Trial Oversight

The trial was approved by the Dutch Minister of Health and the medical ethics committee at each participating site.10 Conceptualization of the trial, funding acquisition, data collection and curation, analysis of the primary outcome, the writing of the first draft of the manuscript, and revision of the manuscript based on review comments were performed by Erasmus MC and University Medical Center Groningen (UMCG). CT screening and follow-up were performed by the four screening sites (UMCG, University Medical Center Utrecht, Spaarne Gasthuis, and University Hospital Leuven). An independent cause-of-death committee defined the cause of death for some of the deceased participants (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Data on workup, cancer diagnosis and stage, treatment, vital status, and cause of death were obtained through linkages with the Dutch Center for Genealogic and Heraldic Studies, Statistics Netherlands, and the Dutch Cancer Registry. Primary outcome data were kept confidential until unblinding. None of the funders had any role in the trial design, the collection or analysis of the data, or the writing of the manuscript. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol (available at NEJM.org). No one who is not an author contributed to the writing of the manuscript.

Power Calculation and Eligibility Criteria

An overview of the previously published power calculation and trial design is available in the Supplementary Appendix.11-13 The preferred risk-based selection scenario (scenario D11) required 17,300 to 27,900 participants (current or former smokers [those who had quit ≤10 years ago] who had smoked >15 cigarettes a day for >25 years or >10 cigarettes a day for >30 years) to show a lung-cancer mortality that was lower by 20 to 25% in the screening group than in the control group at 10 years of follow-up, given the following conditions: one-sided testing, based on experience with the European Randomized Study of Screening for Prostate Cancer (two-sided testing was used for the final analyses); 90% power; 95% adherence in the screening group; 5% contamination (i.e., lung-cancer screening) in the control group; and an expected lung-cancer mortality of 3.4 per 1000 person-years without screening at 10 years of follow-up.11 Exclusion criteria were patient report of moderate or severe health problems and an inability to climb two flights of stairs; a body weight of more than 140 kg; current or past renal cancer, melanoma, or breast cancer; a diagnosis of lung cancer or treatment related to lung cancer within the past 5 years; or a chest CT scan within the past year.11,12 A current smoker was defined as a person who had smoked cigarettes during the last 2 weeks.

The trial focused on men (see the Supplementary Appendix).11 At the time of initiation (2000 through 2004), only a small number of women were eligible, because smoking was much less prevalent and much less intensive among women than among men. Because of the importance of the inclusion of women, a sample of high-risk women was approached for participation.

Recruitment

On the basis of population registries, 606,409 persons 50 to 74 years of age who lived in four selected regions in the Netherlands and Belgium were approached with a general questionnaire and brief information about the trial in 2003 (first recruitment) or 2005 (second recruitment) (see the Supplementary Appendix, including Fig. S2).14 A total of 30,959 respondents of the 150,920 who returned questionnaires were eligible. Eligible persons were invited to participate; 15,822 persons (51.1%), who provided written informed consent, underwent the initial randomization (in a 1:1 ratio) from December 2003 through July 2006 (median randomization date, November 2004) (Fig. S7).11,13,14 After linkage with Statistics Netherlands and the Dutch Center for Genealogic and Heraldic Studies, 30 participants had died after providing informed consent and before the randomization date, which resulted in 15,792 formal participants (13,195 men, 2594 women, and 3 participants with unknown sex) (Table S1).

Screening Rounds and Nodule-Management Protocol

The screening rounds and the nodule-management protocol have been described previously (summarized in Fig. S8).13,15-19 In short, from January 2004 through December 2012, participants in the screening group were invited to undergo four rounds of low-dose CT screening for lung cancer that were performed in the four CT screening sites with intervals of 1, 2, and 2.5 years.

For CT screening, low-dose 16-multidetector or, in later rounds, 64-multidetector CT systems were used to acquire isotropic volume data, without administration of contrast medium. Apart from local readings, all images were analyzed centrally at UMCG with the use of semiautomated software (LungCare, version Somaris/5 VA70C-W, Siemens Medical Solutions). The analysis included the semiautomated segmentation of nodules and determination of the nodule volume.20 If the software was not able to segment a nodule accurately, the volume was corrected manually by the radiologist.21 Depending on the volume and volume-doubling time, a screening could be negative, indeterminate, or positive (Fig. S8). Participants in the control group underwent no screening.

Follow-up Data

Follow-up data were retrieved from national linkages at approximately 5, 7, and 10 to 11 years of complete follow-up. A total of 18 persons (13 men and 5 women) could not be linked, because a digital consent form could not be retrieved. Population data were available regarding randomization date, sex, date of lung-cancer diagnosis, and date and cause of death for all deceased Belgian persons up to December 2013 and September 2018 through linkages in January 2016 and October 2018, respectively.

Cause-of-Death Review

The primary outcome of the NELSON trial was lung cancer–specific mortality. A clinical expert committee was formed to assign the cause of death by an evaluation process using a flow chart and predetermined criteria.22 A total of 296 completed and blinded medical files of 426 deceased Dutch male patients with lung cancer (69.5%) were reviewed and compared with official death certificates (cutoff, 10 years of follow-up or December 31, 2015). The overall concordance among members of the expert committee was 86.1%. The sensitivity and specificity of the official death certificate were 92.6% and 98.8%, respectively.23 Death from lung cancer was considered valid only if the expert committee had concluded that lung cancer was the cause of death. The international mortality advisory committee deemed possible biases to be relatively small and agreed on further use of official statistics for the primary outcome, if lung cancer as the cause of death was recorded in the national registry for vital statistics.

Statistical Analysis

The primary analysis of the trial consisted of a comparison of lung-cancer mortality between the screening group and the control group (main analysis, men; subanalyses, women), according to the intention-to-screen principle. Specifically, the rate ratio for death from lung cancer was compared between the two groups; the rate ratio was derived as the ratio of event rates, under the assumption of a Poisson distribution for the number of events (two-sided test). Secondary analyses compared all-cause mortality and the incidence of first recorded diagnosis of lung cancer between the two groups. The date of censoring of data for first recorded lung cancer, death from lung cancer, and death from any cause was December 31, 2015, or 10 years of follow-up since randomization (whichever came first). Event rates were defined as the ratio of the number of events to the person-years at risk for the event. For the incidence of first recorded lung cancer, person-years were measured from the time of randomization to the date of diagnosis of lung cancer, death, or censoring of data (whichever came first); for mortality, person-years were measured from the time of randomization to the date of death or censoring of data (whichever came first). Previously published definitions are summarized in the Supplementary Appendix.13,15,16

Continuous variables are presented as means and standard deviations (normal distribution) or as medians, interquartile ranges, and ranges (skewed distribution). Differences in distributions of baseline characteristics of participants in the screening group and participants in the control group were analyzed with the use of Pearson’s chi-square test for nominal or categorical variables and the Mann–Whitney test for ordinal or continuous variables with a nonnormal distribution. Analyses were performed with the use of Stata software, R statistical packages, and SPSS software, version 25. Exact methods were used to calculate confidence intervals for the rate ratios. P values were calculated with the use of two-sided exact tests; a P value of less than 0.05 was considered to indicate statistical significance. No corrections for multiple comparisons were included. Missing data for the primary outcome were negligible owing to the linkages with the national registries (>98% coverage).