Abstract
Rationale: The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial.
Objectives: To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials.
Methods: All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials.
Measurements and Main Results: In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB–IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB–IV.
Conclusions: Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy.
Clinical trial registered with www.trialregister.nl (ISRCTN63545820).
Europe’s largest lung cancer screening trial (the NELSON trial) has a volumetry-based strategy, stringent criteria for a positive screening, an increasing length of screening interval, and few female participants. The effect of these features on the characteristics of screen-detected lung cancers is still unknown.
Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the NELSON screening strategy resulted in a favorable cancer stage distribution at diagnosis.
Lung cancer is the leading cause of cancer-related death in males and the second in females globally, accounting for 1.4 million lung cancer deaths per year (1). Despite treatment advances, survival has not improved substantially, mainly because the majority of the patients have distant metastases at the time of diagnosis (2). Several randomized lung cancer screening trials were conducted with low-dose computer tomography (LDCT) scanning of high-risk groups, aiming to detect lung cancer at an earlier and curable stage (3–7).
The world’s largest randomized CT screening trial, the National Lung Screening Trial (NLST), demonstrated in 2011 that early detection by LDCT scanning has yielded a 20% lung cancer mortality reduction compared with screening by chest radiograph (8). Sixty-one percent of the LDCT-detected lung cancers were diagnosed at stage I. To accomplish this impressive result, considerable efforts were made. Namely, 26,722 high-risk subjects underwent annual LDCT screening for 3 years. Positive screening results were defined as any noncalcified pulmonary nodule measuring at least 4 mm in any diameter. In the three screening rounds, 39.1% of the individuals had at least one positive result (8).
Our trial, the Dutch–Belgian Lung Cancer Screening Trial (Nederlands-Leuvens Longkanker Screenings onderzoek; the NELSON trial), is the world’s second-largest randomized CT screening trial and differs from the NLST by screening interval, referral policy, and a control arm wherein individuals receive no screening (3). The 7,915 participants randomized to the screening arm of the NELSON trial underwent LDCT screening at baseline, 1 year later, 2 years later, and finally 2.5 years later. Positive screening results were defined as noncalcified nodules with a volume greater than 500 mm3 (about 9.8 mm in diameter) or volume-doubling time (VDT) less than 400 days (3, 9, 10). In the first three screening rounds, 6.0% of the participants had at least one positive screening. Clearly, the differences between the two largest randomized CT screening trials are substantial. Whether the NELSON trial will be able to demonstrate a significant lung cancer mortality reduction must be awaited, because the mortality analyses are planned 10 years after randomization (11). However, the characteristics of the screen-detected lung cancers, especially the stage distribution, might give an indication of the effectiveness of our screening strategy.
For this study, all participants with screen-detected lung cancer in the first three rounds of the NELSON trial were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and several randomized CT screening trials.
The 15,822 individuals in the NELSON trial were randomized (1:1) to screening (n = 7,915) with LDCT at baseline (first round), 1 year later (second round), 3 years later (third round), and 5.5 years later (fourth round) or no screening (n = 7,907) (Figure 1). The main purpose of the trial is to determine whether LDCT screening will have reduced lung cancer mortality by at least 25% at 10 years of follow-up (11, 12). A more detailed report of the design and conduct was published previously (9, 11).
Figure 1. Participant flowchart in the first three rounds of the NELSON trial. *219 participants were not screened in the second round because of death (n = 27), participant declined (n = 115), participant unattainable or repeatedly no show (n = 47), administrative error (n = 1), still in diagnostic work-up round 1 (n = 1), no screening in second round, but screened in third round (n = 27). #345 participants were not screened in the third round because of lung cancer in round 1 (n = 2), death (n = 84), participant declined (n = 155), participant unattainable or repeatedly no show (n = 98), administrative error (n = 3), unknown (n = 3). Note: Mortality data were available only for the Dutch participants until August 14, 2011.
[More] [Minimize]Individuals aged 50 to 75 years, who had smoked 15 or more cigarettes per day for 25 years or 10 or more cigarettes for 30 years and were still smoking or had quit less than 10 years ago, met the inclusion criteria. The exclusion criteria and calculation of expected lung cancer mortality were published in 2006 (11). For this study, all participants diagnosed with screen-detected lung cancer in the first three screening rounds were included (Figure 1). Hence, the interval cancers were not included in the analyses.
In short, 16-detector CT modality was used in a low-dose setting, without intravenous contrast medium (9). CT images were analyzed with software for semiautomated volume measurements (LungCARE, Siemens Healthcare, Erlangen, Germany) (13, 14).
Briefly, the screening test result could be negative (invitation for the next screen round), indeterminate (invitation for a repeat scan to determine the VDT), or positive (referral for diagnostic work-up). The nodule volume determined the screen result for newly detected nodules: less than 50 mm3 was negative, 50 to 500 mm3 was indeterminate, and more than 500 mm3 was positive. The percentage volume change was calculated for previously detected nodules: at least 25% led to the assessment of the VDT. The VDT was calculated according to the formula: VDT(days) = [ln 2 × (time between current scan and baseline screening)]/[ln(nodule volume on current scan/volume on baseline scan)] (9). The screen result was positive for a VDT less than 400 days. A full description of the protocol was published previously (9, 10).
After a positive screening, the participants were referred for diagnostic work-up via their general practitioner and received usual care according to national and international guidelines (15–19). All data were prospectively collected and histological specimens were reassessed by our chief pathologist (E.T.).
Continuous variables were tested for normality by Kolmogorov–Smirnov test for 50 or more samples and by Shapiro–Wilk test for fewer than 50 samples. Continuous, normally distributed variables were described by means and standard deviations. The difference between the means of continuous variables was calculated by one-way analysis of variance. Nonnormally distributed variables were described by medians and interquartile ranges. The difference between nominal variables was calculated by chi-square test and differences between categorical variables were calculated by Mann–Whitney U test. The difference between more than two samples of a categorical variable was calculated by Kruskal–Wallis H test. Predictors of cancer stage were tested by ordinal logistic regression; variables entered multivariate models when the P value did not exceed 0.05 univariately. P values less than 0.05 were treated as significant. SPSS Statistics version 20 (IBM, Armonk, NY) was used for all analyses.
The NELSON trial was approved by the Dutch Ministry of Health and the ethics board at each participating center. All participants gave written informed consent for participation and the evaluation of personal data from hospital charts.
Of the 7,915 (95.8%) participants randomized to the screening arm of the trial, 7,582 received at least one screening (Figure 1). Their baseline characteristics are presented in Table 1. The three screening rounds yielded 493 positive screen results and 200 (40.6%) participants were diagnosed with lung cancer. Synchronous double tumors were detected in four participants in round 1, in three participants in round 2, and in two participants in round 3. Thus, 200 participants were diagnosed with a total of 209 lung cancers. The patients with lung cancer were significantly older and had smoked significantly more pack-years than had the subjects not diagnosed with lung cancer (Table 1).
| Characteristic* | All Participants | Participants Diagnosed with Lung Cancer† | Participants Not Diagnosed with Lung Cancer | P Value‡ |
|---|---|---|---|---|
| Age (yr), median (IQR) | 58.0 (54.0–62.0) | 61.0 (57.0–66.0) | 58.0 (54.0–62.0) | <0.001 |
| Female sex, n (%) | 1,254 (16.5) | 34 (17.0) | 1,220 (16.5) | 0.86 |
| Current smoker, n (%) | 4,215 (55.6) | 112 (56.0) | 4,103 (55.6) | 0.91 |
| Pack-years, median (IQR) | 38.0 (29.7–49.5) | 43.7 (32.2–75.8) | 38.0 (29.7–49.5) | <0.001 |
| BMI, median (IQR) | 25.8 (23.9–28.1) | 25.4 (23.3–28.0) | 25.8 (23.9–28.1) | 0.09 |
| Total | n = 7,582 | n = 200 | n = 7,382 |
Eleven of the 200 participants (5.5%) had symptoms suspicious of lung cancer before they were diagnosed. Five of them had symptoms before the screening scan was made; however, none of them had symptoms at randomization. Three subjects had symptoms in the period between the positive scan and the first consultation, and three subjects had symptoms in the period between the first consultation and the diagnosis date. Box plots of the time to screening result, referral, and diagnosis of the 200 participants and a detailed description of the symptoms can be found in the online supplement (Figure E1).
More than half of the 209 screen-detected lung cancers were adenocarcinomas (51.2%) and a large majority was diagnosed at an early stage (stage I, 70.8%) (Table 2). Adenocarcinomas appeared to be diagnosed at a significantly lower cancer stage (univariate analysis P = 0.045), but in multivariate analysis this was no longer significant (P = 0.56) (Table E1). However, all bronchoalveolar carcinomas (n = 11) and carcinoids (n = 6) were diagnosed at stage IA (Table 2). Four other histological subtypes were prone to be diagnosed at a higher cancer stage, for example, small cell carcinomas (multivariate analysis P < 0.001) (Table E1).
| Cancer Stage* | ||||||||
|---|---|---|---|---|---|---|---|---|
| IA | IB | IIA | IIB | IIIA | IIIB | IV | Overall | |
| Histology† | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) |
| Adenocarcinoma | 75 (70.1) | 9 (8.4) | 8 (7.5) | 0 (0.0) | 9 (8.4) | 4 (3.7) | 2 (1.9) | 107 (51.2) |
| Bronchoalveolar carcinoma | 11 (100.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 11 (5.3) |
| Squamous cell carcinoma | 21 (61.8) | 0 (0.0) | 3 (8.8) | 0 (0.0) | 8 (23.5) | 0 (0.0) | 2 (5.9) | 34 (16.3) |
| Adenosquamous carcinoma | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (1.9) |
| Large cell carcinoma | 7 (41.2) | 1 (5.9) | 0 (0.0) | 0 (0.0) | 6 (35.3) | 2 (11.8) | 1 (5.9) | 17 (8.1) |
| Large cell neuroendocrine carcinoma | 2 (50.0) | 1 (25.0) | 0 (0.0) | 0 (0.0) | 1 (25.0) | 0 (0.0) | 0 (0.0) | 4 (1.9) |
| Small cell carcinoma | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (62.5) | 0 (0.0) | 3 (37.5) | 8 (3.8) |
| Small/large cell carcinoma | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (50.0) | 0 (0.0) | 1 (50.0) | 2 (1.0) |
| Pleomorphic carcinoma | 0 (0.0) | 0 (0.0) | 1 (100.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.5) |
| NSCLC-NOS | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (50.0) | 1 (50.0) | 2 (1.0) |
| Carcinoid | 6 (100.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 6 (2.9) |
| No histological diagnosis‡ | 12 (92.3) | 0 (0.0) | 1 (7.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 13 (6.2) |
| Total | 137 (65.6) | 11 (5.3) | 14 (6.7) | 0 (0.0) | 30 (14.4) | 7 (3.3) | 10 (4.8) | 209 (100) |
Most lung cancers were localized in the right lung (65.6%) and a large proportion (45.0% of all lung cancers) was localized in the right upper lobe (Figure 2). We also observed that the lung cancers were localized predominantly in the periphery of lungs (Figure 3). Of the nodules, 62.2% were found in the outer one-third of the costal–hilar diameter (Figure 3). In particular, adenocarcinomas were more often detected in the periphery and attached to the pleura than in the middle or central one-third of the lungs (82.2 vs. 17.8%; P = 0.001). But the reverse was not true for squamous cell carcinomas (62.9% peripheral or pleural-attached vs. 37.1% central or middle one-third; P = 0.16).
Figure 2. Localization across the lobes of the 209 screen-detected lung cancers. A schematic depiction of the lungs and large airways. The right lung is displayed on the left side and vice versa, as on a chest radiograph. The left upper lobe is divided in the pars superior and the lingula by the dotted line. The lung cancers are depicted as dark gray dots; their localization corresponds with the lobe where the nodule was detected, not with the exact localization.
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Figure 3. Localization of the 209 screen-detected lung cancers; central versus peripheral. A schematic depiction of the lungs and main carina in the transversal plane. The right lung is displayed on the left side and vice versa as in computer tomography images. The lungs are categorized in four sections: central (inner one-third of the hilar costal diameter), middle (middle one-third of the hilar–costal diameter), peripheral (outer one-third of the hilar–costal diameter) and pleural-attached nodules (nodules depicted on the bold outline of the lungs) The lung cancers are depicted as dark gray dots; their localization corresponds with the section where the nodule was detected, not with the exact localization. One lung cancer is not represented in the figure because the participant was referred for a fast-growing nodule peripheral in the right upper lobe, but this nodule disappeared during the work-up. However, soon thereafter lung cancer developed in the left lower lobe (transversal localization unknown) and the patient was treated with radiotherapy.
[More] [Minimize]The lung cancers detected in round 1 had a slightly higher disease stage (stage IA, 59.5%; stage IV, 6.8%) than in later rounds (round 2: stage IA, 74.1%; stage IV, 3.4% and round 3: stage IA, 64.9%; stage IV, 3.9%) (Tables E2a–E2c). But this was not statistically significant between rounds 1 and 2 (P = 0.09) or across the three rounds (P = 0.23).
Also, the proportion adenocarcinomas was not significantly different between rounds 1 and 2 (47.3 vs. 60.3%; P = 0.14) or across the three rounds (round 3, 48.1% adenocarcinomas; P = 0.26) (Tables E2a–E2c).
Likewise, tumor localization was not significantly different across the screen rounds: neither for the division over the lobes (P = 0.88) nor for the division over the peripheral versus central lung fields (P = 0.09).
The women diagnosed with lung cancer were significantly younger (58.0 vs. 62.0 yr; P = 0.03), had smoked less (pack-years: 36.0 vs. 43.0; P = 0.03) and had a lower BMI (23.8 vs. 25.9; P = 0.03) than the men diagnosed with lung cancer. The percentage current smokers however, was not lower in females (56.7 vs. 55.9%; P = 0.93).
None of the histological subtypes were unevenly distributed between the sexes (Tables E3a and E3b). Also, the localization of the lung cancers was not significantly different between the sexes: neither for the left lung versus right lung localization (P = 0.92), nor for peripheral versus central localization (P = 0.89). However, the cancer stage at diagnosis was significantly lower in women than in men (P = 0.005) (Tables E3a and E3b). When correcting for the sex differences in age, number of pack-years and BMI, women still had a statistically significant lower cancer stage than men (P = 0.028) (Table E4).
Coincidentally, we found that a higher body mass index (BMI) (before randomization) was a significant multivariate predictor (P = 0.004) of a more unfavorable cancer stage at diagnosis in both sexes (Table E4).
A total of 1,078 lung cancers were detected by CT screening in 43,983 participants of randomized screening trials (Table 3). On average, 64.7% of the lung cancers were diagnosed at stage I and 10.9% at stage IIIB–IV (Table 3). The stage distribution in the NELSON trial appears to be relatively favorable compared with the other trials. When we compare the whole range of cancers stages between the two largest trials (NLST and NELSON) we observe that the cancer stage was significantly lower (P < 0.001) in the NELSON trial.
| Participants in Screening Arm | Screening Rounds | Length of Screening Interval | Males to Females | No. of Published CT-Detected Lung Cancers | Stage IA + IB Lung Cancers | Stage IIIB + IV Lung Cancers | |
|---|---|---|---|---|---|---|---|
| Trial (Ref.) | (n) | (n) | (yr) | (%:%) | [n (%)] | [n (%)] | |
| NLST (8) | 26,722 | 3 | 1 | 59.0:41.0 | 649 | 400 (61.6) | 130 (20.0) |
| NELSON | 7,915 | 4 | 1, 2, and 2.5 | 83.5:16.5 | 209 | 148 (70.8) | 17 (8.1) |
| DLST (36) | 2,052 | 5 | 1 | 54.6:45.4 | 69 | 47 (68.1)* | 11 (15.9)† |
| ITALUNG (7) | 1,613 | 4 | 1 | 64.2:35.8 | 22 | 11 (50.0)‡ | 5 (22.7) |
| DANTE (37) | 1,276 | 4 | 1 | 100.0:0.0 | 58 | 41 (70.7) | 4 (6.9) |
| MILD (38) | 1,190 | 10 | 1 | 68.4:31.6 | 29 | 18 (62.1) | 4 (20.0) |
| 1,186 | 5 | 2 | 68.5:31.5 | 20 | 14 (70.0) | 5 (17.2) | |
| LUSI (39) | 2,029 | 4 | 1 | 64.8:35.2 | 22 | 18 (81.8) | 0 (0) |
| Total | 43,983 | 3 to 10 | 1 to 2.5 | 65.4:34.6 | 1,078 | 697 (64.7)§ | 118 (10.9)* |
In this study, we have presented the characteristics of the lung cancers detected in the first three rounds of the NELSON trial. We investigated whether the screening strategy of the NELSON trial led to detection of lung cancer at a more favorable stage and how this relates to other randomized lung cancer CT screening trials.
In the three screening rounds, 493 participants had a positive screening result and were referred for diagnostic work-up. Ultimately, 200 (40.6%) participants were diagnosed with a total of 209 lung cancers. Eleven (5.5%) of these participants had symptomatic lung cancer before diagnosis; in five subjects the symptoms emerged before the screening scan was made.
More than half of the 209 screen-detected lung cancers were adenocarcinomas (51.2%) and a large majority was diagnosed at stage I (70.8%). Moreover, only 10 lung cancers were diagnosed at stage IV. This favorable stage distribution has created the opportunity for most patients to undergo curative surgery, which hopefully will reduce lung cancer mortality. However, screening detected only a few small cell lung cancers and all were diagnosed at stage III–IV. This finding could imply that LDCT screening is not, or is less, capable of early detection in some fast-growing histological subtypes of lung cancer. Further research should be conducted to investigate whether the lung cancers not detected by screening are predominantly of the same histological subtypes that are detected only in small amounts or high stages by screening.
Most screen-detected lung cancers were localized in the periphery of the lungs, which is probably a result of the large amount of adenocarcinomas that are significantly more often localized peripherally (P = 0.001). We also observed that 45.0% of all lung cancers were localized in the right upper lobe. This is a known phenomenon in patients with non–small cell lung cancer and could be explained by the fact that the airflow at the beginning of the breath is the largest toward the right upper lobe bronchus (20, 21). As a result, the deposition of particles in tobacco smoke and their carcinogenic effects are the largest in the right upper lobe (22, 23).
Further, our analyses showed no significant effect of screening round on cancer stage, histology, or tumor localization. However, a decrease in advanced-stage lung cancers was observed at the second screening round (stage IV dropped from 6.8 to 3.4%). This was probably not statistically significant because of the low absolute number of advanced-stage lung cancers. In the third screening round, no evidential increase in stage IV lung cancers was observed (3.9%), despite the screening interval of 2 years.
The differences in lung cancer characteristics between men and women have been studied extensively. In general, studies demonstrated that women are diagnosed at an earlier age (24, 25), at a more favorable cancer stage (25–27), and are more often diagnosed with adenocarcinomas than are men (24, 28, 29). NELSON is the first trial to report on these differences in a screening setting. We also found that women were diagnosed at a significantly more favorable cancer stage than men (P = 0.028, after correction for confounding). However, the histological subtype and localization of the lung cancers were not significantly different between the sexes.
In the NELSON trial, the body mass index (BMI) was not significantly higher in the participants diagnosed with lung cancer than in participants who were not diagnosed (P = 0.09). However, a higher BMI was a significant multivariate predictor of a more unfavorable cancer stage at diagnosis (P = 0.004). This finding is in line with one other study (30). However, most studies demonstrated a negative association between BMI and lung cancer risk and prognosis (31–33). This discrepancy could be explained in the first place by reversed causation: BMI is usually measured at diagnosis, at that time weight loss has often occurred, especially patients with a higher cancer stage. In the NELSON trial, BMI was measured just before randomization and because none of the participants had symptomatic lung cancer at that time, the BMI was not influenced by lung cancer itself. In the second place, the discrepancy could be explained by the strong confounding effect of smoking in many trials: smokers have a lower mean BMI than nonsmokers (34) and smoking is major risk factor for lung cancer mortality (32). This bias is probably limited in the NELSON trial because we included only (ex-)smokers (11).
In this article, we have presented an overview of the disease stage of the LDCT-detected lung cancers of the randomized screening trials. The cancer stage distribution in the NELSON trial appeared favorable relative to the other trials and was significantly lower (P < 0.001) than in the NLST. This last finding should be interpreted with caution because the NELSON trial used the 7th edition and the NLST the 6th edition of the TNM staging system (16, 35). Classification according to the 7th edition results more often in a lower cancer stage than in a higher stage compared with classification according to the 6th edition (16, 35). Consequently, this might have contributed to the lower cancer stage in the NELSON trial. Nonetheless, the NELSON trial has a number of features that could cause a higher cancer stage: first, relatively few female participants (16.5 vs. 41% in NLST), who are diagnosed at a lower stage; second, larger nodules at referral, due to relatively stringent referral criteria (nodule volume > 500 mm3 or nodule VDT < 400 d vs. nodule diameter ≥ 4 mm in NLST); and third, a longer screening interval (1, 2, and 2.5 yr vs. annual screening in NLST). All things considered, it seems that the NELSON strategy is at least as capable as the NLST strategy to diagnose lung cancer at a more favorable stage.
Naturally, this result raises a question concerning what the difference in cancer stage between the two trials would be if all lung cancers in screened participants were compared. Analysis showed no significant difference (P = 0.21), despite the shorter interval between screen rounds in the NLST (8).
Strengths of this study are the robust design (a large, randomized controlled trial) and prospective data collection. Limitations of this study are the lack of data for the control arm of the trial and lung cancer mortality. We have planned to perform analyses with those data 10 years after randomization, in accordance with the main purpose of our trial (11).
In conclusion, despite stringent referral criteria, an increasing length of screening interval, and a small proportion of female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy.
| 1. | Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. |
| 2. | Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. |
| 3. | van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, van Iersel CA, van den Bergh KA, van’t Westeinde S, van der Aalst C, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;361:2221–2229. |
| 4. | National Lung Screening Trial Research Team, Aberle DR, Berg CD, Black WC, Church TR, Fagerstrom RM, Galen B, Gareen IF, Gatsonis C, Goldin J, et al. The National Lung Screening Trial: overview and study design. Radiology 2011;258:243–253. |
| 5. | Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, Thorsen H, Brodersen J, Skov BG, Dossing M, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol 2009;4:608–614. |
| 6. | Infante M, Lutman FR, Cavuto S, Brambilla G, Chiesa G, Passera E, Angeli E, Chiarenza M, Aranzulla G, Cariboni U, et al. Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer 2008;59:355–363. |
| 7. | Lopes Pegna A, Picozzi G, Mascalchi M, Maria Carozzi F, Carrozzi L, Comin C, Spinelli C, Falaschi F, Grazzini M, Innocenti F, et al. Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer 2009;64:34–40. |
| 8. | National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. |
| 9. | Xu DM, Gietema H, de Koning H, Vernhout R, Nackaerts K, Prokop M, Weenink C, Lammers JW, Groen H, Oudkerk M, et al. Nodule management protocol of the NELSON randomised lung cancer screening trial. Lung Cancer 2006;54:177–184. |
| 10. | Ru Zhao Y, Xie X, de Koning HJ, Mali WP, Vliegenthart R, Oudkerk M. NELSON lung cancer screening study. Cancer Imaging 2011;11:S79–S84. |
| 11. | van Iersel CA, de Koning HJ, Draisma G, Mali WP, Scholten ET, Nackaerts K, Prokop M, Habbema JD, Oudkerk M, van Klaveren RJ. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch–Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer 2007;120:868–874. |
| 12. | Horeweg N, van Klaveren RJ, Groen HJ, Lammers JW, Weenink C, Nackaerts K, Mali W, Oudkerk M, de Koning HJ. Blinded and uniform cause of death verification in a lung cancer CT screening trial. Lung Cancer 2012;77:522–525. |
| 13. | Gietema HA, Wang Y, Xu D, van Klaveren RJ, de Koning H, Scholten E, Verschakelen J, Kohl G, Oudkerk M, Prokop M. Pulmonary nodules detected at lung cancer screening: interobserver variability of semiautomated volume measurements. Radiology 2006;241:251–257. |
| 14. | Wang Y, van Klaveren RJ, van der Zaag-Loonen HJ, de Bock GH, Gietema HA, Xu DM, Leusveld AL, de Koning HJ, Scholten ET, Verschakelen J, et al. Effect of nodule characteristics on variability of semiautomated volume measurements in pulmonary nodules detected in a lung cancer screening program. Radiology 2008;248:625–631. |
| 15. | van Meerbeeck JP, Koning CC, Tjan-Heijnen VC, Boekema AG, Kaandorp CJ, Burgers JS. [Guideline on “non–small cell lung carcinoma; staging and treatment”] [article in Dutch]. Ned Tijdschr Geneeskd 2005;149:72–77. |
| 16. | Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L; International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706–714. |
| 17. | Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. World Health Organization classification of tumours: pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press; 2004. |
| 18. | van’t Westeinde SC, de Koning HJ, Thunnissen FB, Oudkerk M, Groen HJ, Lammers JW, Weenink C, Vernhout R, Nackaerts K, Mali W, et al. The role of the 1F-fluorodeoxyglucose-positron emission tomography scan in the Nederlands Leuvens Longkanker Screenings Onderzoek Lung Cancer Screening Trial. J Thorac Oncol 2011;6:1704–1712. |
| 19. | van’t Westeinde SC, Horeweg N, Vernhout RM, Groen HJ, Lammers JW, Weenink C, Nackaerts K, Oudkerk M, Mali W, Thunnissen FB, et al. The role of conventional bronchoscopy in the work-up of suspicious CT screen detected pulmonary nodules. Chest 2012;142:377–384. |
| 20. | Parkash O. Lung cancer: a statistical study based on autopsy data from 1928 to 1972. Respiration 1977;34:295–304. |
| 21. | Lince L, Lulu DJ. Carcinoma of the lung: a comparative series of 687 cases. Arch Surg 1971;102:103–107. |
| 22. | Subramaniam RP, Asgharian B, Freijer JI, Miller FJ, Anjilvel S. Analysis of lobar differences in particle deposition in the human lung. Inhal Toxicol 2003;15:1–21. |
| 23. | Churg A, Stevens B. Association of lung cancer and airway particle concentration. Environ Res 1988;45:58–63. |
| 24. | Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20,561 cases. Ann Oncol 2002;13:1087–1093. |
| 25. | Sagerup CM, Smastuen M, Johannesen TB, Helland A, Brustugun OT. Sex-specific trends in lung cancer incidence and survival: a population study of 40,118 cases. Thorax 2011;66:301–307. |
| 26. | Ries L, Eisner M, Kosary C. SEER cancer statistics review 1975–2002; National Cancer Institute [accessed 2012 Sep 5]. Available from: http://seer.cancer.gov/csr/1975_2002/results_merged/sect_15_lung_bronchus.pdf |
| 27. | Schwartz KL, Crossley-May H, Vigneau FD, Brown K, Banerjee M. Race, socioeconomic status and stage at diagnosis for five common malignancies. Cancer Causes Control 2003;14:761–766. |
| 28. | Caldarella A, Crocetti E, Comin CE, Janni A, Pegna AL, Paci E. Gender differences in non–small cell lung cancer: a population-based study. Eur J Surg Oncol 2007;33:763–768. |
| 29. | Ringer G, Smith JM, Engel AM, Hendy MP, Lang J. Influence of sex on lung cancer histology, stage, and survival in a Midwestern United States tumor registry. Clin Lung Cancer 2005;7:180–182. |
| 30. | Ramos Chaves M, Boleo-Tome C, Monteiro-Grillo I, Camilo M, Ravasco P. The diversity of nutritional status in cancer: new insights. Oncologist 2010;15:523–530. |
| 31. | Parr CL, Batty GD, Lam TH, Barzi F, Fang X, Ho SC, Jee SH, Ansary-Moghaddam A, Jamrozik K, Ueshima H, et al. Body-mass index and cancer mortality in the Asia–Pacific Cohort Studies Collaboration: pooled analyses of 424,519 participants. Lancet Oncol 2010;11:741–752. |
| 32. | Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569–578. |
| 33. | Kabat GC, Wynder EL. Body mass index and lung cancer risk. Am J Epidemiol 1992;135:769–774. |
| 34. | Canoy D, Wareham N, Luben R, Welch A, Bingham S, Day N, Khaw KT. Cigarette smoking and fat distribution in 21,828 British men and women: a population-based study. Obes Res 2005;13:1466–1475. |
| 35. | American Joint Committee on Cancer. AJCC cancer staging manual, 6th ed. Chicago, IL: AJCC; 2002. pp. 167–177. |
| 36. | Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF, Dossing M, Hansen H, Kofoed KF, Larsen KR, et al. CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax 2012;67:296–301. |
| 37. | Infante M, Chiesa G, Solomon D, Morenghi E, Passera E, Lutman FR, Bottoni E, Cariboni U, Errico V, Voulaz E, et al. Surgical procedures in the DANTE trial, a randomized study of lung cancer early detection with spiral computed tomography: comparative analysis in the screening and control arm. J Thorac Oncol 2011;6:327–335. |
| 38. | Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012;21:308–315. |
| 39. | Becker N, Motsch E, Gross ML, Eigentopf A, Heussel CP, Dienemann H, Schnabel PA, Pilz L, Eichinger M, Optazaite DE, et al. Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round. J Cancer Res Clin Oncol 2012;138:1475–1486. |
Supported by Zorg Onderzoek Nederland-Medische Wetenschappen (ZonMw), KWF Kankerbestrijding, and Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ). Roche Diagnostics provided a grant for the performance of proteomics research. Siemens Germany provided four digital workstations and LungCARE for the performance of 3D measurements.
Author Contributions: Involvement in the conception, hypotheses delineation, and design of the study: N.H., C.M.v.d.A., E.T., J.v.R., H.J.d.K.; acquisition of the data or the analysis and interpretation of such information: N.H., C.M.v.d.A., E.T., K.N., C.W., H.J.M.G., J.-W.J.L., E.T.S., J.v.R., W.M., M.O., H.J.d.K.; writing the article or substantial involvement in its revision before submission: N.H., C.M.v.d.A., K.N., H.J.M.G., J.G.A., J.v.R., H.J.d.K.
This article has an online supplement, which is available from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201209-1651OC on January 24, 2013
Author disclosures are available with the text of this article at www.atsjournals.org.
