Elsevier

The Lancet Oncology

Volume 15, Issue 12, November 2014, Pages 1342-1350
The Lancet Oncology

Articles
Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers

https://doi.org/10.1016/S1470-2045(14)70387-0Get rights and content

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.

Introduction

Until the 1990s, no effective screening test for lung cancer was available. Screening studies using sputum cytology or chest radiography did not show a significant reduction in lung cancer mortality. In the 1990s, cohort studies using low-dose CT as a lung cancer screening test were initiated.1, 2, 3 Low-dose CT seemed to be able to detect more and smaller lung cancers than chest radiography, with most being diagnosed at stage I.4, 5, 6 Moreover, survival in patients with screen-detected lung cancer was impressive. Findings from the National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality using low-dose CT compared with screening using chest radiography.7 The CISNET lung cancer working group modelled and assessed hundreds of screening scenarios using data from NLST; 26 selected efficient screening scenarios led to reductions in lung cancer mortality of between 4·6% and 21·2%.8 As a result, the US Preventive Services Task Force and medical societies recommended annual low-dose CT screening in the USA for people at high risk of developing lung cancer.8, 9, 10 However, no reduction in lung cancer mortality with an annual low-dose CT screening strategy has been reported in three smaller European trials,11, 12, 13 and results of several larger European trials are still awaited. In many European countries, the outcome of the NELSON trial or pooled analyses is awaited before a decision about implementation of a national service lung cancer screening programme is made.

Efficacy and acceptance of low-dose CT screening for lung cancer depends on the sensitivity of the screening test (ie, the risk of not detecting a lung cancer through screening). Lung cancers not detected by screening but diagnosed during the screening interval, known as interval cancers, might have been missed at screening or might have developed between screening and detection. Few studies about the incidence and characteristics of interval cancers in lung cancer screening have been reported.11, 14, 15, 16 None of these studies assessed causes of interval cancers, or whether improvements to the screening algorithm were possible.

The NELSON trial is a randomised trial to assess whether low-dose CT screening with an increasing length of screening interval (1, 2, and 2·5 years) compared with no screening reduces lung cancer mortality.17, 18 In this prespecified analysis, we aimed to assess the performance of the screening test to detect interval cancers, and provide insights into the incidence, histopathology, and causes for failed detection of these cancers.

Section snippets

Study design and participants

Individuals from four centres in the Netherlands and Belgium were enrolled and randomly assigned to receive low-dose CT screening or no screening. Eligible participants were adults aged 50–75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes per day for more than 30 years, and were still smoking or had stopped smoking less than 10 years previously. People with self-reported moderate or bad health (first question of SF-36), inability to climb

Results

Between Dec 23, 2003, and July 6, 2006, 15 822 individuals from four centres in the Netherlands and Belgium were enrolled and randomly assigned to receive low-dose CT screening (n=7915) or no screening (n=7907). For this prespecified analysis, we excluded the 7907 participants randomly assigned to the no screening group, the 477 participants from Belgium (because no data were yet available from the Belgian cancer registry), and 283 participants who did not attend their screening examinations

Discussion

In this study, we assessed the epidemiological, radiological, and clinical characteristics of screen-detected and interval lung cancers in the NELSON trial. 187 (3%) of the 7155 participants studied were diagnosed with lung cancer detected by screening, and another 34 (<1%) participants were diagnosed with interval lung cancer. Overall, sensitivity was about 85%, specificity about 99%, positive predictive value about 40%, and negative predictive value greater than 99%. Retrospectively, about a

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