Lung Cancer Screening with Low-Dose CT: a Meta-Analysis

Abstract

Background

Randomized controlled trials have evaluated the efficacy of low-dose CT (LDCT) lung cancer screening on lung cancer (LC) outcomes.

Objective

Meta-analyze LDCT lung cancer screening trials.

Methods

We identified studies by searching PubMed, Google Scholar, the Cochrane Registry, ClinicalTrials.gov, and reference lists from retrieved publications. We abstracted data on study design features, stage I LC diagnoses, LC and overall mortality, false positive results, harm from invasive diagnostic procedures, overdiagnosis, and significant incidental findings. We assessed study quality using the Cochrane risk-of-bias tool. We used random-effects models to calculate relative risks and assessed effect modulators with subgroup analyses and meta-regression.

Results

We identified 9 studies that enrolled 96,559 subjects. The risk of bias across studies was judged to be low. Overall, LDCT screening significantly increased the detection of stage I LC, RR = 2.93 (95% CI, 2.16–3.98), I2 = 19%, and reduced LC mortality, RR = 0.84 (95% CI, 0.75–0.93), I2 = 0%. The number needed to screen to prevent an LC death was 265. Women had a lower risk of LC death (RR = 0.69, 95% CI, 0.40–1.21) than men (RR = 0.86, 95% CI, 0.66–1.13), p value for interaction = 0.11. LDCT screening did not reduce overall mortality, RR = 0.96 (95% CI, 0.91–1.01), I2 = 0%. The pooled false positive rate was 8% (95% CI, 4–18); subjects with false positive results had < 1 in 1000 risk of major complications following invasive diagnostic procedures. The most valid estimates for overdiagnosis and significant incidental findings were 8.9% and 7.5%, respectively.

Discussion

LDCT screening significantly reduced LC mortality, though not overall mortality, with women appearing to benefit more than men. The estimated risks for false positive results, screening complications, overdiagnosis, and incidental findings were low. Long-term survival data were available only for North American and European studies limiting generalizability.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. 2.

    US Department of Health and Human Services. The health consequences of smoking: 50 years of progress. A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Natonal Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.

  3. 3.

    Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev. 2016;3:CD008286.

    Google Scholar 

  4. 4.

    National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.

  5. 5.

    de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med. 2020;382:503–13.

    PubMed  Google Scholar 

  6. 6.

    Huang KL, Wang SY, Lu WC, Chang YH, Su J, Lu YT. Effects of low-dose computed tomography on lung cancer screening: a systematic review, meta-analysis, and trial sequential analysis. BMC Pulm Med. 2019;19:126.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Rota M, Pizzato M, La Vecchia C, Boffetta P. Efficacy of lung cancer screening appears to increase with prolonged intervention: results from the MILD trial and a meta-analysis. Ann Oncol. 2019;30:1040–3.

    CAS  PubMed  Google Scholar 

  8. 8.

    Snowsill T, Yang H, Griffin E, et al. Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation. Health Technol Assess. 2018;22:1–276.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    openMetaAnalysis. Methods. (Accessed February 2, 2020, at http://openmetaanalysis.github.io/methods.html)

  10. 10.

    Patnode CD, Eder ML, Walsh ES, Viswanathan M, Lin JS. The Use of Rapid Review Methods for the U.S. Preventive Services Task Force. Am J Prev Med. 2018;54:S19–S25.

    PubMed  Google Scholar 

  11. 11.

    Riaz IB, Khan MS, Riaz H, Goldberg RJ. Disorganized Systematic Reviews and Meta-analyses: Time to Systematize the Conduct and Publication of These Study Overviews? Am J Med. 2016;129:339 e11-8.

    Google Scholar 

  12. 12.

    Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65–94.

    Google Scholar 

  13. 13.

    Coureau G, Salmi LR, Etard C, Sancho-Garnier H, Sauvaget C, Mathoulin-Pelissier S. Low-dose computed tomography screening for lung cancer in populations highly exposed to tobacco: A systematic methodological appraisal of published randomised controlled trials. Eur J Cancer. 2016;61:146–56.

    PubMed  Google Scholar 

  14. 14.

    Usman Ali M, Miller J, Peirson L, et al. Screening for lung cancer: A systematic review and meta-analysis. Prev Med. 2016;89:301–14.

    PubMed  Google Scholar 

  15. 15.

    Riaz IB, Badgett RG. Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis. Ann Intern Med. 2016;164:634–5.

    PubMed  Google Scholar 

  16. 16.

    Cochrane Library. Table 8.7.a: Possible approach for summary assessments of the risk of bias for each important outcome (across domains) within and across studies. 2011. (Accessed January 12, 2020, at http://handbook-5-1.cochrane.org/chapter_8/table_8_7_a_possible_approach_for_summary_assessments_of_the.htm)

  17. 17.

    Cornell JE, Mulrow CD, Localio R, et al. Random-effects meta-analysis of inconsistent effects: a time for change. Ann Intern Med. 2014;160:267–70.

    PubMed  Google Scholar 

  18. 18.

    Cornell University. The OpenCPU System: Towards a Universal Interface for Scientific Computing through Separaration of Concerns. Cornell University; 2014. (Accessed January 12, 2020, at https://arxiv.org/abs/1406.4806.)

  19. 19.

    Schwarzer G. meta: General Package for Meta-Analysis 4.9-9.: The Comprehensive R Archive Network; 2019.

  20. 20.

    Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58:882–93.

    PubMed  Google Scholar 

  21. 21.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Rucker G, Schwarzer G, Carpenter J. Arcsine test for publication bias in meta-analyses with binary outcomes. Stat Med. 2008;27:746–63.

    PubMed  Google Scholar 

  24. 24.

    Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94.

    PubMed  Google Scholar 

  25. 25.

    Pinto RZ, Maher CG, Ferreira ML, et al. Epidural corticosteroid injections in the management of sciatica: a systematic review and meta-analysis. Ann Intern Med. 2012;157:865–77.

    PubMed  Google Scholar 

  26. 26.

    Doroudi M, Pinsky PF, Marcus PM. Lung Cancer Mortality in the Lung Screening Study Feasibility Trial. JNCI Cancer Spectr. 2018;2:pky042.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Infante M, Cavuto S, Lutman FR, et al. Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. Am J Respir Crit Care Med. 2015;191:1166–75.

    PubMed  Google Scholar 

  28. 28.

    Wille MM, Dirksen A, Ashraf H, et al. Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. Am J Respir Crit Care Med. 2016;193:542–51.

    CAS  PubMed  Google Scholar 

  29. 29.

    Pastorino U, Silva M, Sestini S, et al. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol. 2019;30:1672.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Paci E, Puliti D, Lopes Pegna A, et al. Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax. 2017;72:825–31.

    PubMed  Google Scholar 

  31. 31.

    Becker N, Motsch E, Trotter A, et al. Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial. Int J Cancer. 2019.

  32. 32.

    Yang W, Qian F, Teng J, et al. Community-based lung cancer screening with low-dose CT in China: Results of the baseline screening. Lung Cancer. 2018;117:20–6.

    PubMed  Google Scholar 

  33. 33.

    Gohagan J, Marcus P, Fagerstrom R, et al. Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan vs chest radiograph: the Lung Screening Study of the National Cancer Institute. Chest. 2004;126:114–21.

    PubMed  Google Scholar 

  34. 34.

    Gohagan JK, Marcus PM, Fagerstrom RM, et al. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer. 2005;47:9–15.

    PubMed  Google Scholar 

  35. 35.

    Infante M, Lutman FR, Cavuto S, et al. Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer. 2008;59:355–63.

    PubMed  Google Scholar 

  36. 36.

    Infante M, Cavuto S, Lutman FR, et al. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med. 2009;180:445–53.

    PubMed  Google Scholar 

  37. 37.

    Infante M, Chiesa G, Solomon D, et al. Surgical procedures in the DANTE trial, a randomized study of lung cancer early detection with spiral computed tomography: comparative analysis in the screening and control arm. J Thorac Oncol. 2011;6:327–35.

    PubMed  Google Scholar 

  38. 38.

    National Lung Screening Trial Research Team, Aberle DR, Berg CD, et al. The National Lung Screening Trial: overview and study design. Radiology. 2011;258:243–53.

  39. 39.

    National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst. 2010;102:1771–9.

  40. 40.

    Patz EF, Jr., Pinsky P, Gatsonis C, et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med. 2014;174:269–74.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    National Lung Screening Trial Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368:1980–91.

  42. 42.

    Pinsky PF, Bellinger CR, Miller DP, Jr. False-positive screens and lung cancer risk in the National Lung Screening Trial: Implications for shared decision-making. J Med Screen. 2018;25:110–2.

    PubMed  Google Scholar 

  43. 43.

    van Iersel CA, de Koning HJ, Draisma G, et al. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer. 2007;120:868–74.

    PubMed  Google Scholar 

  44. 44.

    van de Wiel JC, Wang Y, Xu DM, et al. Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT. Eur Radiol. 2007;17:1474–82.

    PubMed  Google Scholar 

  45. 45.

    van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009;361:2221–9.

    PubMed  Google Scholar 

  46. 46.

    Horeweg N, Scholten ET, de Jong PA, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol. 2014;15:1342–50.

    PubMed  Google Scholar 

  47. 47.

    Xu DM, Gietema H, de Koning H, et al. Nodule management protocol of the NELSON randomised lung cancer screening trial. Lung Cancer. 2006;54:177–84.

    PubMed  Google Scholar 

  48. 48.

    Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax. 2017;72:48–56.

    PubMed  Google Scholar 

  49. 49.

    Van’t Westeinde SC, Horeweg N, De Leyn P, et al. Complications following lung surgery in the Dutch-Belgian randomized lung cancer screening trial. Eur J Cardiothorac Surg. 2012;42:420–9.

    Google Scholar 

  50. 50.

    Pedersen JH, Ashraf H, Dirksen A, et al. The Danish randomized lung cancer CT screening trial--overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608–14.

    PubMed  Google Scholar 

  51. 51.

    Saghir Z, Dirksen A, Ashraf H, et al. CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax. 2012;67:296–301.

    PubMed  Google Scholar 

  52. 52.

    Heleno B, Siersma V, Brodersen J. Estimation of Overdiagnosis of Lung Cancer in Low-Dose Computed Tomography Screening: A Secondary Analysis of the Danish Lung Cancer Screening Trial. JAMA Intern Med. 2018;178:1420–2.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lopes Pegna A, Picozzi G, Mascalchi M, et al. Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer. 2009;64:34–40.

    PubMed  Google Scholar 

  54. 54.

    Lopes Pegna A, Picozzi G, Falaschi F, et al. Four-year results of low-dose CT screening and nodule management in the ITALUNG trial. J Thorac Oncol. 2013;8:866–75.

    PubMed  Google Scholar 

  55. 55.

    Pastorino U, Rossi M, Rosato V, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012;21:308–15.

    PubMed  Google Scholar 

  56. 56.

    Sverzellati N, Silva M, Calareso G, et al. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. Eur Radiol. 2016;26:3821–9.

    PubMed  Google Scholar 

  57. 57.

    Pastorino U, Sverzellati N, Sestini S, et al. Ten-year results of the Multicentric Italian Lung Detection trial demonstrate the safety and efficacy of biennial lung cancer screening. Eur J Cancer. 2019;118:142–8.

    CAS  PubMed  Google Scholar 

  58. 58.

    Becker N, Motsch E, Gross ML, et al. Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round. J Cancer Res Clin Oncol. 2012;138:1475–86.

    CAS  PubMed  Google Scholar 

  59. 59.

    Becker N, Motsch E, Gross ML, et al. Randomized Study on Early Detection of Lung Cancer with MSCT in Germany: Results of the First 3 Years of Follow-up After Randomization. J Thorac Oncol. 2015;10:890–6.

    CAS  PubMed  Google Scholar 

  60. 60.

    National Lung Screening Trial Research Team. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol. 2019;14:1732–42.

    Google Scholar 

  61. 61.

    Sedgwick P, Marston L. How to read a funnel plot in a meta-analysis. BMJ. 2015;351:h4718.

    PubMed  Google Scholar 

  62. 62.

    Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2016. Bethesda, MD: National Cancer Institute; 2016.

    Google Scholar 

  63. 63.

    Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2027–35.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Nelson HD, Fu R, Cantor A, Pappas M, Daeges M, Humphrey L. Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation. Ann Intern Med. 2016;164:244–55.

    PubMed  Google Scholar 

  65. 65.

    Fitzpatrick-Lewis D, Ali MU, Warren R, Kenny M, Sherifali D, Raina P. Screening for Colorectal Cancer: A Systematic Review and Meta-Analysis. Clin Colorectal Cancer. 2016;15:298–313.

    PubMed  Google Scholar 

  66. 66.

    Ten Haaf K, de Koning HJ. Overdiagnosis in lung cancer screening: why modelling is essential. J Epidemiol Community Health. 2015;69:1035-9.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    American College of Radiology. Lung CT Screening Reporting & Data System (Lung-RADS). (Accessed April 10, 2020, at https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/Lung-Rads.)

  68. 68.

    Pinsky PF, Gierada DS, Black W, et al. Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med. 2015;162:485–91.

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Heijnsdijk EAM, Csanadi M, Gini A, et al. All-cause mortality versus cancer-specific mortality as outcome in cancer screening trials: A review and modeling study. Cancer Med. 2019;8:6127–38.

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer. 2013;119:3976–83.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    U.S. Preventive Services Task Force. Final Research Plan for Lung Cancer: Screening. 2018. (Accessed February 15, 2020, at https://www.uspreventiveservicestaskforce.org/Page/Document/final-research-plan/lung-cancer-screening1)

  72. 72.

    Field JK, Duffy SW, Baldwin DR, et al. The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer. Health Technol Assess. 2016;20:1–146.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Robbins HA, Berg CD, Cheung LC, Chaturvedi AK, Katki HA. Identification of Candidates for Longer Lung Cancer Screening Intervals Following a Negative Low-Dose Computed Tomography Result. J Natl Cancer Inst. 2019;111:996–9.

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Patz EF, Jr., Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. Lancet Oncol. 2016;17:590–9.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Tammemagi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med. 2013;368:728–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Barta JA, Powell CA, Wisnivesky JP. Global Epidemiology of Lung Cancer. Ann Glob Health. 2019;85.

  77. 77.

    Centers for Medicare & Medicaid Services. MEDCAC Meeting 4/30/2014-Lung Cancer Screening with Low Dose Computed Tomography. 2014. (Accessed February 2, 2020, at https://www.cms.gov/medicare-coverage-database/details/medcac-meeting-details.aspx?MEDCACId=68)

Download references

Acknowledgments

We appreciate the literature search assistance provided by Heather Healy, Clinical Education Librarian, University of Iowa Hardin Library for the Health Sciences.

Funding

Dr. Hoffman’s cancer-related work is supported by Cancer Center Support Grant PO30 CA086862

Author information

Affiliations

Authors

Corresponding author

Correspondence to Richard M. Hoffman MD, MPH.

Ethics declarations

Conflict of Interest

The authors declare that they do not have a conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This study has not been presented previously.

Electronic supplementary material

ESM 1

(DOCX 54 kb).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hoffman, R.M., Atallah, R.P., Struble, R.D. et al. Lung Cancer Screening with Low-Dose CT: a Meta-Analysis. J GEN INTERN MED (2020). https://doi.org/10.1007/s11606-020-05951-7

Download citation

Key Words

  • lung neoplasms
  • meta-analysis
  • mortality
  • low-dose computed tomography
  • lung cancer screening