Abstract
BACKGROUND: Prospective validation and comparison of the performance of nodule management protocols is limited. The aim of this study was to examine the performance of size and risk thresholds for assessing malignancy in solid nodules at baseline low-dose CT (LDCT) in a lung cancer screening (LCS) programme. METHODS: This was an observational study using data from the SUMMIT Study, a prospective longitudinal study investigating LDCT for LCS. Participants were 55-77 years old and met either the United States Preventative Services Task Force (2013) criteria or had a PLCO(m2012) risk of ≥1.3%. LDCTs were reported using computer-aided detection software (Veolity, MeVIS) with semiautomated volumetry. Cancer outcomes were reported for solid nodules reported at baseline CT, with participants represented by the single largest solid nodule where more than one was present. Malignancy risk was stratified by long-axis diameter and volume using predefined size thresholds taken from British Thoracic Society and European Position statement guidelines: a 5/6 mm long axis diameter or 80/100 mm(3) volume 'rule out' thresholds for low-risk nodules and ≥300 mm(3) or ≥8 mm diameter with or without Brock score ≥10% 'Rule in' thresholds for high-risk nodules.Pearson's χ(2) test was used to calculate statistical significance for nominal variables, McNemar's test for comparison of sensitivity/specificity and DeLong' test for comparison of areas under the receiver operating characteristic curve (AUROC). Optimal thresholds were determined with Youden's J statistic. Net benefit calculations were undertaken to compare the existing thresholds with 95% CIs calculated by bootstrap sampling. RESULTS: 11 355 participants were included. Crude risk of malignancy in solid nodules at baseline LDCT was 3.8% (228/5929). Risk of malignancy in solid nodules <6 mm long-axis diameter or <100 mm(3) volume was equivalent to that in participants with no nodules at baseline LDCT (0.88% and 0.84% vs 0.77%, p=0.4600 and p=0.7932, respectively). A <80 mm(3) volume and <5 mm diameter 'rule out' threshold achieved sensitivity 86.8% and 93.4%, specificity 65.4% and 24.64%, and negative predictive value (NPV) 99.2% and 98.9%, respectively. The <80 mm(3) volume threshold encompassed 63.3% of participants with a baseline solid nodule compared with 24.0% by the <5 mm diameter threshold.For nodules ≥8 mm diameter, the addition of a risk score (Brock ≥10%) was associated with a significant net benefit when compared with using size threshold alone by net effect analysis (31.24; 95% CI 26.19 to 35.89). CONCLUSIONS: Solid nodules <100 mm(3) or <6 mm diameter are not associated with increased risk of lung cancer compared with participants with no nodules at baseline LDCT. Volumetric rule-out thresholds achieve equivalent NPV to long-axis diameter thresholds while encompassing significantly more participants, reducing the number of interval scans required.