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Optimization of nodule management in CT lung cancer screening
Heuvelmans, Marjolein
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4
Optimization of volume-doubling time cutoff
for fast-growing lung nodules in CT lung
cancer screening reduces false-positive
referrals
Marjolein A Heuvelmans
Matthijs Oudkerk
Geertuida H de Bock
Harry J de Koning
Xiequan Xie
Peter M A van Ooijen
Marcel J Greuter
Pim A de Jong
Harry JM Groen
Rozemarijn Vliegenthart
Published in European Radiology
2013, vol. 23, no. 7, pp. 1836-1845.
42
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
Abstract
Objective: To retrospectively investigate whether optimization of volume-doubling time
(VDT) cut-off for fast-growing nodules in lung cancer screening can reduce false-positive
referrals.
Methods: Screening participants of the NELSON study underwent low-dose CT. For
indeterminate nodules (volume 50-500 mm3 ), follow-up CT was performed 3 months after
baseline. A negative baseline screen resulted in a regular second-round examination, one
year later. Subjects referred to a pulmonologist because of a fast-growing (VDT <400 days)
solid nodule in the baseline or regular second-round were included in this study. Histology
was the reference for diagnosis, or stability on subsequent CTs, confirming benignity. Mean
follow-up of non-resected nodules was 4.4 years. Optimization of the false-positive rate
was evaluated at maintained sensitivity for lung cancer diagnosis with VDT <400 days as
reference.
Results: 68 fast-growing nodules were included; 40% were malignant. The optimal VDT
cut-off for the 3-month follow-up CT after baseline was 232 days. This cut-off reduced
false-positive referrals by 33% (20 versus 30). For the regular second-round, VDTs varied
more among malignant nodules, precluding lowering of the VDT cut-off of 400 days.
Conclusion: All malignant fast-growing lung nodules referred after the 3-month follow-up
CT in the baseline lung cancer screening round had VDT ≤232 days. Lowering the VDT
cut-off may reduce false-positive referrals.
Key points
•
•
•
•
•
Lung nodules are common in CT lung cancer screening, most being benign.
Short-term follow-up CT can identify fast-growing intermediate-size lung nodules.
Most fast-growing nodules on short-term follow-up CT still prove to be benign.
A new volume-doubling time (VDT) cut-off is proposed for lung screening.
The optimized VDT cutoff may decrease false-positive case referrals for lung cancer.
Introduction
In view of the prospective results of the National Lung Screening Trial (NLST) [1], and
the baseline results of other trials [2–6], interest in computed tomography (CT) for lung
cancer screening in high-risk individuals is increasing. A drawback of CT screening is
the high prevalence of small and intermediate-sized (<10 mm diameter) lung nodules,
most of which are benign [7, 8]. The nodule management strategy should allow sensitive
and timely diagnosis of malignant nodules. At the same time, patient anxiety, cost and
morbidity associated with unnecessary diagnostic procedures for benign nodules should be
minimized.
In the NLST screening rounds, the rate of positive tests, defined as the presence of one
or more nodules of at least 4 mm in diameter, was 24.2% [1]. No less than 96.4%
comprised false-positive results [1]. Volume-based nodule management has been suggested to be more accurate, potentially leading to lower false-positive rates [9]. The
nodule management strategy of the Dutch-Belgian randomized lung cancer screening trial
(Dutch acronym NELSON) is based on volume and volume-doubling time (VDT) assessment [10]. In the baseline screening round, participants with a nodule with volume
>500 mm3 were referred for work-up and diagnosis. For intermediate sized nodules (50500 mm3 ) a short-term follow-up CT was performed, to evaluate growth. Because nodules
with rapid growth rates are more likely to be malignant [9], nodules with volume >50 mm3
and VDT <400 days were also referred [10]. The second-round CT was based on volume
measurements for newly detected nodules and growth evaluation of previously detected
nodules (Figure 4.1). This strategy yielded a rather low rate of positive screening tests
(2.6% in the baseline screening; 1.8% in the second-round screening) [6], while only 3 of
the 7557 screening participants were diagnosed with an interval cancer (NPV 99.7%) [6].
Still, most suspicious lung nodules that resulted in referral to a pulmonologist turned out
to be benign (60.4% in the baseline screening; 54.2% in the second-round screening) [6].
We hypothesized that by optimizing the VDT cut-off for fast-growing nodules, the rate
of false-positive referrals can be further reduced.
Therefore, our objective was to retrospectively evaluate the VDTs of fast-growing solid
pulmonary nodules in order to find the optimal VDT cut-off for differentiating benign and
malignant nodules in the first two screening rounds of the NELSON trial.
Materials and Methods
Study population
The NELSON multi-center trial was approved by the Dutch Minister of Health and the
ethics board at each participating center. All participants provided written informed consent. Participants were current and former smokers, aged 50-75 years, at high risk of lung
cancer. Recruitment procedures and selection criteria in the NELSON trial have been
published [11].
In this retrospective sub-study, participants with at least two low-dose CT examinations
during the baseline round and regular second-round screening in year 2 (April 2004 to April
2007) and a small-to-intermediate-size lung nodule (volume <500 mm3 ) with fast growth
(VDT <400 days) either at the short-term follow-up examination after baseline (the extra
44
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
CT for nodules of 50-500 mm3 at baseline), or at the regular second round CT one year
after baseline (for any nodule <500 mm3 at baseline) were included. Only participants who
were subsequently referred to a pulmonologist because of this fast-growing lung nodule
and had either a histological diagnosis or a 2-year follow-up period after negative outcome
of work-up to confirm benignity were included (Figure 4.1). The reason for including
only participants who were referred to a pulmonologist was because diagnosis based on
histology was our aim. Work-up was left to the discretion of the pulmonologist.
A total of 8,623 lung nodules were detected in the baseline round of the NELSON trail. 210
of those showed fast-growth at the 3-month follow-up CT after baseline or at the regular
second-round scan (Figure 4.2). The majority (127 nodules) did not warrant referral to a
pulmonologist for a variety of reasons. Of the screening participants that were referred to
a pulmonologist (83 nodules), another 15 were excluded since they had less than 2 years
follow-up period after a negative outcome of workup. Sixty-eight fast-growing nodules
were included. Of these, 27 nodules were malignant. Of the 41 benign nodules, eight
(20%) were classified benign based on histology. The mean follow-up time of the other
benign nodules was 4.4 years (95% CI, 3.9-4.9 years; range 2.7-5.7 years), showing stable
or decreased size over time. In three of the excluded participants who were initially not
referred because of a measurement error in the volume, malignancy was confirmed after
the third-round examination.
Figure 4.1: Overview of the NELSON screening protocol.
Nodule management and diagnostic work-up (Figure 4.1)
The baseline screening result was positive if any non-calcified pulmonary nodule was larger
than 500 mm3 . The result was indeterminate in case of a non-calcified nodule of 50500 mm3 [6, 10]. In the case of smaller non-calcified nodules, the screening was negative.
Subjects with an indeterminate result had follow-up CT 3 months after the baseline exam-
ination to assess growth. Growth was defined as a volume increase of at least 25% [12].
If a growing lesion had a VDT <400 days, the final baseline result was positive. In case of
slower growing lesions, the baseline screening result was negative and the participant was
invited for the regular second-round examination in year 2.
Figure 4.2: Flow chart of subjects selected with fast-growing pulmonary nodules. VDT =
volume-doubling time.
At the regular second-round CT, either a nodule was new, and the result was based on
nodule size (similar to the baseline examination), or a nodule was pre-existing [10]. For
pre-existing lung nodules, the result was based on the VDT. If the VDT was <400 days,
the regular second-round screening result was positive [6].
Test positive cases were referred to a pulmonologist for work-up. Work-up, staging,
and treatment were standardized according to (inter-)national guidelines [10, 13, 14].
Nodules were classified as benign or malignant based on histological examination. Also,
nodules could be classified benign based on stable or decreased size two years after first
detection (Figure 4.3) [15, 16]. In the case of diagnosed lung cancer, the participant
was treated and was no longer invited for screening examinations; otherwise the regular
next-round CT was scheduled.
Imaging methods and volumetric analysis
Data acquisition and image analysis were reported previously [10]. In brief, low-dose,
unenhanced chest CTs were performed using 16-row detector CT systems (Sensation-16,
Siemens Medical Systems; Forchheim, Germany; Mx8000 IDT or Brilliance 16P, Philips
Medical Systems; Cleveland, OH, USA). Spiral mode with 16x0.75 mm collimation and
pitch 1.39-1.5 was used. Depending on the body weight (<50, 50-80, and >80 kg), the
46
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
kilovolt-peak settings were 80-90, 120, and 140 kVp, respectively. The milliampere-second
values were 20-30 mAs and were adjusted accordingly dependent on the machine used.
This corresponds to an effective radiation dose of less than 1.6 mSv. Data sets of the lung
were reconstructed at 1.0-mm slice thickness, with a 0.7-mm reconstruction increment.
A reconstructed slice thickness of 1.0 mm has been found to be accurate for estimating
VDT [17]. Data acquisition and imaging conditions were standard across screening centers
and equal for baseline and repeat screening.
Digital workstations (Leonardo; Siemens Medical Solutions; Erlangen, Germany) with
software for semi-automated three-dimensional (3D) volume measurements (LungCare,
version Somaris/5: VA70C-W; Siemens Medical Solutions) were used for nodule volumetric analysis. CT examinations were read twice, by independent readers. Experience for
the first readers ranged from none to >20 years. Both second readers had six years of
experience in thoracic CT. If the results between first and second reader were discrepant,
the readers re-evaluated the examination to reach consensus. If consensus could not be
reached, a third, expert thoracic radiologist arbitrated [10]. After a nodule was selected by
a radiologist, the system automatically calculated nodule volume. Information was saved
in the NELSON Management System, which calculated the percentage volume change
and VDT. The VDT was calculated by comparing nodule volume at the latest CT with the
volume at the baseline examination as a reference time point. For additional analysis, we
also calculated the VDT by comparing nodule volume at the time of the positive screening
result with the nodule volume at the latest CT before the positive screening for nodules
detected at more than two CTs before referral after the regular second-round examination.
Ko’s model for nodule growth
Recently, a volumetric model for identification of malignancy in pulmonary nodules in CT
lung cancer screening was introduced by Ko et al [18]. We applied this model to evaluate
whether the false-positive rate in our screening study could be lowered by using this
method. We compared the reduction in false-positive rate found by using Ko’s method,
to the reduction found by using our own optimized VDT cut-off.
Data analysis
Parametric data were expressed as mean and 95% confidence interval (95%-CI), nonparametric data as median and interquartile ranges. The non-parametric Mann-Whitney
U test was used for analysis of volume and VDT. In additional analysis, we compared the
VDT using as a reference point the nodule volume at first detection or the volume at
the latest CT before the examination with a positive screening result, with the Wilcoxon
signed-rank test.
To identify the optimal VDT cut-off values for differentiating growing benign and
malignant pulmonary nodules at 3-month follow-up of the baseline screening round and
at the regular second-round examination, the false-positive rate at different VDTs was
evaluated, while maintaining 100% sensitivity, with the current cut-off value of VDT
<400 days as reference.
Statistical analyses were performed using PASW 18 (SPSS, Chicago, IL, USA). Pvalues <0.05 were considered significant.
Figure 4.3: Growing benign lesion in a 64-year-old man. Axial computed tomography (CT)
(a) shows a nodule (arrow) with a volume of 66.4 mm3 in the right upper lobe. Three
months later (b), the nodule volume increased to 83.3 mm3 , the VDT was 342 days and
the participant was referred to a pulmonologist. Work-up showed no malignancy. At the
regular second-round examination (c) the nodule volume was 86.8 days (VDT 1104 days).
In the fourth screening round (d), more than 5 years after referral, the nodule volume was
96.5 mm3 (VDT >10 000 days). The growth curve is shown in (e).
Table 4.1: Characteristics of nodules with volume-doubling time <400 days observed during
the first two screening rounds, at the moment of referral to pulmonologist due to positive
examination.
Benign nodules
Nodule volume
(mm)
n (%)
50-500
>500
Total
37 (90) 121 (82, 171)
4 (10) 836 (693, 2207)
41 (100) 124 (84, 206)
a
Malignant nodules
Median volume
n (%)
(mm3 ) (25th , 75th %a )
P-value
Median volume
(mm3 ) (25th , 75th %a )
15 (56) 280 (126, 362)
12 (44) 777 (618, 1201)
27 (100) 486 (227, 774)
<0.001
25th % = 25th percentile, 75th % = 75th percentile
Results
Sixty-eight fast-growing nodules (VDT <400 days) in 61 participants were included (Figure 4.2). Of these, 27 nodules (27 participants) were malignant. Twenty-three men (85%)
and four women (15%) had a malignant nodule (mean age at positive examination 63.8
years; 95% CI, 61.6-66.0 years); 24 men (71%) and ten women (29%) had benign nodules
(mean age 63.5 years; 95% CI, 61.6-65.4 years).
Eighty-two % of the fast-growing nodules was of intermediate size (volume 50-500 mm3 )
at baseline, and 16% was of small size (<50 mm3 ). The remaining 2% (one nodule) was
of large size (>500 mm3 ) but was initially diagnosed as non-malignant after workup in the
baseline screening round, and returned into the screening regimen. Of the nodules leading
48
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
Figure 4.4: Growing malignant lesion in a 54-year-old man. Axial computed tomography
(CT) (a) shows a nodule (arrow) with a volume of 146.4 mm3 in the right lower lobe. Three
months later (b), the nodule volume increased to 150.6 mm3 (volume-doubling time [VDT]
= 2303 days). At the second-year examination, 1 year after baseline CT (c), the nodule
volume was 553.8 mm3 . The VDT at that time was 187 days. Work-up revealed a stage IA
adenocarcinoma. The growth curve is shown in (d).
to referral after the 3-month follow-up CT in the baseline round, malignant nodules (median 250 mm3 ) had a significantly larger baseline volume than benign nodules (median
81 mm3 ; P<0.01).
Of the malignant nodules, 52% (14/27) had shifted upward in volume category at
the positive screening, compared with 24% (10/41) of the benign nodules. For example,
an intermediate-sized pulmonary nodule, 151 mm3 , at the CT before the one with the
positive screening result, had grown to a large size, 554 mm3 at the next examination
(see Figure 4.4). Nodule characteristics at positive screening CT examination are shown
in Table 4.1.
No difference was found in VDTs of nodules referred after the regular second-round
examination calculated by using volume at first detection or volume of the last examination
before the CT with the positive screening result (median VDT 269 versus 237 days;
P=NS).
Histological Features
The 27 lung cancers were histologically classified as follows: 15 (55%) adenocarcinomas,
6 (22%) squamous cell carcinomas, 4 (15%) large cell carcinomas, 1 (4%) small cell lung
cancer, and 1 large cell neuroendocrine carcinoma (4%) (Table 4.2).
Table 4.2: Histological features and volume-doubling time of malignant nodules per screening round.
Moment of referral
Histological type
n
VDT (days)
Percentage (median (25th ,
75th )a )
3-month follow-up
baseline
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Large cell neuroendocrine
carc.
Total
4
5
1
36%
45%
9%
110 (63, 208)
118 (84, 187)
24 (-b , -b )
1
9%
68 (-b , -b )
11 100%
98 (68, 169)
Regular second-round Adenocarcinoma
examination
Squamous cell carcinoma
Large cell carcinoma
Small cell lung cancer
Total
11
1
3
1
16
213 (185, 327)
165 (-b , -b )
289 (124, -b )
84 (-b ,-b )
205 (165, 318)
Total
15 55%
6 22%
4 15%
196 (135, 250)
142 (91, 178)
207 (49, 326)
1
68 (-b , -b )
a
b
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Large cell neuroendocrine
carc.
Small cell lung cancer
Total
69%
6%
19%
6%
100%
4%
1 4%
27 100%
84 (-b ,-b )
198 (122, 264)
25th = 25th percentile, 75th = 75th percentile.
Too few nodules available for the calculation.
VDTs at Different Time Points of Referral
Forty-one participants with 48 nodules were referred after the 3-month follow-up CT in the
baseline screening round. Eleven of these were malignant (positive predictive value [PPV],
23%). Twenty participants with 20 fast-growing nodules were referred after the regular
second-round examination in year 2, of which 16 were malignant (PPV, 80%) (Table 4.3).
Ten of the 16 participants with malignant nodules referred after the regular second-round
CT also underwent a 3-month follow-up CT after the baseline examination, showing no
fast growth (VDT >400 days). The six remaining malignancies were <50 mm3 at baseline
(n = 4), or were initially not considered suspicious based on CT and therefore did not
receive a 3-month follow-up examination (n = 2, baseline volumes 57.6 and 117.6 mm3 ).
The median VDT for malignant nodules was significantly lower than for benign nodules at the 3-month follow-up CT in the baseline screening round (98 versus 203 days;
P=0.013). The difference in median VDT for malignant versus benign nodules at the regular second-round examination did not reach statistical significance (205 versus 291 days;
P=NS, Figure 4.5, Table 4.3).
50
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
Table 4.3: Nodule volume category at baseline screening and VDT at different moments of
referral, with differentiation by tumor nature.
Nodule
Tumour
Moment of
volume
nature
referral
(mm3 )
VDT (days)
Percentage
P
N (nodules /
(median (25th ,
a (nodules /
value
participants)
participants)a ) 75th )a )
3-month
follow-up
baseline
Benign
Benign
Malignant
Benign
Malignant
5
32/28
11
37/30
11
100%
74%/72%
26%/28%
77%/73%
23%/27%
173 (112, 284)
204 (132, 264)
98 (68, 169)
203 (133, 262)
98 (68, 169)
Benign
Malignant
Benign
Malignant
Benign
Malignant
3
5
1
11
4
16
37%
63%
8%
92%
20%
80%
293
185
289
213
291
205
<50
50-500
Total
Regular
<50
secondround
50-500
examination
Total
(214,
(104,
(289,
(165,
(233,
(165,
-c )
314)
-c )
327)
353)
318)
0.013
0.12
VDT = volume-doubling time.
a
When only one number is shown, the number of nodules is equal to the number of participants.
b
25th = 25th percentile, 75th = 75th percentile.
c
Too few nodules available for the calculation.
VDT cut-off
Based on the VDTs of fast-growing nodules referred after the 3-month follow-up CT in
the baseline round, a VDT cut-off of 232 days was determined. Fourteen benign nodules
(30% of total benign nodules) in 12 subjects had higher VDTs than 232 days. Two of the
12 subjects however, had another faster-growing benign nodule, so they would still have
been referred to a pulmonologist. In total, ten of the 30 participants (33%) with a benign
nodule would not have been referred with the optimized VDT cut-off.
At the regular second-round examination in year 2, VDTs varied more among the
malignant nodules (ranging from 84 to 358 days). VDTs of the four benign nodules
referred after the second-year examination ranged from 214 to 373 days.
Comparison with Ko’s model
When applied to our selection of fast-growing pulmonary nodules, the model introduced
by Ko et al. [18] reduced false-positive tests by 4 (9%) and false-positive referrals by
only 2 (7%) for the 3-month follow-up CT in the baseline round. In the second-round
screening, all benign nodules showed abnormal growth according to this model, leading
to false-positive test results.
Figure 4.5: Box plots of volume-doubling times of malignant and benign nodules at 3-month
follow-up CT in the baseline screening (A) and at the regular second-round screening (B).
NS = not significant.
Discussion
Our results show that lowering the VDT cut-off from 400 to 232 days at the 3-month
follow-up CT in the baseline lung cancer screening round led to a third fewer false-positive
referrals, at maintained sensitivity for lung cancer diagnosis. This is especially important
as the baseline screening was the round with the most fast-growing pulmonary nodules
relatively speaking. For the regular second-round examination, the VDT cut-off of 400 days
could not be lowered owing to the larger variation in VDTs of malignant nodules.
In the NELSON trial, nodule management is based on volume and VDT. The only other
lung cancer screening study with volume-based nodule management found a slightly higher
false-positive rate at baseline (7.9%) [19]. These false-positive rates are considerably
lower than those in other screening trials with diameter measurements [1–4]. In the latter
trials, 13.4-28.8% false-positive results were found in the baseline round. Minimizing the
false-positive rate remains important, to reduce negative psychological effects [20, 21],
unnecessary invasive procedures, radiation exposure from additional CT examinations and
cost.
Previous research showed more rapid growth rates in new nodules found on repeat
rounds. The VDTs of nodules referred after the regular second-round examination in our
study were longer than the VDTs of nodules referred after the 3-month follow-up CT in
the baseline screening round. This may seem counterintuitive at first glance. However,
this finding can be explained by our nodule selection (not new nodules at follow-up examinations, but only nodules already visible at the baseline, prevalence screening). Nodules
detected at baseline typically include more slow-growing cancers, compared with nodules
first detected after the baseline screening round [22]. In our study, all 20 nodules referred
after the regular second-round examination had already been detected at the baseline CT,
and 14 also had a 3-month follow-up CT after baseline showing VDT>400 days. Therefore,
it makes sense that nodules referred after the regular second-round examination had longer
VDTs than nodules referred after the 3-month follow-up CT in the baseline screening.
The higher PPV in the second-round examination indicates that the malignancy risk is
52
4. OPTIMIZATION OF VDT FOR FAST-GROWING NODULES
considerable for nodules showing increased growth rates after a longer follow-up period.
This is in accordance with a previous analysis in the NELSON study, in which growth
was found to be an especially important risk factor for malignancy at the second-round
screening [14]. Van Klaveren et al showed that the negative predictive value of the
baseline CT screening of the NELSON trial, which included nodules with volume <50 mm3
or VDT >400 days, was 99.7% [6]. We excluded nodules with a VDT >400 days to
avoid overdiagnosis [23]. A VDT of 500 days is regarded to be the upper limit for
malignancy [24, 25]. Potentially it could be valuable to raise the VDT cut-off for CT
examinations after the baseline screening round beyond 400 days, to avoid missing lung
cancer cases. This was however not the topic of the current study. We recommend
further research, with inclusion of nodules with longer VDTs, to determine the optimal
VDT cut-off for follow-up CTs after baseline screening.
Recently, Ko et al. introduced a nodule growth model, using at least two CT examinations,
based on stable nodules [18]. They demonstrated abnormal growth in a handful of
histologically proven malignant nodules. When applied to our selection of fast-growing
pulmonary nodules, only very small reduction in false-positive referrals was found (7% for
the 3-month follow-up CT after baseline, 0% for the regular second-round examination).
Ko et al based their model on the study of Lindell et al, which showed no exponential
growth pattern in any pulmonary nodule and thereby concluded that VDT may not be
suited to pulmonary nodule management. However, Lindell et al used two-dimensional
(2D) measurements for doubling time calculations. Compared with computer-aided 3D
volumetric measurement, 2D measurements have been found to be unreliable in volume
change detection [9, 26]. Therefore, in the NELSON study 3D volumetric measurements
were used to calculate volume and VDT.
The 3-month interval was based on the VDT of 400 days that was initially chosen as cutoff value to identify fast-growing lung nodules [10]. The result of the current study implies
that this interval for follow-up may be shortened for the short-term follow-up examination
as part of the baseline screening round. For nodules with a volume increase >25%, the
newly calculated screen interval with VDT cut-off of 232 days is 75 days. The median
interval of the short-term follow-up CT examination for the participants included in our
study was 93 days, so this period could be slightly shortened. However, it is questionable
if the difference between 3 months and 2.5 months is relevant in terms of screening
organization.
A limitation of our study was the relatively small number of participants referred with
fast-growing nodules, despite our study representing one of the largest CT lung cancer
screening studies. The number of nodules included differed from the number of nodules
with VDT <400 days in a previous publication because of our inclusion criteria [6]. The
number of different lung cancer types in our study did not allow in-depth analysis of VDT
by histology. If no histological diagnosis was obtained, we used as standard an absence
of lung cancer diagnosis within 2 years of CT, a period that is considered long enough to
classify a nodule as benign [15]. Mikita et al found that nodules with VDT <400 days all
turned out to be malignant within a 2-year follow-up [27]. Actually, the mean follow-up
in our study was 4.4 years, so it is unlikely that a lung cancer case has been overlooked
among nodules assessed as benign. The chief limitation was the lack of external validation.
The optimized VDT cut-off for the 3-month follow-up CT in the baseline round should
be validated in another lung cancer screening study to assess its generalizability.
In conclusion, all malignant, fast-growing lung nodules referred after the 3-month followup CT in the baseline screening round of the NELSON trial had a VDT ≤232 days.
Lowering the VDT cut-off for this screening round may reduce false-positive referrals.
Acknowledgements
The NELSON-trial was sponsored by: Netherlands Organisation for Health Research and
Development (ZonMw); Dutch Cancer Society Koningin Wilhelmina Fonds (KWF); Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ);
Siemens Germany; Rotterdam Oncologic Thoracic Steering committee (ROTS); G. Ph.
Verhagen Trust, Flemish League Against Cancer, Foundation Against Cancer and Erasmus
Trust Fund.
The funders played no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
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