title: Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.
authors.affiliation: Department of Public Health, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: n.horeweg@erasmusmc.nl.
authors.forename: Nanda
authors.initials: N
authors.lastname: Horeweg
authors.affiliation: Department of Radiology, Kennemer Gasthuis, Haarlem, Netherlands; Department of Pulmonary Medicine, Kennemer Gasthuis, Haarlem, Netherlands.
authors.forename: Ernst Th
authors.initials: ET
authors.lastname: Scholten
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Pim A
authors.initials: PA
authors.lastname: de Jong
authors.affiliation: Department of Public Health, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Carlijn M
authors.initials: CM
authors.lastname: van der Aalst
authors.affiliation: Department of Pulmonary Medicine, Kennemer Gasthuis, Haarlem, Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Weenink
authors.affiliation: Department of Pulmonary Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jan-Willem J
authors.initials: JW
authors.lastname: Lammers
authors.affiliation: Department of Pulmonary Medicine, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Nackaerts
authors.affiliation: Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Center for Medical Imaging-North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Rozemarijn
authors.initials: R
authors.lastname: Vliegenthart
authors.affiliation: Department of Public Health, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: ten Haaf
authors.affiliation: Department of Public Health, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Uraujh A
authors.initials: UA
authors.lastname: Yousaf-Khan
authors.affiliation: Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Center for Medical Imaging-North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: Heuvelmans
authors.affiliation: Department of Pathology, VU Medical Center, Amsterdam, Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.affiliation: Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Center for Medical Imaging-North East Netherlands, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Oudkerk
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Mali
authors.affiliation: Department of Public Health, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: de Koning
mesh_terms: D000368:Aged; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects; D014057:Tomography, X-Ray Computed