1、Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial,2,of,39,Lung cancer is a leading cause of death worldwid

2、e. US guidelines now recommend lung cancer screening with low-dose CT for high-risk individuals. So far, most research has focused on lung nodules detected during baseline screening.,Introduction,3,of,39,Introduction

3、,Reports of new nodules after baseline screening have been scarce and are inconsistent because of differences in definitions used.,Because these nodules developed within a short time-interval, Lung cancers found in incid

4、ence screening rounds tend to be more aggressive than those detected at baseline.,4,of,39,Up to now, no study has focused on new solid nodules found during lung cancer screening. We aimed to identify the occurrence of

5、new solid nodules and their probability of being lung cancer at incidence screening rounds in the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON).,Introduction,5,of,39,Dutch Belgian randomised lung cancer s

6、creening trial (NELSON),6,of,39,Organisation：Erasmus Medical Centre (Netherlands),Participating centres: University Medical Centre Groningen, University Medical Centre Utrecht, Kennemer Gasthuis Haarlem (the Netherla

7、nds), and University Hospital Leuven (Belgium).,Dutch Belgian randomised lung cancer screening trial (NELSON),7,of,39,Dutch Belgian randomised lung cancer screening trial (NELSON),8,of,39,Participant inclusion criteria

8、 1. Born between 1928 and 1956（50-75years）2. Smoked:2.1. More than 15 cigarettes per day for more than 25 years, or2.2. More than 10 cigarettes per day for more than 30 years3. Current or former smokers who quit s

9、moking less than or equal to 10 years ago Participant exclusion criteria 1. Moderate or bad self-reported health who were unable to climb two flights of stairs2. Body weight greater than or equal to 140 kg3. Curr

10、ent or past renal cancer, melanoma or breast cancer4. Lung cancer, diagnosed less than five years ago or greater than or equal to five years but still under treatment5. Had a chest CT examination less than one year,Dut

11、ch Belgian randomised lung cancer screening trial (NELSON),9,of,39,Intervention 1. Screen arm:1.1. 16-detector multi-slice computed tomography of the chest in year one, two and four of the study1.2. Pulmonary func

12、tion test1.3. Blood sampling1.4. Questionnaires1.5. Smoking cessation advice for current smokers2. Control arm:Smoking cessation advice for current smokers.,Dutch Belgian randomised lung cancer screening trial (NEL

13、SON),Methods-Study design and participants,10,of,39,In the ongoing, multicentre, randomised controlled NELSON trial, between Dec 23, 2003, and July 6, 2006.15?822 participants were enrolled and randomly assigned to rece

14、ive either screening with low-dose CT (n=7915) or no screening (n=7907). 7557 individuals underwent baseline; 7295 participants underwent second and third screening rounds.,Methods-Study design and participants,11,of,3

15、9,Methods-Study design and participants,12,of,39,We included all participants with solid non-calcified nodules, registered by the NELSON radiologists as new or smaller than 15 mm3 (study detection limit) at previous

16、 screens.,Methods-Procedures,13,of,39,Nodule volume was generated semiautomatically by software. The semiautomated volumetric software (LungCARE, version Somaris/5 VA70C-W, Siemens Medical Solutions, Forchheim, Germany)

17、. On the basis of the three-dimensional nodule volume, this software also simulated longest and perpendicular nodule diameter in the axial plane.,Methods-Procedures,14,of,39,For subsequent CT scans, nodules were individ

18、ually matched on previous scans by the software‘s matching algorithm(depending on consistency, size, and location), and visually checked by the radiologists.,Methods-Procedures,15,of,39,Methods-Procedures,16,of,39,After

19、initial detection, subsequent evaluation of a nodule was based on growth and volume doubling time.We calculated the maximum volume doubling time for nodules with an estimated percentage volume change of 25% or more.,17

20、,of,39,Methods-Procedures,In theory, the actual volume doubling time in the examined time interval might have been faster, but not slower, than the calculated maximum time.,Methods-Procedures,18,of,39,For nodules eventua

21、lly diagnosed as cancer, we supplemented data with cancer-specific information obtained at diagnosis, such as histology and stage.  Malignancy was based on histology, and benignity was based on histology or stable

22、 size for at least 2 years.,Methods-Statistical analysis,19,of,39,Methods-Statistical analysis,20,of,39,Receiver operating characteristic (ROC) analysis was done for nodule volume with eventual lung cancer diagnosis as t

23、he outcome to evaluate their performance as predictors of lung cancer and to estimate cutoff values.We derived cutoff values with a predefined overall sensitivity of 95%.,Methods-Statistical analysis,21,of,39,We develop

24、ed a risk prediction model to assess whether the established relation between volume of a new solid nodule and lung cancer diagnosis remained significant independent of other risk factors (ie, age, sex, pack-years, smoki

25、ng status, time since previous scan, solid nodule count at baseline, and nodule imaging and volume).,Results,22,of,39,We analysed data for participants with at least one solid non-calcified nodule at the second or third

26、screening round. In the two incidence screening rounds, the NELSON radiologists registered 1222 new solid nodules in 787 (11%) participants.,23,of,39,Table 1 shows characteristics of included participants. A higher

27、 number of pack-years smoked and a lower number of solid nodules at baseline screening significantly increased the probability of a new solid nodule being lung cancer .Increased age was not significantly associated with

28、 lung cancer .,Results,24,of,39,In 49 (6%) participants with new solid nodules, a new solid nodule was lung cancer . One participant was diagnosed with synchronous double tumours in two new nodules. In total, 50 lung can

29、cers were found, representing 4% of all new solid nodules.,25,of,39,Table 2:New solid new nodules detected during second and third screening rounds (N=1222; 1172 benign nodules and 50 lung cancer nodules).,Results,26,of

30、,39,Nodule volume had a high discriminatory power (area under the receiver operating curve 0·795 [95% CI 0·728–0·862]; p<0·0001).,27,of,39,Results,28,of,39,29,of,39,Results,30,of,39,Less than half

31、of screen-detected lung cancers in new solid nodules were 500 mm3 or more at first nodule detection. Histologically, most lung cancers were adenocarcinomas, squamous-cell carcinomas, or small-cell lung carcinomas .

32、 Most small-cell lung carcinomas and squamous-cell carcinomas had volumes greater than 500 mm3 at first nodule detection .However, few adenocarcinomas initially presented with volumes of 500 mm3 and more, wher

33、eas roughly two-fifths were smaller than 50 mm3 at first detection. Most lung cancers were diagnosed at stage I .In about half the lung cancer cases, participants were referred immediately after first new solid no

34、dule detection. Adenocarcinomas tended to be referred later.,Discussion,31,of,39,Few studies of lung cancer screening have published detailed data regarding new nodules at incidence screening rounds. Furthermore, to our

35、 knowledge, this is the first time nodule volume cutoff values have been established as a guide for further management of new solid nodules.,1.,Discussion,32,of,39,2. mere detection of a new solid nodule during incidence

36、 screening might carry the same lung cancer probability as a suspicious test result during baseline screening (6% vs 5%; p=0·25).,Discussion,33,of,39,3. At these tiny nodule sizes, growth detection based o

37、n two-dimensional diameter evaluation is unreliable, favouring volumetry.,Discussion,34,of,39,Age was not significantly associated with new nodule lung cancer. Possible explanations could be that the number of cases was

38、 too low to show the correlation, or perhaps fast nodule growth is less associated with age, possibly even with a converse relation, with older individuals having less fast-growing nodules.,4.,Discussion,35,of,39,5.,The

39、 maximum volume doubling time was significantly lower in new nodule lung cancers than in benign new solid nodules. Notably, the median maximum volume doubling time of adenocarcinomas (191 days [IQR 146–348]) and squamou

40、s-cell carcinomas (133 days [105–182]) was similar to previously published volume doubling time of fast-growing baseline cancers in the NELSON trial of the same histological type (196 days [IQR 135–250] and 142 days [91–

41、178], respectively).,Discussion,36,of,39,6.,Compared with the overall screening results of the first three rounds, new solid nodule cancer comprised 11 (19%) of 58 cancers found in the second screening; and 34 (44%

42、) of 77 cancers even in the third screening;Thus, management of new solid nodules has a great impact on the outcome of a lung cancer screening programme.,Discussion,37,of,39,7.limitations,Discussion,38,of,39,Our study s

43、hows that new solid nodules are detected at each screening round in 5–7% of individuals who undergo screening for lung cancer with low-dose CT. These new nodules have a high probability of malignancy even at a small siz

44、e. These findings should be considered in future screening guidelines.New solid nodules should be followed up more aggressively than nodules detected at baseline screening, for example by using lower volume cutoff valu