ES 02.01 The Dutch-Belgian Lung Cancer Screening Trial (NELSON)

Abstract

Lung cancer is the most important tobacco-related health problem worldwide, accounting for an estimated 1.3 million deaths each year, representing 28% of all deaths from cancer. Lung cancer screening aims to reduce lung cancer-related mortality with relatively limited harm through early detection and treatment. The US National Lung Screening Trial showed that individuals randomly assigned to screening with low-dose CT scans had 20% lower lung cancer mortality than did those screened with conventional chest radiography. On the basis of a review of the literature and a modelling study, the US Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer for high-risk individuals. However, the balance between benefits and harms of lung cancer screening is still greatly debated. Some investigators suggest the ratio between benefits and harms could be improved through various means. Nevertheless, many questions remain with regard to the implementation of lung cancer screening. Whether nationally implemented programs can provide similar levels of quality as achieved in these trials remains unclear. The NELSON trial is Europe’s largest running lung cancer screening trial. The main purposes of this trial are: (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. The NELSON trial was set up in 2003 in which subjects with high risk for lung cancer were selected from the general population. After informed consent, 15,792 participants were randomized (1:1) to the screen arm (n = 7,900) or the control arm (n=7,892). Screen arm participants received CT-screening at baseline, after 1 year, after 2 years and after 2,5 years. Control arm participants received usual care (no screening). In the NELSON trial a unique nodule management protocol was used. According to the size and volume doubling time of the nodules, initially three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Those with an indeterminate scan result received a follow-up scan in order to classify the final result as positive or negative. All scans were accomplished at the end of 2012. The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. The cumulative lung cancer detection rate is 3.2% which is comparable with the Danish Lung Cancer Screening Trial (DLCST). Relative to the National Lung Screening Trial (NLST), more lung cancers were found in the NELSON: 3.2% vs. 2.4%. However, the NLST had less screening rounds and a different nodule management protocol and a different study population. False-positive rate after a positive screen result of the NELSON is 59.4%. The overall false-positive (over four rounds) is 1.2% in the NELSON study, which is lower compared to other lung cancer screening studies. A 2-year interval did not lead to significantly more advanced stage lung cancers compared with a 1-year interval (p=0.09). However, a 2.5-year interval led to a stage shift in screening-detected cancers that was significantly less favorable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). It also led to significantly higher proportions of squamous-cell carcinoma, boncho-alveolar carcinoma, and small-cell carcinoma (p<0.001). Compared with a 2-year screening interval, there was a similar tendency towards unfavorable change in stage distribution for a 2.5-year screening interval although this did not reach statistical significance. Also, the interval cancer rate was 1.47(28/19) times higher in the 2.5-year interval compared with the 2-year interval. Moreover, in the last six months before the final fourth screening round the interval rate was 1.3(16/12) times higher than in the first 24 months after the third round, suggesting that a 2.5-year interval may be too long. On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. This cumulative stage distribution of the screening-detected lung cancers in the NELSON trial appears to be favorable compared to those of the DLCST and the NLST (68.1% and 61.6% of cancers at stage I, and 15.9% and 20.0% at stage IIIb/IV, respectively).However, this finding should be interpreted with caution because 1) the NLST used the 6th edition of the TNM staging system, while the NELSON trial used the 7th edition, 2) the NLST and DLCST applied different eligibility criteria than the NELSON trial, and 3) the proportion of over-diagnosed lung cancers in the screening group is yet unknown. The lung cancers found in the NELSON control group have yet to be investigated. Lung cancer; screening; Europe's largest running trial