A comparative analysis of heterogeneity in lung cancer screening effectiveness in two randomised controlled trials

Max Welz (), Carlijn M. Aalst, Andreas Alfons, Andrea A. Naghi, Marjolein A. Heuvelmans, Harry J. M. Groen, Pim A. Jong, Joachim Aerts, Matthijs Oudkerk, Harry J. Koning and Kevin Haaf ()
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Max Welz: Erasmus MC–University Medical Center Rotterdam
Carlijn M. Aalst: Erasmus MC–University Medical Center Rotterdam
Andreas Alfons: Erasmus University Rotterdam
Andrea A. Naghi: Erasmus University Rotterdam
Marjolein A. Heuvelmans: Department of Epidemiology
Harry J. M. Groen: Rijksuniversiteit Groningen
Pim A. Jong: University Medical Center Utrecht
Joachim Aerts: Erasmus MC–University Medical Center Rotterdam
Matthijs Oudkerk: Institute for Diagnostic Accuracy
Harry J. Koning: Erasmus MC–University Medical Center Rotterdam
Kevin Haaf: Erasmus MC–University Medical Center Rotterdam

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Clinical trials demonstrate that screening can reduce lung cancer mortality by over 20%. However, lung cancer screening effectiveness (reduction in lung cancer specific mortality) may vary by personal risk-factors. Here we evaluate heterogeneity in lung cancer screening effectiveness through traditional sub-group analyses, predictive modelling approaches and machine-learning in individual-level data from the Dutch-Belgian lung cancer screening trial (NELSON; 14,808 participants, 12,429 men, 2377 women, 2 persons with an unknown sex) and the National Lung Screening Trial (NLST; 53,405 participants, 31,501 men, 21,904 women). We find that screening effectiveness varies by pack-years (screening effectiveness ranges across trials: lowest groups = 26.8-50.9%, highest groups = 5.5-9.5%), smoking status (screening effectiveness ranges across trials: former smokers = 37.8-39.1%, current smokers = 16.1-22.7%) and sex (screening effectiveness ranges across trials: women = 24.6-25.3%; men = 8.3-24.9%). Furthermore, screening effectiveness varies by histology (screening effectiveness ranges across trials: adenocarcinoma = 17.8-23.0%, other lung cancers = 24.5-35.5%, small-cell carcinoma = 9.7%-11.3%). Screening is ineffective for squamous-cell carcinoma in NLST (screening effectiveness = 27.9% (95% confidence interval: 69.8% increase to 4.5% decrease) mortality increase) but effective in NELSON (screening effectiveness = 52.2% (95% confidence interval: 25.7-69.1% decrease) mortality reduction). We find that variations in screening effectiveness across pack-years, smoking status, and sex are primarily explained by a greater prevalence of histologies with favourable screening effectiveness in these groups. Our study shows that heterogeneity in lung screening effectiveness is primarily driven by histology and that relaxing smoking-related screening eligibility criteria may enhance screening effectiveness.

Date: 2025
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DOI: 10.1038/s41467-025-63471-6

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