Summary 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 mm3 (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 mm3 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 mm3 up to 206 mm3 had an intermediate probability (17 3·1% of 542 nodules; lung cancer probability 3·1% 1·9–5·0), and nodules of 206 mm3 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 mm3 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.
Summary Background Low-dose CT screening is recommended for individuals at high risk of developing lung cancer. However, CT screening does not detect all lung cancers: some might be missed at ...screening, and others can develop in the interval between screens. The NELSON trial is a randomised trial to assess the effect of screening with increasing screening intervals on lung cancer mortality. In this prespecified analysis, we aimed to assess screening test performance, and the epidemiological, radiological, and clinical characteristics of interval cancers in NELSON trial participants assigned to the screening group. Methods Eligible participants in the NELSON trial were those aged 50–75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes for more than 30 years, and were still smoking or had quit less than 10 years ago. We included all participants assigned to the screening group who had attended at least one round of screening. Screening test results were based on volumetry using a two-step approach. Initially, screening test results were classified as negative, indeterminate, or positive based on nodule presence and volume. Subsequently, participants with an initial indeterminate result underwent follow-up screening to classify their final screening test result as negative or positive, based on nodule volume doubling time. We obtained information about all lung cancer diagnoses made during the first three rounds of screening, plus an additional 2 years of follow-up from the national cancer registry. We determined epidemiological, radiological, participant, and tumour characteristics by reassessing medical files, screening CTs, and clinical CTs. The NELSON trial is registered at www.trialregister.nl , number ISRCTN63545820. Findings 15 822 participants were enrolled in the NELSON trial, of whom 7915 were assigned to low-dose CT screening with increasing interval between screens, and 7907 to no screening. We included 7155 participants in our study, with median follow-up of 8·16 years (IQR 7·56–8·56). 187 (3%) of 7155 screened participants were diagnosed with 196 screen-detected lung cancers, and another 34 (<1%; 19 56% in the first year after screening, and 15 44% in the second year after screening) were diagnosed with 35 interval cancers. For the three screening rounds combined, with a 2-year follow-up, sensitivity was 84·6% (95% CI 79·6–89·2), specificity was 98·6% (95% CI 98·5–98·8), positive predictive value was 40·4% (95% CI 35·9–44·7), and negative predictive value was 99·8% (95% CI 99·8–99·9). Retrospective assessment of the last screening CT and clinical CT in 34 patients with interval cancer showed that interval cancers were not visible in 12 (35%) cases. In the remaining cases, cancers were visible when retrospectively assessed, but were not diagnosed because of radiological detection and interpretation errors (17 50%), misclassification by the protocol (two 6%), participant non-compliance (two 6%), and non-adherence to protocol (one 3%). Compared with screen-detected cancers, interval cancers were diagnosed at more advanced stages (29 83% of 35 interval cancers vs 44 22% of 196 screen-detected cancers diagnosed in stage III or IV; p<0·0001), were more often small-cell carcinomas (seven 20% vs eight 4%; p=0·003) and less often adenocarcinomas (nine 26% vs 102 52%; p=0·005). Interpretation Lung cancer screening in the NELSON trial yielded high specificity and sensitivity, with only a small number of interval cancers. The results of this study could be used to improve screening algorithms, and reduce the number of missed cancers. Funding Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.
Summary Background The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds ...for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols. Methods Eligible participants in the NELSON trial were those aged 50–75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl , number ISRCTN63545820. Findings Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm3 or smaller (0·6% 95% CI 0·4–0·8) or maximum transverse diameter smaller than 5 mm (0·4% 0·2–0·7), and not significantly different from participants without nodules (0·4% 0·3–0·6, p=0·17 and p=1·00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100–300 mm3 (2·4% 95% CI 1·7–3·5) or a diameter 5–10 mm (1·3% 1·0–1·8). Volume doubling time further stratified the probabilities: 0·8% (95% CI 0·4–1·7) for volume doubling times 600 days or more, 4·0% (1·8–8·3) for volume doubling times 400–600 days, and 9·9% (6·9–14·1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm3 or bigger (16·9% 95% CI 14·1–20·0) or diameters 10 mm or bigger (15·2% 12·7–18·1). The simulated ACCP management protocol yielded a sensitivity and specificity of 90·9% (95% CI 81·2–96·1), and 87·2% (86·4–87·9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92·4% 95% CI 83·1–97·1), and a higher specificity (90·0% 89·3–90·7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90·9% 95% CI 81·2–96·1), and a higher specificity (94·9% 94·4–95·4). Interpretation Small nodules (those with a volume <100 mm3 or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm3 or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100–300 mm3 or diameter of 5–10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol. Funding Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.
Highlights • Exponential growth is assumed for lung cancer but has never been quantified in-vivo. • Growth patterns of 47 screen-detected solid lung cancers were quantified. • Lung cancer growth ...could be described by an exponential function with excellent fit. • Therefore, volume-doubling time can be used to describe growth of pulmonary nodules.
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