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

Author

Listed:
  • Max Welz

    (Erasmus MC–University Medical Center Rotterdam
    Erasmus University Rotterdam)

  • Carlijn M. Aalst

    (Erasmus MC–University Medical Center Rotterdam)

  • Andreas Alfons

    (Erasmus University Rotterdam)

  • Andrea A. Naghi

    (Erasmus University Rotterdam
    Queen Mary University of London)

  • Marjolein A. Heuvelmans

    (Department of Epidemiology
    Institute for Diagnostic Accuracy
    Amsterdam University Medical Center)

  • 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)

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.

Suggested Citation

  • 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 & Kevin Haaf, 2025. "A comparative analysis of heterogeneity in lung cancer screening effectiveness in two randomised controlled trials," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63471-6
    DOI: 10.1038/s41467-025-63471-6
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    1. Friedman, Jerome H. & Hastie, Trevor & Tibshirani, Rob, 2010. "Regularization Paths for Generalized Linear Models via Coordinate Descent," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 33(i01).
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