagnostic
evaluation. Two showed growth and proved to be malignant
(Table 3).
Thus, at baseline 179 participants (8.7%) had a positive
finding, and in 162 participants (7.9%) the finding proved to
be false positive.
Invasive Procedures
A total of 40 invasive diagnostic procedures were
performed in 25 participants (Table 4). In eight participants
no evidence of lung cancer was found. The most invasive
diagnostic procedure was VATS wedge resection, which in
nine cases was followed by definitive surgical treatment by
lobectomy in the same anesthesia. In two cases VATS wedge
resection was due to a false-positive diagnosis.
Lung Cancer Cases
A total of 17 cases of lung cancer were detected during
the prevalence screening including 3 cases in whom biopsy
TABLE 1. Clinical Characteristics of 4104 Participants at
Baseline in DLCST
Control Group n
(% of Specified)
Screen Group n
(% of Specified)
No. of participants 2052 (50.0%) 2052 (50.0%)
Age
49 yr 6 8
50–54 yr 586 586
55–59 yr 699 676
60–64 yr 571 604
65–69 yr 184 169
70–74 yr 6 9
Gender
Male 1120 (27.3%) 1147 (27.9%)
Female 932 (22.7%) 905 (22.1%)
FEV1 (Mean SD)
Male 3.3 L 0.7 3.3 L 0.7
Female 2.4 L 0.5 2.4 L 0.5
Smoking status
Current smoker 1579 1545
Former smoker 473 507
Smoking duration
Current smokers
26 yr 24 22
26–30 yr 85 81
31–35 yr 307 303
36–40 yr 511 504
41–45 yr 400 395
45 yr 252 240
Former smokers
26 yr 12 19
26–30 yr 56 53
31–35 yr 130 143
36–40 yr 167 164
41–45 yr 76 96
45 yr 32 31
Missing 0 1
Cigarettes/d
Current smokers
10 cig/d 170 158
10–20 cig/d 701 713
21–30 cig/d 412 419
40 cig/d 103 111
None 45 28
Missing 148 117
Former smokers
10 cig/d 22 22
10–20 cig/d 239 257
21–30 cig/d 136 137
40 cig/d 49 69
None 4 1
Missing 23 21
Duration of smoking
cessation (former smokers)
5 yr 353 386
6–10 yr 111 110
10 yr 9 8
Missing 0 3
DLCST, Danish Lung Cancer Screening Trial; FEV1, forced expiratory volume in
1 second.
Journal of Thoracic Oncology Volume 4, Number 5, May 2009 Danish Randomized Lung Cancer CT Screening Trial
Copyright © 2009 by the International Association for the Study of Lung Cancer 611
Page 4
from enlarged mediastinal lymph nodes showed lung cancer,
but no obvious primary focus was found in the lung.
Treatment was surgical in 11 patients (65% resection
rate), 5 had chemotherapy, and 1 patient refused treatment.
Surgical treatment was minimal invasive (VATS) in 8 of 11
cases (72%). In 3 cases thoracotomy with lobectomy (n 2)
or pneumonectomy (n 1) was performed (Table 5).
A 65-year-old man was discharged on day 10 after
uneventful open lobectomy for a 12 mm adenocarcinoma in
the right lung. He was readmitted on day 25 with pneumonia
and died of myocardial infarction with congestive heart
failure on day 34. No other treatment related deaths or
complications were observed.
Pathology
A morphologic diagnosis was obtained in all lung
cancer cases, in 14 cases by histology and 3 cases by
cytology: 2 squamous cell carcinoma, 12 adenocarcinoma,
and 3 non-small cell carcinoma. No cases of pure bronchi-
oloalveolar carcinoma were observed. In four patients who
were treated with chemotherapy only, the final diagnosis was
obtained by mediastinoscopy, fiberbroncoscopy or transtho-
racic fine needle biopsy.
DISCUSSION
The screening regimen used in this trial is based pri-
marily on the reports by Claudia Henscke and the Early Lung
Cancer Action Program (ELCAP) group
2,3,21,22
and on the
guidelines agreed by the EU-US Collaborative spiral CT
working group under the IASLC. In addition, the regimen
was harmonized with the currently running CT screening trial
in The Netherlands and Belgium (the NELSON trial)
12
to
allow pooling of results.
To our satisfaction the randomization process in this
study did not result in any significant difference between the
CT and the control group with regards to key parameters such
as age, sex, pulmonary lung function, pack years, smoking
status, and social class.
In screening trials the false-positive rate is often of
concern. In the present study the false-positive rate at base-
line was 7.9% only, which compares favorably with other
trials
3,8,23
where 12 to 19% false positives at baseline have
been reported. In the Mayo Clinic trial almost 69% of
participants had false-positive test results in 3 years of
study,
23,24
however, the criteria for a false-positive test dif-
fered from the one used here. The psychologic consequences
of false-positive test results are currently evaluated and will
be published separately.
The specificity of CT-detected nodules in the preva-
lence round of the present study is high (92.6%). However,
high specificity usually implies low sensitivity, which is
supported by a relatively small number of persons diagnosed
with lung cancer. Therefore, some prevalent cancers will
most likely appear at later screenings rounds, as was reported
TABLE 2. Distribution of CT Detected Pulmonary Nodules in 2052 Participants in DLCST
Category Size
No. of
Participants
Pts. with 1
Nodule
Pts. with 2
Nodules
Pts. with 3
Nodules
Pts. with >4
Nodules
Total No. of
Nodules
1 5–20 mm 263 198 57 7 1 337
2 5 mm 268 202 42 15 9 371
3 5–15 mm 142 134 7 1 0 151
4 15 mm 37 36 1 0 0 38
Pts, participants; DLCST, Danish Lung Cancer Screening Trial.
TABLE 3. Management of Noncalcified Pulmonary Nodules 5 mm Detected by CT at the Prevalence Screening
Category Size Diagnostic Evaluation
Repeat CT Scan
Total
After 3 mo
After 1 yrRegress Stable Growth
3 5–15 mm 6 (3) 29 (0) 112 (0) 4 (3) 0 151 (6)
4 15 mm 7 (6) 6 (0) 18 (0) 2 (2) 5 (0) 38 (8)
No. of nodules diagnosed as lung cancer in brackets.
CT, computed tomography.
TABLE 4. Diagnostic Invasive Procedures in 25 of 2052
Participants at Prevalence Screening Round of the DLCST
Diagnostic Result
Lung Cancer Benign Total
No. of procedures
Mediastinoscopy 6 1 7
Bronchoscopy with biopsy 10 3 13
EUS 1 1 2
EBUS 3 2 5
VATS 9 2 11
Percutaneous biopsy 1 1 2
Total 30 10 40
Total no. of participants 17 8 25
EUS, endoscopic ultrasound; EBUS, endobronchial ultrasound; VATS, video
assisted thoracic surgery.
Pedersen et al. Journal of Thoracic Oncology Volume 4, Number 5, May 2009
Copyright © 2009 by the International Association for the Study of Lung Cancer612
Page 5
by Veronesi et al.
25
The extent of this “delayed diagnosis” in
the DLCST will be apparent in the following incidence
screenings and will allow quantification of the number of
false-negative test results.
We discovered 17 cases of lung cancer corresponding
to a detection rate of 0.83% only. This is lower than previ-
ously reported by others: 2.7%,
3
2.0%,
19,23
1.9%,
8
1.7%,
26
1.3%
27
but close to the detection rate in the NELSON trial
(Rob van Klaveren, oral communication, November 2007).
There are many possible explanations for this discrepancy;
the risk profile of the Danish study population (smoking
exposure, age etc) may differ; participation and self-selection
for a screening trial in the United States and Europe may be
different, and the radiologic expertise may differ. We used a
modern multislice CT scanner, and both our radiologists have
more than 10 years of experience in chest radiology.
The distribution of the stage of lung cancers detected in
this trial showed that nine of total 17 LC were stage 1 (53%).
This is lower than in the ELCAP reports
3,26
but similar to
other reports.
19,27
We expect the proportion of stage 1 cancers
to be higher in the following incidence rounds of screening.
Furthermore, the use of growth and volume doubling time to
detect malignant nodules differ from the ELCAP experience.
Of the 17 patients with cancer only five were judged as
growing by the radiologist, and nine nodules were removed
because of malignant CT morphology at baseline without
waiting for the results of a rescan after 3 months. Three were
referred to oncological treatment because of metastasis to
lymph nodes in the mediastinum. In our experience at base-
line CT morphology is important for distinguishing benign
and malignant nodules as also reported by Xu et al.
28
Mea-
surement of growth contributed to detection of malignancy in
5 of 17 (29%) of lung cancers, however, this rate may
increase in the incidence screening rounds. The use of growth
as a predictor for malignant disease has still to be evaluated
in more detail. Although five of the six growing nodules were
lung cancer, one did not show growth when evaluated in
retrospect by Siemens software. Three of the five growing
nodules had a VDT less than 400 days. Some studies have
shown that a VDT less than 400 days is suggestive of a
malignant nodule.
29
VDT greater than 400 days may be slow
growing tumors that do not develop into clinical cancers and
thereby cause overdiagnosis.
29,30
The extent of overdiagnosis
is an important issue, but cannot be evaluated in this trial yet.
Lung cancer cases in the incidence screening rounds and in
the control group must be included in the evaluation, before
any meaningful interpretation can be made. The detection and
treatment of GGO lesions, that presumably represent very
early lung cancer,
31,32
may carry a risk of treating lesions that
in some cases may resolve spontaneously and untreated. This
is an exciting new area of research made possible by CT
screening.
The procedure for evaluation and follow-up of nodules
at baseline was apparently safe for the participants. The
burden of diagnostic work up and invasive procedures was
close to that reported by the ELCAP group
3,19
and was lower
than previously reported by investigators from the Mayo
clinic.
23,24
This may reflect differences in patient selection
and criteria for use of invasive procedures. In the study by
Swensen et al.
23
of 1520 individuals 13 participants under-
went 15 surgical procedures for benign disease. In this study
(2052 screened) only 2 benign nodules were removed by
local VATS resection. All other nodules that were removed
turned out to be malignant. In a screening setting the number
of invasive procedures should be reduced as much as possi-
ble, as is also reflected in the guidelines from the ACCP.
33
However, in our study it remains to be seen to what extent the
low false-positive rate and low frequency of invasive proce-
dures has been achieved at the expense of a high rate of
false-negative diagnoses. Truly, malignant nodules missed in
TABLE 5. Characteristics of 17 Primary Lung Cancers Found on Screening with CT in the Prevalence Round of the DLCST
Pts no Sex Age (yr) Size (mm) Stage TNM Classific Histology Treatment
1 F 60 3A T0N2M0 ACL Chemotherapy
2 M 56 15 1A T1N0M0 SQC VATS lobectomy
3 M 60 93 3A T3N1M0 ACL Thoracotomy pneumonectomy
4 M 65 12 1A T1N0M0 ACL Thoracotomy lobectomy
5 F 52 20 1B T2N0M0 ACL VATS lobectomy
6 F 61 30 3A T2N2M0 NSCLC Chemotherapy
7 F 58 13 3B T4N2M0 ACL VATS lobectomy
8 M 63 16 1A T1N0M0 ACL Thoracotomy lobectomy
9 F 55 19 1B T2N0M0 ACL VATS lobectomy
10 M 67 18 3A T1N2M0 SQC Chemotherapy
11 F 58 22 1A T1N0M0 ACL VATS lobectomy
12 M 68 18 1A T1N0M0 ACL VATS lobectomy
13 F 61 3A T0N2M0 NSCLC Chemotherapy
14 F 59 22 1A T1N0M0 ACL VATS lobectomy
15 F 50 3B T0N3M0 ACL Refused treatment
16 F 54 14 3A T1N2M0 NSCLC Chemotherapy
17 M 59 10 1A T2N0M0 ACL VATS lobectomy
VATS, video assisted thoracoscopic surgery; ACL, adenocarcinoma; SQC, squamous cell carcinoma; NSCLC, non-small cell carcinoma; TNM, tumor node metastasis; CT,
computed tomography.
Journal of Thoracic Oncology Volume 4, Number 5, May 2009 Danish Randomized Lung Cancer CT Screening Trial
Copyright © 2009 by the International Association for the Study of Lung Cancer 613
Page 6
the prevalence round will inevitably grow and present them-
selves in the incidence screening rounds.
In this study at baseline 11 of 17 patients (65%) with
lung cancer could be offered surgical treatment, and a high
proportion 8 of 11(72%) was performed as minimal invasive
surgery (VATS lobectomy), illustrating that early detection
of lung cancer implies more minimal invasive treatment
options.
The randomized study design employed in this and
other current trials will, hopefully, in the coming years,
provide information on the efficacy, benefits and hazards of
lung cancer screening. Such knowledge is essential for bal-
anced and nonbiased recommendations for its eventual im-
plementation in health practice.
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