Joan E. Walter

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

BACKGROUND US guidelines now recommend lung cancer screening with low-dose CT for high-risk individuals. Reports of new nodules after baseline screening have been scarce and are inconsistent because of differences in definitions used. We aimed to identify the occurrence of new solid nodules and their probability of being lung cancer at incidence screening rounds in the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). METHODS In the ongoing, multicentre, randomised controlled NELSON trial, between Dec 23, 2003, and July 6, 2006, 15 822 participants who had smoked at least 15 cigarettes a day for more than 25 years or ten cigarettes a day for more than 30 years and were current smokers, or had quit smoking less than 10 years ago, were enrolled and randomly assigned to receive either screening with low-dose CT (n=7915) or no screening (n=7907). From Jan 28, 2004, to Dec 18, 2006, 7557 individuals underwent baseline screening with low-dose CT; 7295 participants underwent second and third screening rounds. We included all participants with solid non-calcified nodules, registered by the NELSON radiologists as new or smaller than 15 mm(3) (study detection limit) at previous screens. Nodule volume was generated semiautomatically by software. We calculated the maximum volume doubling time for nodules with an estimated percentage volume change of 25% or more, representing the minimum growth rate for the time since the previous scan. Lung cancer diagnosis was based on histology, and benignity was based on histology or stable size for at least 2 years. The NELSON trial is registered at trialregister.nl, number ISRCTN63545820. FINDINGS We analysed data for participants with at least one solid non-calcified nodule at the second or third screening round. In the two incidence screening rounds, the NELSON radiologists registered 1222 new solid nodules in 787 (11%) participants. A new solid nodule was lung cancer in 49 (6%) participants with new solid nodules and, in total, 50 lung cancers were found, representing 4% of all new solid nodules. 34 (68%) lung cancers were diagnosed at stage I. Nodule volume had a high discriminatory power (area under the receiver operating curve 0·795 [95% CI 0·728-0·862]; p<0·0001). Nodules smaller than 27 mm(3) had a low probability of lung cancer (two [0·5%] of 417 nodules; lung cancer probability 0·5% [95% CI 0·0-1·9]), nodules with a volume of 27 mm(3) up to 206 mm(3) had an intermediate probability (17 [3·1%] of 542 nodules; lung cancer probability 3·1% [1·9-5·0]), and nodules of 206 mm(3) or greater had a high probability (29 [16·9%] of 172 nodules; lung cancer probability 16·9% [12·0-23·2]). A volume cutoff value of 27 mm(3) or greater had more than 95% sensitivity for lung cancer. INTERPRETATION Our study shows 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 size. These findings should be considered in future screening guidelines, and new solid nodules should be followed up more aggressively than nodules detected at baseline screening. FUNDING Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds Kankerbestrijding.

Risk stratification based on screening history: the NELSON lung cancer screening study

Background Debate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts the screening outcome (test result and lung cancer risk) of the final screening round. Methods 15 792 participants were randomised (1:1) of which 7900 randomised into a screening group. CT screening took place at baseline, and after 1, 2 and 2.5 years. Initially, three screening outcomes were possible: negative, indeterminate or positive scan result. Probability for screening outcome in the fourth round was calculated for subgroups of participants. Results Based on results of the first three rounds, three subgroups were identified: (1) those with exclusively negative results (n=3856; 73.0%); (2) those with ≥1 indeterminate result, but never a positive result (n=1342; 25.5%); and (3) with ≥1 positive result (n=81; 1.5%). Group 1 had the highest probability for having a negative scan result in round 4 (97.2% vs 94.8% and 90.1%, respectively, p<0.001), and the lowest risk for detecting lung cancer in round 4 (0.6% vs 1.6%, p=0.001). ‘Smoked pack-years’ and ‘screening history’ significantly predicted the fourth round test result. The third round results implied that the risk for detecting lung cancer (after an interval of 2.5 years) was 0.6% for those with negative results compared with 3.7% of those with indeterminate results. Conclusions Previous CT lung cancer screening results provides an opportunity for further risk stratifications of those who undergo lung cancer screening. Trial registration number Results, ISRCTN63545820.

Management of baseline and new sub-solid nodules in CT lung cancer screening

While reading thoracic CT examinations, three different subtypes of pulmonary nodules are differentiated based on the nodule’s density. Until now, most existing evidence concentrated on solid lung nodules. However, in recent years gradually more studies are published focusing on subsolid nodules including pure ground-glass (nonsolid) nodules (GGNs) and part-solid nodules. A GGN is defined as a circumscribed area of increased pulmonary attenuation with preservation of the bronchial and vascular margins. When part of the groundglass opacity completely obscures the parenchyma, the nodule is defined as part solid. In baseline rounds of CT lung cancer screening, part-solid nodules comprise a higher risk of malignancy than do solid nodules [1]. Management of subsolid nodules in lung cancer screening trials and incidentally detected subsolid nodules in clinical practice is based on nodule size and growth [2]. In most guidelines, no differentiation is made between subsolid nodules already present at a previous CT examination and new subsolid nodules. Recently, it was shown that new solid nodules detected in CT lung cancer screening have a significantly higher lung cancer probability at smaller nodule size compared to baseline solid nodules and need lower size cutoffs [3]. Some guidelines, such as the British Thoracic Society (BTS) guideline and Lung-RADS, have incorporated the higher malignancy risk in solid new nodules [4,5]. However, the question remains whether new subsolid nodules should be followed more aggressively as well.

Small pulmonary nodules in baseline and incidence screening rounds of low-dose CT lung cancer screening

Currently, lung cancer screening by low-dose computed tomography (LDCT) is widely recommended for high-risk individuals by US guidelines, but there still is an ongoing debate concerning respective recommendations for European countries. Nevertheless, the available data regarding pulmonary nodules released by lung cancer screening studies could improve future screening guidelines, as well as the clinical practice of incidentally detected pulmonary nodules on routine CT scans. Most lung cancer screening trials present results for baseline and incidence screening rounds separately, clustering pulmonary nodules initially found at baseline screening and newly detected pulmonary nodules after baseline screening together. This approach does not appreciate possible differences among pulmonary nodules detected at baseline and firstly detected at incidence screening rounds and is heavily influenced by methodological differences of the respective screening trials. This review intends to create a basis for assessing non-calcified pulmonary nodules detected during LDCT lung cancer screening in a more clinical relevant manner. The aim is to present data of non-calcified pulmonary baseline nodules and new non-calcified pulmonary incident nodules without clustering them together, thereby also simplifying translation to the clinical practice of incidentally detected pulmonary nodules. Small pulmonary nodules newly detected at incidence screening rounds of LDCT lung cancer screening may possess a greater lung cancer probability than pulmonary baseline nodules at a smaller size, which is essential for the development of new guidelines.

Disagreement of diameter and volume measurements for pulmonary nodule size estimation in CT lung cancer screening

We studied 2240 indeterminate solid nodules (volume 50–500mm3) to determine the correlation of diameter and semi-automated volume measurements for pulmonary nodule size estimation. Intra-nodular diameter variation, defined as maximum minus minimum diameter through the nodule’s center, varied by 2.8 mm (median, IQR:2.2–3.7 mm), so above the 1.5 mm cutoff for nodule growth used in Lung CT Screening Reporting and Data System (Lung-RADS). Using mean or maximum axial diameter to assess nodule volume led to a substantial mean overestimation of nodule volume of 47.2% and 85.1%, respectively, compared to semi-automated volume. Thus, size of indeterminate nodules is poorly represented by diameter. Trial registration number Pre-results, ISRCTN63545820.

Influence of lung nodule margin on volume- and diameter-based reader variability in CT lung cancer screening

OBJECTIVE: To evaluate the influence of nodule margin on inter- and intrareader variability in manual diameter measurements and semi-automatic volume measurements of solid nodules detected in low-dose CT lung cancer screening. METHODS: 25 nodules of each morphological category (smooth, lobulated, spiculated and irregular) were randomly selected from 93 participants of the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). Semi-automatic volume measurements were performed using Syngo LungCARE® software (Version Somaris/5 VB10A-W, Siemens, Forchheim, Germany). Three radiologists independently measured mean diameters manually. Impact of nodule margin on interreader variability was evaluated based on systematic error and 95% limits of agreement. Interreader variability was compared with the nodule growth cut-off as used in Lung CT Screening Reporting and Data System (LungRADS; +1.5-mm diameter) and the Dutch-Belgian Randomized Lung Cancer Screening Trial(acronym: NELSON) /British Thoracic Society (+25% volume). RESULTS: For manual diameter measurements, a significant systematic error (up to 1.2 mm) between readers was found in all morphological categories. For semi-automatic volume measurements, no statistically significant systematic error was found. The interreader variability in mean diameter measurements exceeded the 1.5-mm cut-off for nodule growth for all morphological categories [smooth: ±1.9 mm (+27%), lobulated: ±2.0 mm (+33%), spiculated: ±3.5 mm (+133%), irregular: ±4.5 mm (+200%)]. The 25% vol growth cut-off was exceeded slightly for spiculated [28% (+12%)] and irregular [27% (+8%)] nodules. CONCLUSION: Lung nodule sizing based on manual diameter measurement is affected by nodule margin. Interreader variability increases especially for nodules with spiculated and irregular margins, and causes substantial misclassification of nodule growth. This effect is almost neglectable for semi-automated volume measurements. Semi-automatic volume measurements are superior for both size and growth determination of pulmonary nodules. ADVANCES IN KNOWLEDGE: Nodule assessment based on manual diameter measurements is susceptible to nodule margin. This effect is almost neglectable for semi-automated volume measurements. The larger interreader variability for manual diameter measurement results in inaccurate lung nodule growth detection and size classification.

Relationship between nodule count and lung cancer probability in baseline CT lung cancer screening: The NELSON study

OBJECTIVES To explore the relationship between nodule count and lung cancer probability in baseline low-dose CT lung cancer screening. MATERIALS AND METHODS Included were participants from the NELSON trial with at least one baseline nodule (3392 participants [45% of screen-group], 7258 nodules). We determined nodule count per participant. Malignancy was confirmed by histology. Nodules not diagnosed as screen-detected or interval cancer until the end of the fourth screening round were regarded as benign. We compared lung cancer probability per nodule count category. RESULTS 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had>4 nodules. Lung cancer in a baseline nodule was diagnosed in 134 participants (139 cancers; 4.0%). Median nodule count in participants with only benign nodules was 1 (Inter-quartile range [IQR]: 1-2), and 2 (IQR 1-3) in participants with lung cancer (p=NS). At baseline, malignancy was detected mostly in the largest nodule (64/66 cancers). Lung cancer probability was 62/1746 (3.6%) in case a participant had one nodule, 33/800 (4.1%) for two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) for>4 nodules (p=NS). CONCLUSION In baseline lung cancer CT screening, half of participants with lung nodules have more than one nodule. Lung cancer probability does not significantly change with the number of nodules. Baseline nodule count will not help to differentiate between benign and malignant nodules. Each nodule found in lung cancer screening should be assessed separately independent of the presence of other nodules.

Characteristics of new solid nodules detected in incidence screening rounds of low-dose CT lung cancer screening: the NELSON study

Purpose New nodules after baseline are regularly found in low-dose CT lung cancer screening and have a high lung cancer probability. It is unknown whether morphological and location characteristics can improve new nodule risk stratification by size. Methods Solid non-calcified nodules detected during incidence screening rounds of the randomised controlled Dutch-Belgian lung cancer screening (NELSON) trial and registered as new or previously below detection limit (15 mm3) were included. A multivariate logistic regression analysis with lung cancer as outcome was performed, including previously established volume cut-offs (<30 mm3, 30–<200 mm3 and ≥200 mm3) and nodule characteristics (location, distribution, shape, margin and visibility <15 mm3 in retrospect). Results Overall, 1280 new nodules were included with 73 (6%) being lung cancer. Of nodules ≥30 mm3 at detection and visible <15 mm3 in retrospect, 22% (6/27) were lung cancer. Discrimination based on volume cut-offs (area under the receiver operating characteristic curve (AUC): 0.80, 95% CI 0.75 to 0.84) and continuous volume (AUC: 0.82, 95% CI 0.77 to 0.87) was similar. After adjustment for volume cut-offs, only location in the right upper lobe (OR 2.0, P=0.012), central distribution (OR 2.4, P=0.001) and visibility <15 mm3 in retrospect (OR 4.7, P=0.003) remained significant predictors for lung cancer. The Hosmer-Lemeshow test (P=0.75) and assessment of bootstrap calibration curves indicated adequate model fit. Discrimination based on the continuous model probability (AUC: 0.85, 95% CI 0.81 to 0.89) was superior to volume cut-offs alone, but when stratified into three risk groups (AUC: 0.82, 95% CI 0.78 to 0.86), discrimination was similar. Conclusion Contrary to morphological nodule characteristics, growth-independent characteristics may further improve volume-based new nodule lung cancer prediction, but in a three-category stratification approach, this is limited. Trial registration number ISRCTN63545820; pre-results.

Relationship between the number of new nodules and lung cancer probability in incidence screening rounds of CT lung cancer screening: The NELSON study

BACKGROUND New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participants number of new nodules and lung cancer probability is unknown. METHODS Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participants new nodule count and the largest new nodule size was assessed using Spearmans rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed. RESULTS In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8-13%) or >1 new nodule (6% [9/154], 95%CI 3-11%, P = .116). An increased number of new nodules positively correlated with a participants largest nodule size (P < 0.001, Spearmans rho 0.177). When adjusted for largest new nodule size, the new nodule count had a significant negative association with lung cancer (odds ratio 0.59, 0.37-0.95, P = .03). CONCLUSION A participants new nodule count alone only has limited association with lung cancer. However, a higher new nodule count correlates with an increased largest new nodule size, while the lung cancer probability remains equivalent, and may improve lung cancer risk prediction by size only.

New Subsolid Pulmonary Nodules in Lung Cancer Screening: The NELSON Trial

Introduction: Low‐dose computed tomography (LDCT) lung cancer screening is recommended in the United States. While new solid nodules after baseline screening have a high lung cancer probability at small size and require lower size cutoff values than baseline nodules, there only is limited evidence on management of new subsolid nodules. Methods: Within the Dutch‐Belgian randomized controlled LDCT lung cancer screening trial (NELSON), 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new subsolid nodules detected after the baseline screening round were included. Results: In the three incidence screening rounds, 60 new subsolid nodules (43 [72%] part‐solid, 17 [28%] nonsolid) not visible in retrospect were detected in 51 participants, representing 0.7% (51 of 7295) of participants with at least one incidence screening. Eventually, 6% (3 of 51) of participants with a new subsolid nodule were diagnosed with (pre‐)malignancy in such a nodule. All (pre‐)malignancies were adenocarcinoma (in situ) and diagnostic workup (referral 950, 364, and 366 days after first detection, respectively) showed favorable staging (stage I). Overall, 67% (33 of 49) of subsolid nodules with an additional follow‐up screening were resolving. Conclusions: Less than 1% of participants in LDCT lung cancer screening presents with a new subsolid nodule after baseline. Contrary to new solid nodules, data suggest that new subsolid nodules may not require a more aggressive follow‐up.