Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group

Abstract

Background: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy.

Methods: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell).

Results: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively.

Conclusions: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

FIGURE 1

CONSORT diagram. COPD: chronic obstructive pulmonary disease; AFB: autofluorescence bronchoscopy; LDCT: low-dose computed tomography. Supplementary table S1 provides further details about number of participants approached and trial uptake. ^#: it transpired that one person actually had lung cancer >1 year prior to randomisation but did not inform the trial staff (they would have been ineligible). Because this was only discovered at the end of the trial (cancer notification by the national registry), the person was kept in the intention-to-screen analyses. The person had normal sputum samples throughout and no AFB or CT (and not counted as a cancer case). Counting this as a cancer case had only a small effect on sensitivity (44.7% without it (figure 2) and 43.6% with it). ^¶: even though some participants withdrew from the trial procedures before 5 years, they were still flagged for cancer occurrence.

FIGURE 2

Summary of screening performance for the three tests in the surveillance group based on results at any time during the trial. FPR: false-positive rate; AFB: autofluorescence bronchoscopy; LDCT: low-dose computed tomography. Sensitivity indicates percentage of cancers with abnormal results. FPR indicates percentage of individuals without lung cancer with abnormal results (same as 1−specificity).