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Meta-Analysis
. 2022 Aug 3;8(8):CD013829.
doi: 10.1002/14651858.CD013829.pub2.

Impact of low-dose computed tomography (LDCT) screening on lung cancer-related mortality

Asha Bonney  1   2 , Reem Malouf  3 , Corynne Marchal  4 , David Manners  5 , Kwun M Fong  6   7 , Henry M Marshall  8 , Louis B Irving  1 , Renée Manser  1   9
Affiliations
Meta-Analysis

Impact of low-dose computed tomography (LDCT) screening on lung cancer-related mortality

Asha Bonney et al. Cochrane Database Syst Rev. .

Abstract

Background: Lung cancer is the most common cause of cancer-related death in the world, however lung cancer screening has not been implemented in most countries at a population level. A previous Cochrane Review found limited evidence for the effectiveness of lung cancer screening with chest radiography (CXR) or sputum cytology in reducing lung cancer-related mortality, however there has been increasing evidence supporting screening with low-dose computed tomography (LDCT). OBJECTIVES: To determine whether screening for lung cancer using LDCT of the chest reduces lung cancer-related mortality and to evaluate the possible harms of LDCT screening.

Search methods: We performed the search in collaboration with the Information Specialist of the Cochrane Lung Cancer Group and included the Cochrane Lung Cancer Group Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, current issue), MEDLINE (accessed via PubMed) and Embase in our search. We also searched the clinical trial registries to identify unpublished and ongoing trials. We did not impose any restriction on language of publication. The search was performed up to 31 July 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) of lung cancer screening using LDCT and reporting mortality or harm outcomes. DATA COLLECTION AND ANALYSIS: Two review authors were involved in independently assessing trials for eligibility, extraction of trial data and characteristics, and assessing risk of bias of the included trials using the Cochrane RoB 1 tool. We assessed the certainty of evidence using GRADE. Primary outcomes were lung cancer-related mortality and harms of screening. We performed a meta-analysis, where appropriate, for all outcomes using a random-effects model. We only included trials in the analysis of mortality outcomes if they had at least 5 years of follow-up. We reported risk ratios (RRs) and hazard ratios (HRs), with 95% confidence intervals (CIs) and used the I2 statistic to investigate heterogeneity. MAIN RESULTS: We included 11 trials in this review with a total of 94,445 participants. Trials were conducted in Europe and the USA in people aged 40 years or older, with most trials having an entry requirement of ≥ 20 pack-year smoking history (e.g. 1 pack of cigarettes/day for 20 years or 2 packs/day for 10 years etc.). One trial included male participants only. Eight trials were phase three RCTs, with two feasibility RCTs and one pilot RCT. Seven of the included trials had no screening as a comparison, and four trials had CXR screening as a comparator. Screening frequency included annual, biennial and incrementing intervals. The duration of screening ranged from 1 year to 10 years. Mortality follow-up was from 5 years to approximately 12 years. None of the included trials were at low risk of bias across all domains. The certainty of evidence was moderate to low across different outcomes, as assessed by GRADE. In the meta-analysis of trials assessing lung cancer-related mortality, we included eight trials (91,122 participants), and there was a reduction in mortality of 21% with LDCT screening compared to control groups of no screening or CXR screening (RR 0.79, 95% CI 0.72 to 0.87; 8 trials, 91,122 participants; moderate-certainty evidence). There were probably no differences in subgroups for analyses by control type, sex, geographical region, and nodule management algorithm. Females appeared to have a larger lung cancer-related mortality benefit compared to males with LDCT screening. There was also a reduction in all-cause mortality (including lung cancer-related) of 5% (RR 0.95, 95% CI 0.91 to 0.99; 8 trials, 91,107 participants; moderate-certainty evidence). Invasive tests occurred more frequently in the LDCT group (RR 2.60, 95% CI 2.41 to 2.80; 3 trials, 60,003 participants; moderate-certainty evidence). However, analysis of 60-day postoperative mortality was not significant between groups (RR 0.68, 95% CI 0.24 to 1.94; 2 trials, 409 participants; moderate-certainty evidence). False-positive results and recall rates were higher with LDCT screening compared to screening with CXR, however there was low-certainty evidence in the meta-analyses due to heterogeneity and risk of bias concerns. Estimated overdiagnosis with LDCT screening was 18%, however the 95% CI was 0 to 36% (risk difference (RD) 0.18, 95% CI -0.00 to 0.36; 5 trials, 28,656 participants; low-certainty evidence). Four trials compared different aspects of health-related quality of life (HRQoL) using various measures. Anxiety was pooled from three trials, with participants in LDCT screening reporting lower anxiety scores than in the control group (standardised mean difference (SMD) -0.43, 95% CI -0.59 to -0.27; 3 trials, 8153 participants; low-certainty evidence). There were insufficient data to comment on the impact of LDCT screening on smoking behaviour. AUTHORS' CONCLUSIONS: The current evidence supports a reduction in lung cancer-related mortality with the use of LDCT for lung cancer screening in high-risk populations (those over the age of 40 with a significant smoking exposure). However, there are limited data on harms and further trials are required to determine participant selection and optimal frequency and duration of screening, with potential for significant overdiagnosis of lung cancer. Trials are ongoing for lung cancer screening in non-smokers.

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Conflict of interest statement

Asha Bonney has a Postgraduate Scholarship from the Australian National Health and Medical Research Council.

Reem Malouf: none known

Corynne Marchal: none known

David Manners has received speaking honoraria from Astra Zeneca and research grant funding from Curtin Medical School, Curtin University.

Kwun M Fong: Co‐investigator on the International Lung Screening Trial. This is an international, multicentre, investigator initiated study, funded in Australia by a National Health and Medical Research Grant. The study is an observational cohort study examining low‐dose screening for lung cancer in high‐risk former and current smokers. KF also undertook the QLCSS lung cancer screening trial, a pilot one‐armed study which is not eligible as it is not a RCT ‐ Queensland Smart State Grant. Chair of the Lung Cancer Consultative Group for NGO Lung Foundation Australia (no payment). KF declares occasional speaking on lung cancer at conferences and meetings where industry may be the organiser or a sponsor. KF has an Australian Medical Research Future Fund Fellowship. KF received in‐kind support with software licences for MeVis Veolity Computer Aided Diagnosis for the ILST clinical trial. KF is a reviewer for UpToDate (not related to CT screening). KF is Editor for the Cochrane Lung Cancer Group.

Henry M Marshall is an investigator on the International Lung Screen Trial. He has received honoraria to speak on the subjects of smoking cessation, lung cancer screening and COPD.

Louis B Irving: none known

Renée Manser: none known. Co‐editor, Cochrane Lung Cancer Review Group Co‐investigator on the International Lung Screening Trial. This is an international, multicentre, investigator initiated trial, funded in Australia by a National Health and Medical Research Grant. The study is an observational cohort study examining low‐dose screening for lung cancer in high‐risk former and current smokers.

Figures

1
1
Study selection flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Lung cancer mortality ‐ Planned time points ‐ Sensitivity analysis
5
5
All‐cause mortality ‐ Planned time points ‐ Sensitivity analysis
1.1
1.1. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 1: Lung cancer‐related mortality ‐ planned time points
1.2
1.2. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 2: Lung cancer‐related mortality ‐ planned time points
1.3
1.3. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 3: Lung cancer‐related mortality at different follow‐up time points (including unplanned)
1.4
1.4. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 4: Lung cancer‐related mortality by screening arm ‐ planned time points
1.5
1.5. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 5: Lung cancer‐related mortality – by time postscreening cessation (including unplanned time points)
1.6
1.6. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 6: Lung cancer‐related mortality by screening interval ‐ planned time points
1.7
1.7. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 7: Lung cancer‐related mortality by sex ‐ planned time points
1.8
1.8. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 8: Lung cancer‐related mortality by sex ‐ planned time points
1.9
1.9. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 9: Lung cancer‐related mortality by age ‐ planned time points
1.10
1.10. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 10: Lung cancer related to smoking ‐ latest time point (including unplanned)
1.11
1.11. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 11: Lung cancer‐related mortality by geography ‐ planned time points
1.12
1.12. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 12: Nodule management algorithm ‐ planned follow‐up time points
1.13
1.13. Analysis
Comparison 1: Primary outcome: lung cancer‐related mortality, Outcome 13: Nodule management criteria ‐ planned follow‐up time points
2.1
2.1. Analysis
Comparison 2: Primary outcome: number of non‐invasive and invasive tests ‐ all time points, Outcome 1: Number of invasive tests
2.2
2.2. Analysis
Comparison 2: Primary outcome: number of non‐invasive and invasive tests ‐ all time points, Outcome 2: Non‐invasive tests
2.3
2.3. Analysis
Comparison 2: Primary outcome: number of non‐invasive and invasive tests ‐ all time points, Outcome 3: Number of invasive test for false positive
2.4
2.4. Analysis
Comparison 2: Primary outcome: number of non‐invasive and invasive tests ‐ all time points, Outcome 4: Death postsurgery
3.1
3.1. Analysis
Comparison 3: Secondary outcome: all‐cause mortality, Outcome 1: All‐cause mortality ‐ planned time points (latest time points)
3.2
3.2. Analysis
Comparison 3: Secondary outcome: all‐cause mortality, Outcome 2: All‐cause mortality ‐ all time points (planned and unplanned)
3.3
3.3. Analysis
Comparison 3: Secondary outcome: all‐cause mortality, Outcome 3: All‐cause mortality ‐ planned time points
3.4
3.4. Analysis
Comparison 3: Secondary outcome: all‐cause mortality, Outcome 4: All‐cause mortality by sex ‐ planned time points
3.5
3.5. Analysis
Comparison 3: Secondary outcome: all‐cause mortality, Outcome 5: Cardiovascular mortality ‐ planned and unplanned
4.1
4.1. Analysis
Comparison 4: Secondary outcome: lung cancer incidence, Outcome 1: Lung cancer incidence ‐ by different time points
4.2
4.2. Analysis
Comparison 4: Secondary outcome: lung cancer incidence, Outcome 2: Lung cancer incidence ‐ by control group at ≥ 10 years
4.3
4.3. Analysis
Comparison 4: Secondary outcome: lung cancer incidence, Outcome 3: Overdiagnosis at ≥ 10 years
5.1
5.1. Analysis
Comparison 5: Secondary outcome: false positives, negatives and recalls (number of screens), Outcome 1: False positive at baseline
5.2
5.2. Analysis
Comparison 5: Secondary outcome: false positives, negatives and recalls (number of screens), Outcome 2: False negative
5.3
5.3. Analysis
Comparison 5: Secondary outcome: false positives, negatives and recalls (number of screens), Outcome 3: Recall rates at baseline
6.1
6.1. Analysis
Comparison 6: Secondary outcome: impact on smoking behaviour, Outcome 1: stop smoking
6.2
6.2. Analysis
Comparison 6: Secondary outcome: impact on smoking behaviour, Outcome 2: smoking relapse
7.1
7.1. Analysis
Comparison 7: Secondary outcome: health‐related quality of life, Outcome 1: Anxiety ‐ at 10 months to 5 years (change over time and endpoints)
7.2
7.2. Analysis
Comparison 7: Secondary outcome: health‐related quality of life, Outcome 2: Quality of life measures at different time points
7.3
7.3. Analysis
Comparison 7: Secondary outcome: health‐related quality of life, Outcome 3: SF‐36v2: PCS by different components at baseline and at 6 months
7.4
7.4. Analysis
Comparison 7: Secondary outcome: health‐related quality of life, Outcome 4: SF‐36v2: MCS by different components at baseline and 6 months
7.5
7.5. Analysis
Comparison 7: Secondary outcome: health‐related quality of life, Outcome 5: Anxiety by different results at 1 and 6 months
8.1
8.1. Analysis
Comparison 8: Secondary outcome: lung cancer by stages at different time points, Outcome 1: baseline
8.2
8.2. Analysis
Comparison 8: Secondary outcome: lung cancer by stages at different time points, Outcome 2: at 1 year
8.3
8.3. Analysis
Comparison 8: Secondary outcome: lung cancer by stages at different time points, Outcome 3: At year 2
8.4
8.4. Analysis
Comparison 8: Secondary outcome: lung cancer by stages at different time points, Outcome 4: 5 to < 10 years
8.5
8.5. Analysis
Comparison 8: Secondary outcome: lung cancer by stages at different time points, Outcome 5: ≥ 10 years
9.1
9.1. Analysis
Comparison 9: Secondary outcome: lung cancer histology at different time points, Outcome 1: Histology types at baseline
9.2
9.2. Analysis
Comparison 9: Secondary outcome: lung cancer histology at different time points, Outcome 2: Histology at year 1
9.3
9.3. Analysis
Comparison 9: Secondary outcome: lung cancer histology at different time points, Outcome 3: Histology at follow‐up
10.1
10.1. Analysis
Comparison 10: Secondary outcome: other outcomes, Outcome 1: contamination
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013829

References

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References to studies excluded from this review

Bradley 2021 {published data only}
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Brodersen 2014 {published data only}
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Dawson 2020 {published data only}
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de‐Torres 2021 {published data only}
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Favre 2003 {published data only}
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Fink 2012 {published data only}
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Garg 2002 {published data only}
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Goulart 2013 {published data only}
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Guldbrandt 2015 {published data only}
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Hassannezhad 2018 {published data only}
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Henschke 2000 {published data only}
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Henschke 2002 {published data only}
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Henschke 2015 {published data only}
    1. Henschke CI, Boffetta P, Ankelevitz DF, Altorki N. Computed tomography screening: the international early lung cancer action program experience. Thoracic Surgery Clinics 2015;25(2):129-43. [DOI: 10.1016/j.thorsurg.2014.12.001] - DOI - PubMed
Horeweg 2013 {published data only}
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ISRCTN42704678 {published data only}
    1. ISRCTN42704678. The Yorkshire Lung Screening Trial. www.isrctn.com/ISRCTN42704678 (first received 26 March 2018).
Kramer 2011 {published data only}
    1. Kramer BS, Berg CD, Aberle DR, Prorok PC. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). Journal of Medical Screening 2011;18(3):109-11. [DOI: 10.1258/jms.2011.011055] - DOI - PMC - PubMed
Kulaga 2007 {published data only}
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Marcus 2006 {published data only}
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NCT02431962 {published data only}
    1. NCT02431962. Alberta Lung Cancer Screening Program. clinicaltrials.gov/ct2/show/NCT02431962 (first received 1 May 2015).
Park 2022 {published data only}
    1. Park S, Park H, Lee SM, Ahn Y, Kim W, Jung K, et al. Application of computer-aided diagnosis for Lung-RADS categorization in CT screening for lung cancer: effect on inter-reader agreement. European Radiology 2022;32(2):1054-64. [DOI: 10.1007/s00330-021-08202-3] - DOI - PubMed
Robbins 2019 {published data only}
    1. Robbins HA, Callister M, Sasieni P, Quaife SL, Cheung LC, Brennan P, et al. Benefits and harms in the National Lung Screening Trial: expected outcomes with a modern management protocol. Lancet Respiratory Medicine 2019;7(8):655-6. [DOI: 10.1016/S2213-2600(19)30136-5] - DOI - PMC - PubMed
Schabath 2019 {published data only}
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Schreuder 2021 {published data only}
    1. Schreuder A, Mets OM, Schaefer-Prokop CM, Jacobs C, Prokop M. Microsimulation modeling of extended annual CT screening among lung cancer cases in the National Lung Screening Trial. Lung Cancer 2021;156:5-11. [DOI: 10.1016/j.lungcan.2021.04.004] - DOI - PubMed
Spiro 2019 {published data only}
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Strauss 2012 {published data only}
    1. Strauss GM, Dominioni L. Computed tomography (CT) and chest X-ray (CXR) screening in the national lung screening trial (NLST): do mortality differences provide an unbiased measure of the effectiveness of CT screening? American Journal of Respiratory and Critical Care Medicine 2012;185:A5063.
Strauss 2015 {published data only}
    1. Strauss G, Flores JP, Dominioni L. Computed tomography (CT) and chest x-ray (CXR) screening for lung cancer (LC): mortality (MORT), survival (SURV), and randomized population trials (RPTs) analysis of the Mayo lung project (MLP) and the National Lung Screening Trial (NLST). Chest 2015;148(4):554A. [DOI: 10.1378/chest.2264144] - DOI
Sullivan 2019 {published data only}
    1. Sullivan F, Schembri S. PL02.03 Early detection of cancer of the lung Scotland (ECLS): trial results. Journal of Thoracic Oncology 2019;14(10):S5. [DOI: 10.1016/j.jtho.2019.08.056] - DOI
Sullivan 2021 {published data only}
    1. Sullivan FM, Mair FS, Anderson W, Armory P, Briggs A, Chew C, et al. Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging. European Respiratory Journal 2021;57(1):2000670. [DOI: 10.1183/13993003.00670-2020] - DOI - PMC - PubMed
Yang 2008 {published data only}
    1. Yang M, Wang J, Meng LJ, Wang Y, Xu L, Liu FY, et al. Analysis of feasibility of lung cancer screening with low-radiation-dose spiral CT scan plus detection of p16 gene methylation in serum. Chinese Journal of Cancer Prevention and Treatment 2008;15(1):8-10.
Yip 2013 {published data only}
    1. Yip R, Yankelevitz DF, Henschke CI. CT screening for lung cancer: definition of positive test result in the national lung screening trial CT cohort compared with i-elcap. Journal of Thoracic Oncology 2013;8:S326. [DOI: 10.1097/01.JTO.0000438438.14562.c8] - DOI

References to ongoing studies

Sagawa 2012 {published data only}
    1. Sagawa M, Nakayama T, Tanaka M, Sakuma T, Sobue T. A randomized controlled trial on the efficacy of thoracic CT screening for lung cancer in non-smokers and smokers of <30 pack-years aged 50-64 years (JECS study): research design. Japanese Journal of Clinical Oncology 2012;42(12):1219-21. [DOI: 10.1093/jjco/hys157] - DOI - PubMed
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Yang 2018 {published data only}
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    1. NCT02898441. Early stage lung cancer screening with low-dose computed tomographic. clinicaltrials.gov/ct2/show/NCT02898441 (first received 13 September 2016).
    1. Qian F, Yang W, Wang H, Teng J, Zhang Y, Chen Q, et al. Community-based lung cancer screening of high-risk population with low-dose computed tomography in China. Annals of Oncology 2017;28:v502. [DOI: 10.1093/annonc/mdx383.001] - DOI
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