University of Groningen

Optimization of nodule management in CT lung cancer screeningHeuvelmans, Marjolein

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4Optimization of volume-doubling time cutoff

for fast-growing lung nodules in CT lungcancer screening reduces false-positive

referrals

Marjolein A HeuvelmansMatthijs Oudkerk

Geertuida H de BockHarry J de Koning

Xiequan XiePeter M A van Ooijen

Marcel J GreuterPim A de Jong

Harry JM GroenRozemarijn Vliegenthart

Published in European Radiology2013, 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-positivereferrals.Methods: Screening participants of the NELSON study underwent low-dose CT. Forindeterminate nodules (volume 50-500 mm3), follow-up CT was performed 3 months afterbaseline. A negative baseline screen resulted in a regular second-round examination, oneyear 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. Histologywas the reference for diagnosis, or stability on subsequent CTs, confirming benignity. Meanfollow-up of non-resected nodules was 4.4 years. Optimization of the false-positive ratewas evaluated at maintained sensitivity for lung cancer diagnosis with VDT <400 days asreference.Results: 68 fast-growing nodules were included; 40% were malignant. The optimal VDTcut-off for the 3-month follow-up CT after baseline was 232 days. This cut-off reducedfalse-positive referrals by 33% (20 versus 30). For the regular second-round, VDTs variedmore 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-upCT in the baseline lung cancer screening round had VDT ≤232 days. Lowering the VDTcut-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.

IntroductionIn view of the prospective results of the National Lung Screening Trial (NLST) [1], andthe baseline results of other trials [2–6], interest in computed tomography (CT) for lungcancer screening in high-risk individuals is increasing. A drawback of CT screening isthe 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 sensitiveand timely diagnosis of malignant nodules. At the same time, patient anxiety, cost andmorbidity associated with unnecessary diagnostic procedures for benign nodules should beminimized.In the NLST screening rounds, the rate of positive tests, defined as the presence of oneor 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 sug-gested to be more accurate, potentially leading to lower false-positive rates [9]. Thenodule management strategy of the Dutch-Belgian randomized lung cancer screening trial(Dutch acronym NELSON) is based on volume and volume-doubling time (VDT) as-sessment [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 (50-500 mm3) a short-term follow-up CT was performed, to evaluate growth. Because noduleswith 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 volumemeasurements for newly detected nodules and growth evaluation of previously detectednodules (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 ofthe 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 outto 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 rateof false-positive referrals can be further reduced.Therefore, our objective was to retrospectively evaluate the VDTs of fast-growing solidpulmonary nodules in order to find the optimal VDT cut-off for differentiating benign andmalignant 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 theethics board at each participating center. All participants provided written informed con-sent. Participants were current and former smokers, aged 50-75 years, at high risk of lungcancer. Recruitment procedures and selection criteria in the NELSON trial have beenpublished [11].

In this retrospective sub-study, participants with at least two low-dose CT examinationsduring the baseline round and regular second-round screening in year 2 (April 2004 to April2007) 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 yearafter baseline (for any nodule <500 mm3 at baseline) were included. Only participants whowere subsequently referred to a pulmonologist because of this fast-growing lung noduleand had either a histological diagnosis or a 2-year follow-up period after negative outcomeof work-up to confirm benignity were included (Figure 4.1). The reason for includingonly participants who were referred to a pulmonologist was because diagnosis based onhistology 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. 210of those showed fast-growth at the 3-month follow-up CT after baseline or at the regularsecond-round scan (Figure 4.2). The majority (127 nodules) did not warrant referral to apulmonologist for a variety of reasons. Of the screening participants that were referred toa pulmonologist (83 nodules), another 15 were excluded since they had less than 2 yearsfollow-up period after a negative outcome of workup. Sixty-eight fast-growing noduleswere 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 otherbenign nodules was 4.4 years (95% CI, 3.9-4.9 years; range 2.7-5.7 years), showing stableor decreased size over time. In three of the excluded participants who were initially notreferred because of a measurement error in the volume, malignancy was confirmed afterthe 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 largerthan 500 mm3. The result was indeterminate in case of a non-calcified nodule of 50-500 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 ofslower growing lesions, the baseline screening result was negative and the participant wasinvited 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 onnodule size (similar to the baseline examination), or a nodule was pre-existing [10]. Forpre-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 firstdetection (Figure 4.3) [15, 16]. In the case of diagnosed lung cancer, the participantwas treated and was no longer invited for screening examinations; otherwise the regularnext-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, PhilipsMedical Systems; Cleveland, OH, USA). Spiral mode with 16x0.75 mm collimation andpitch 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-secondvalues 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 lungwere 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 estimatingVDT [17]. Data acquisition and imaging conditions were standard across screening centersand equal for baseline and repeat screening.

Digital workstations (Leonardo; Siemens Medical Solutions; Erlangen, Germany) withsoftware for semi-automated three-dimensional (3D) volume measurements (LungCare,version Somaris/5: VA70C-W; Siemens Medical Solutions) were used for nodule volumet-ric analysis. CT examinations were read twice, by independent readers. Experience forthe first readers ranged from none to >20 years. Both second readers had six years ofexperience 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 bereached, a third, expert thoracic radiologist arbitrated [10]. After a nodule was selected bya radiologist, the system automatically calculated nodule volume. Information was savedin the NELSON Management System, which calculated the percentage volume changeand VDT. The VDT was calculated by comparing nodule volume at the latest CT with thevolume at the baseline examination as a reference time point. For additional analysis, wealso calculated the VDT by comparing nodule volume at the time of the positive screeningresult with the nodule volume at the latest CT before the positive screening for nodulesdetected 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 CTlung cancer screening was introduced by Ko et al [18]. We applied this model to evaluatewhether the false-positive rate in our screening study could be lowered by using thismethod. 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), non-parametric data as median and interquartile ranges. The non-parametric Mann-WhitneyU test was used for analysis of volume and VDT. In additional analysis, we compared theVDT using as a reference point the nodule volume at first detection or the volume atthe latest CT before the examination with a positive screening result, with the Wilcoxonsigned-rank test.

To identify the optimal VDT cut-off values for differentiating growing benign andmalignant pulmonary nodules at 3-month follow-up of the baseline screening round andat the regular second-round examination, the false-positive rate at different VDTs wasevaluated, 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). P-values <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. Threemonths later (b), the nodule volume increased to 83.3 mm3, the VDT was 342 days andthe participant was referred to a pulmonologist. Work-up showed no malignancy. At theregular 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 was96.5 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 duringthe first two screening rounds, at the moment of referral to pulmonologist due to positiveexamination.

Benign nodules Malignant nodules P-value

Nodule volume(mm) n (%) Median volume

(mm3) (25th, 75th%a) n (%) Median volume(mm3) (25th, 75th%a)

50-500 37 (90) 121 (82, 171) 15 (56) 280 (126, 362)>500 4 (10) 836 (693, 2207) 12 (44) 777 (618, 1201)Total 41 (100) 124 (84, 206) 27 (100) 486 (227, 774) <0.001

a 25th % = 25th percentile, 75th% = 75th percentile

Results

Sixty-eight fast-growing nodules (VDT <400 days) in 61 participants were included (Fig-ure 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 63.8years; 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) wasof large size (>500 mm3) but was initially diagnosed as non-malignant after workup in thebaseline 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. Threemonths 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 nodulevolume was 553.8 mm3. The VDT at that time was 187 days. Work-up revealed a stage IAadenocarcinoma. The growth curve is shown in (d).

to referral after the 3-month follow-up CT in the baseline round, malignant nodules (me-dian 250 mm3) had a significantly larger baseline volume than benign nodules (median81 mm3; P<0.01).

Of the malignant nodules, 52% (14/27) had shifted upward in volume category atthe 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 thepositive 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 shownin Table 4.1.

No difference was found in VDTs of nodules referred after the regular second-roundexamination calculated by using volume at first detection or volume of the last examinationbefore 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 lungcancer, and 1 large cell neuroendocrine carcinoma (4%) (Table 4.2).

Table 4.2: Histological features and volume-doubling time of malignant nodules per screen-ing round.

Moment of referral Histological type n PercentageVDT (days)(median (25th,75th)a)

3-month follow-up Adenocarcinoma 4 36% 110 (63, 208)baseline Squamous cell carcinoma 5 45% 118 (84, 187)

Large cell carcinoma 1 9% 24 (-b, -b)Large cell neuroendocrinecarc. 1 9% 68 (-b, -b)

Total 11 100% 98 (68, 169)

Regular second-round Adenocarcinoma 11 69% 213 (185, 327)examination Squamous cell carcinoma 1 6% 165 (-b , -b)

Large cell carcinoma 3 19% 289 (124, -b)Small cell lung cancer 1 6% 84 (-b,-b)Total 16 100% 205 (165, 318)

Total Adenocarcinoma 15 55% 196 (135, 250)Squamous cell carcinoma 6 22% 142 (91, 178)Large cell carcinoma 4 15% 207 (49, 326)Large cell neuroendocrinecarc. 1 4% 68 (-b, -b)

Small cell lung cancer 1 4% 84 (-b,-b)Total 27 100% 198 (122, 264)

a 25th = 25th percentile, 75th = 75th percentile.b 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 thebaseline screening round. Eleven of these were malignant (positive predictive value [PPV],23%). Twenty participants with 20 fast-growing nodules were referred after the regularsecond-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-roundCT also underwent a 3-month follow-up CT after the baseline examination, showing nofast 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 notreceive 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 nod-ules 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 reg-ular 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 ofreferral, with differentiation by tumor nature.

Moment ofreferral

Nodulevolume(mm3)

Tumournature

N (nodules /participants)a

Percentage(nodules /participants)a)

VDT (days)(median (25th,75th)a)

Pvalue

3-month <50 Benign 5 100% 173 (112, 284)follow-up 50-500 Benign 32/28 74%/72% 204 (132, 264)baseline Malignant 11 26%/28% 98 (68, 169)

Total Benign 37/30 77%/73% 203 (133, 262) 0.013Malignant 11 23%/27% 98 (68, 169)

Regular <50 Benign 3 37% 293 (214, -c)second- Malignant 5 63% 185 (104, 314)round 50-500 Benign 1 8% 289 (289, -c)examination Malignant 11 92% 213 (165, 327)

Total Benign 4 20% 291 (233, 353) 0.12Malignant 16 80% 205 (165, 318)

VDT = volume-doubling time.a When only one number is shown, the number of nodules is equal to the number of partici-pants.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 inthe 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 the12 subjects however, had another faster-growing benign nodule, so they would still havebeen referred to a pulmonologist. In total, ten of the 30 participants (33%) with a benignnodule would not have been referred with the optimized VDT cut-off.

At the regular second-round examination in year 2, VDTs varied more among themalignant nodules (ranging from 84 to 358 days). VDTs of the four benign nodulesreferred 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 introducedby Ko et al. [18] reduced false-positive tests by 4 (9%) and false-positive referrals byonly 2 (7%) for the 3-month follow-up CT in the baseline round. In the second-roundscreening, all benign nodules showed abnormal growth according to this model, leadingto false-positive test results.

Figure 4.5: Box plots of volume-doubling times of malignant and benign nodules at 3-monthfollow-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-monthfollow-up CT in the baseline lung cancer screening round led to a third fewer false-positivereferrals, at maintained sensitivity for lung cancer diagnosis. This is especially importantas the baseline screening was the round with the most fast-growing pulmonary nodulesrelatively speaking. For the regular second-round examination, the VDT cut-off of 400 dayscould 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 otherlung cancer screening study with volume-based nodule management found a slightly higherfalse-positive rate at baseline (7.9%) [19]. These false-positive rates are considerablylower than those in other screening trials with diameter measurements [1–4]. In the lattertrials, 13.4-28.8% false-positive results were found in the baseline round. Minimizing thefalse-positive rate remains important, to reduce negative psychological effects [20, 21],unnecessary invasive procedures, radiation exposure from additional CT examinations andcost.

Previous research showed more rapid growth rates in new nodules found on repeatrounds. The VDTs of nodules referred after the regular second-round examination in ourstudy were longer than the VDTs of nodules referred after the 3-month follow-up CT inthe 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 exam-inations, but only nodules already visible at the baseline, prevalence screening). Nodulesdetected at baseline typically include more slow-growing cancers, compared with nodulesfirst detected after the baseline screening round [22]. In our study, all 20 nodules referredafter 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 longerVDTs 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 growthwas found to be an especially important risk factor for malignancy at the second-roundscreening [14]. Van Klaveren et al showed that the negative predictive value of thebaseline 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 toavoid overdiagnosis [23]. A VDT of 500 days is regarded to be the upper limit formalignancy [24, 25]. Potentially it could be valuable to raise the VDT cut-off for CTexaminations after the baseline screening round beyond 400 days, to avoid missing lungcancer cases. This was however not the topic of the current study. We recommendfurther research, with inclusion of nodules with longer VDTs, to determine the optimalVDT 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 ofhistologically proven malignant nodules. When applied to our selection of fast-growingpulmonary nodules, only very small reduction in false-positive referrals was found (7% forthe 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 exponentialgrowth pattern in any pulmonary nodule and thereby concluded that VDT may not besuited to pulmonary nodule management. However, Lindell et al used two-dimensional(2D) measurements for doubling time calculations. Compared with computer-aided 3Dvolumetric measurement, 2D measurements have been found to be unreliable in volumechange detection [9, 26]. Therefore, in the NELSON study 3D volumetric measurementswere used to calculate volume and VDT.

The 3-month interval was based on the VDT of 400 days that was initially chosen as cut-off value to identify fast-growing lung nodules [10]. The result of the current study impliesthat this interval for follow-up may be shortened for the short-term follow-up examinationas part of the baseline screening round. For nodules with a volume increase >25%, thenewly calculated screen interval with VDT cut-off of 232 days is 75 days. The medianinterval of the short-term follow-up CT examination for the participants included in ourstudy was 93 days, so this period could be slightly shortened. However, it is questionableif the difference between 3 months and 2.5 months is relevant in terms of screeningorganization.

A limitation of our study was the relatively small number of participants referred withfast-growing nodules, despite our study representing one of the largest CT lung cancerscreening studies. The number of nodules included differed from the number of noduleswith VDT <400 days in a previous publication because of our inclusion criteria [6]. Thenumber of different lung cancer types in our study did not allow in-depth analysis of VDTby histology. If no histological diagnosis was obtained, we used as standard an absenceof lung cancer diagnosis within 2 years of CT, a period that is considered long enough toclassify a nodule as benign [15]. Mikita et al found that nodules with VDT <400 days allturned out to be malignant within a 2-year follow-up [27]. Actually, the mean follow-upin our study was 4.4 years, so it is unlikely that a lung cancer case has been overlookedamong 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 shouldbe validated in another lung cancer screening study to assess its generalizability.

In conclusion, all malignant, fast-growing lung nodules referred after the 3-month follow-up 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 andDevelopment (ZonMw); Dutch Cancer Society Koningin Wilhelmina Fonds (KWF); Stich-ting 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 ErasmusTrust Fund.

The funders played no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript.

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