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

Asha Bonney, Reem Malouf, Corynne Marchal, David Manners, Kwun M Fong, Henry M Marshall, Louis B Irving, Renée Manser, Asha Bonney, Reem Malouf, Corynne Marchal, David Manners, Kwun M Fong, Henry M Marshall, Louis B Irving, Renée Manser

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 We also searched the clinical trial registries to identify unpublished and ongoing trials.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.

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.