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Sequential screening for lung cancer in a
high-riskgroup:randomisedcontrolledtrial
LungSEARCH: a randomised controlled trial of Surveillance using sputum and
imaging for the EARly detection of lung Cancer in a High-risk group
Stephen G. Spiro
1,22
, Pallav L. Shah
2
, Robert C. Rintoul
3
, Jeremy George
4
,
Samuel Janes
4
, Matthew Callister
5
, Marco Novelli
6
, Penny Shaw
7
,
Gabrijela Kocjan
6
,ChrisGriffiths
8
, Mary Falzon
6
, Richard Booton
9
, Nicholas Magee
10
,
Michael Peake
11,12
, Paul Dhillon
13
, Kishore Sridharan
14
, Andrew G. Nicholson
15
,
Simon Padley
16
, Magali N. Taylor
7
, Asia Ahmed
7
, Jack Allen
17
, Yenting Ngai
17
,
Nyasha Chinyanganya
17
, Victoria Ashford-Turner
18
, Sarah Lewis
19
,
Dahmane Oukrif
20
, Pamela Rabbitts
21
, Nicholas Counsell
17
and Allan Hackshaw
17,22
@ERSpublications
While low-dose CT is now preferred for lung cancer screening, our randomised trial of smokers with
COPD showed that a proposed sequential policy using sputum testing to select who receives low-dose
CT and autofluorescence bronchoscopy was ineffective http://bit.ly/2JZujnx
Cite this article as: Spiro SG, Shah PL, Rintoul RC, et al. Sequential screening for lung cancer in a high-risk
group: randomised controlled trial. Eur Respir J 2019; 54: 1900581 [https://doi.org/10.1183/13993003.00581-
2019].
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.
This article has supplementary material available from erj.ersjournals.com
This study is registered at the ISRCTN registry with identifier ISRCTN80745975. Research groups can contact the trial
investigators who would consider requests for access to the data.
Received: 22 March 2019 | Accepted after revision: 11 July 2019
Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons Attribution
Licence 4.0.
https://doi.org/10.1183/13993003.00581-2019 Eur Respir J 2019; 54: 1900581
|
ORIGINAL ARTICLE
LUNG CANCER
Introduction
Lung cancer is associated with poor survival because most cases are diagnosed at a late stage. However, early
detection with intended curative treatments can have an 80% 1-year survival rate for stage I disease [1].
During the 2000s, several randomised trials were developed to evaluate low-dose computed tomography
(LDCT) [2]. Expected major issues with LDCT screening included affordability and high false-positive
rates (FPRs) (which can be reduced through improved management of pulmonary nodules) [3].
Furthermore, LDCT might miss early squamous cell tumours located in the central airways [4].
Two major LDCT trials (the US National Lung Screening Trial (NLST) and the NELSON study) now
show a clear reduction in lung cancer mortality among current/ex-smokers who had annual LDCT
compared with either chest radiography or no screening [5, 6]. LDCT screening is recommended in the
USA [7] and suggested for Europe [8]. However, uptake in the USA is low (<5% of those eligible) [9, 10].
Our LungSEARCH study was developed in 2006, long before NLST and NELSON were published [5, 6].
We proposed a different strategy to make screening more efficient. Instead of offering a single screening
test, we created a novel approach of sequential screening (using sputum and imaging) and in a particularly
high-risk group, i.e. current/ex-smokers with chronic obstructive pulmonary disease (COPD), based on
promising evidence for the component tests.
COPD is correlated with lung cancer risk, and is an independent risk factor to smoking and other
characteristics [11, 12]. Decreasing lung function (using Global Initiative for Chronic Obstructive Lung
Disease (GOLD) criteria) is associated with increasingly worse survival [13, 14]. Therefore, targeted lung
cancer screening among individuals with COPD is appealing [11, 15–17].
Sputum cytology is a noninvasive and nonradiological test for lung disease, especially central airway
tumours. Sample procurement can be done at home without specialist equipment. Many smokers
(particularly those with COPD) produce more sputum, containing exfoliated cells from the bronchial tree.
There is an established association between having abnormal sputum cytology and lung cancer [18, 19],
although the earlier randomised trials of cytology failed to reduce lung cancer mortality [20]. However,
modern cytology methods have better sensitivity. Another sputum test involves computer-assisted image
analysis (automated image cytometry), which quantitatively analyses the nuclear structure and DNA
content of individual cells, distinguishing normal from suspicious cells [21–23]. In a large study of
smokers, 80% of lung cancers with sputum samples had abnormal cytometry compared with only 4% who
had abnormal cytology [21]. We hypothesised that the high-performance sensitivities expected using
modern cytology/cytometry would miss few cancers as a first screening test.
Autofluorescence bronchoscopy (AFB) is an optical imaging technique that compares fluorescence properties
between normal and malignant/pre-malignant bronchial mucosa [24–26]. AFB has a sensitivity for
early-stage lung cancer of 44–82% compared with 9–58% using conventional white light bronchoscopy [26].
The sensitivity for detecting abnormal lesions using AFB with white light could be two times that using
white light alone [27]. In a prior study of individuals with pre-invasive lesions, 73% had one or more
high-grade lesions and one in six of these lesions progressed to invasive carcinoma [28, 29].
Affiliations:
1
Dept of Respiratory Medicine, University College Hospital, London, UK.
2
Dept of Respiratory
Medicine, Royal Brompton Hospital, Chelsea and Westminster Hospital and Imperial College London, London,
UK.
3
Dept of Oncology, Royal Papworth Hospital and University of Cambridge, Cambridge, UK.
4
UCL
Respiratory, Dept of Medicine, University College London, London, UK.
5
Dept of Respiratory Medicine, Leeds
Teaching Hospitals NHS Trust, Leeds, UK.
6
Cellular Pathology, University College Hospital, London, UK.
7
Radiology (Imaging), University College Hospital, London, UK.
8
Institute of Population Health Sciences, Barts
and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
9
Lung
Cancer and Thoracic Surgery Directorate, Manchester University NHS Trust and University of Manchester,
Manchester, UK.
10
Respiratory Medicine, Belfast City Hospital, Belfast, UK.
11
Dept of Immunity, Infection and
Inflammation, University of Leicester, Leicester, UK.
12
Centre for Cancer Outcomes, University College
London Hospitals NHS Foundation Trust, London, UK.
13
Respiratory Medicine, University Hospitals Coventry
and Warwickshire, Coventry, UK.
14
Dept of Thoracic Medicine, Sunderland Royal Hospital, Sunderland, UK.
15
Dept of Histopathology, Royal Brompton Hospital and Harefield NHS Foundation Trust and National Heart
and Lung Institute, London, UK.
16
Radiology, Royal Brompton Hospital and National Heart and Lung Institute,
Imperial College London, London, UK.
17
Cancer Research UK and UCL Cancer Trials Centre, London, UK.
18
Cardio-Respiratory Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
19
Research and
Development, Royal Papworth Hospital, Cambridge, UK.
20
Dept of Pathology, University College Hospital,
London, UK.
21
Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, Leeds, UK.
22
These
authors are joint lead authors.
Correspondence: Allan Hackshaw, Cancer Research UK and UCL Cancer Trials Centre, 90 Tottenham Court
Road, London, W1T 4TJ, UK. E-mail: a.hackshaw@ucl.ac.uk
https://doi.org/10.1183/13993003.00581-2019 2
LUNG CANCER | S.G. SPIRO ET AL.
LungSEARCH evaluated sequential testing for detecting lung cancer in a high-risk group, in which a
cheap first screen is used to select who is offered LDCT and AFB. To date, it is the only randomised lung
cancer screening study to triage participants.
Methods
Design and participants
LungSEARCH was a national multicentre randomised trial. The objective was to examine whether annual
surveillance of individuals at high risk of lung cancer (current/ex-smokers with COPD) can lead to a shift
in cancer stage at diagnosis.
Participants were identified primarily from general practice. A research nurse visited each practice to
perform an electronic search of their COPD register and those potentially eligible were invited by
telephone to attend for baseline assessments. We also approached participants within outpatient COPD or
pulmonary rehabilitation hospital clinics in which the trial investigators worked.
Baseline COPD (by spirometry) was classified according to GOLD criteria as mild (forced expiratory volume
in 1 s (FEV1)/forced vital capacity (FVC) <70%; FEV1⩾80% predicted) or moderate (FEV1/FVC <70%;
FEV150–80% predicted) [30, 31]. Those with mild/moderate COPD were eligible for the trial if they
currently smoked or were ex-smokers who had quit within 8 years (agreed by the investigators to still have a
high risk of lung cancer), and both groups had ⩾20 pack-years and/or had smoked for ⩾20 years (thresholds
often used in studies at the time), had no history of malignant disease during the previous 5 years, and were
without serious comorbidities. The trial had multicentre ethics approval and participants gave written
informed consent. The trial is registered at the ISRCTN registry with identifier ISRCTN80745975.
Randomisation
Participants were randomised (1:1) to have annual screening/surveillance or not (controls). Research
nurses telephoned the Cancer Trials Centre (London, UK), where the random allocation (minimisation)
was performed by computer, stratified by location, 10-year age bands, sex, smoking status (ex-smoker or
current smoker) and mild/moderate COPD.
Procedures
Individuals in the control arm had no trial-specific procedures, but to encourage study continuation they
were offered an exit chest radiograph 5 years post-randomisation (or sooner if they withdrew earlier) if
they had not developed lung cancer. This was also offered to the screened group.
Individuals in the screened group had sputum cytology and cytometry as initial tests, and only those with
abnormal findings were offered LDCT and AFB, expecting that these in combination would be better than
either alone at finding cancer in the central airways (by AFB) and peripheral airways (by LDCT)
(supplementary figure S1). The three component tests are described in the supplementary material. Screened
individuals posted sputum samples to the central laboratory for assessment, annually. Those with normal
cytology/cytometry provided sputum samples the following year. Unless participants formally withdrew
from the trial, they were asked to provide sputum annually even if they had not done so previously.
Specimens obtained via AFB were categorised as positive/abnormal if the cells exhibited squamous
metaplasia, mild to severe dysplasia, carcinoma in situ or carcinoma. LDCT (target radiation dose <2 mSv)
was conducted without contrast. A positive/abnormal LDCT (nodule size ⩾9 mm) could initiate cancer
investigations according to local practice. Individuals with both normal AFB and LDCT continued to have
these tests annually. Individuals with abnormal AFB or LDCT, not indicative of invasive cancer, could be
seen 4–6 months later, depending on nodule size. Neither group provided further sputum samples.
All participants were flagged with established cancer registries (Health and Social Care Information Centre
in England or the Northern Ireland Cancer Registry); notifications were received until April 2018.
Research nurses also periodically checked patient records for cancer diagnoses. These two sources provided
the cancer notifications; stage and histology at diagnosis were then manually retrieved from medical records.
Outcomes
The primary outcome was the proportion of lung cancers diagnosed at an early stage, an end-point used
previously [32, 33]: stage I/II for nonsmall cell lung cancer or limited disease for small cell lung cancer.
For completeness, we also examined the proportion with advanced lung cancer ( post hoc), which might be
less influenced by overdiagnosis. Other end-points included: uptake of sputum sampling, AFB and LDCT;
proportion of participants in the surveillance arm with abnormal sputum cytology and/or cytometry;
number of failed/inadequate sputum samples; and prevalence of pre-invasive disease among participants
with abnormal cytometry/cytology.
https://doi.org/10.1183/13993003.00581-2019 3
LUNG CANCER | S.G. SPIRO ET AL.
The proportion of individuals with lung cancer who were diagnosed at an early (or advanced) stage was
compared between the trial arms (relative risk) and also rate ratio using person-years. Additional analyses
were performed to check consistency in the findings. Estimates of screening performance for each test
separately were: 1) sensitivity (proportion of all lung cancers with positive test results) and 2) FPR
(proportion of all those without lung cancer with positive test results).
Statistical methods
15% of controls were expected to be diagnosed at an early stage [34]. From prior LDCT studies and our
pilot study of pre-invasive disease, 80% of cancers were stage I/II [29], so we conservatively used 50%. To
detect a difference of 15% versus 50% required a target sample size of at least 37 lung cancers per arm
(95% power and 5% one-sided significance test pre-specified for this preliminary study). The expected
total proportion of prevalent and incident lung cancers was ∼6% [9], so to obtain 74 cancers required
about 1700 individuals.
Results
1568 participants (785 screened and 783 controls) were recruited from 10 UK centres between August 2007
and March 2011 (figure 1 and supplementary table S1). Baseline characteristics were balanced (table 1).
Participants with COPD (n=1568)
August 2007–March 2011
Exit chest radiography at 5 years or earlier if
participants decided to leave the study
Control arm
Early withdrawal (n=70):¶
51 lost to follow-up
13 subject choice
6 reasons unknown
Lung cancer diagnosis
(primary outcome): 36
Surveillance arm
Early withdrawal (n=145):¶
48 lost to follow-up
95 subject choice
2 reasons unknown
Lung cancer diagnosis
(primary outcome): 42
Control arm (n=783)
5 years usual clinical follow-up
Surveillance arm (n=785)#
5 years annual sputum screen
If either sputum cytology or cytometry
show abnormalities, participants then have
annual AFB and LDCT (frequency of CT
depends on nodule assessment)
Those with normal sputum had annual
sputum tests
Randomisation
Stratified according to site, age, sex,
COPD severity and smoking history
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.
https://doi.org/10.1183/13993003.00581-2019 4
LUNG CANCER | S.G. SPIRO ET AL.
Seven centres routinely collected screening logs of individuals approached: 38.7% of all those contacted by
telephone after the initial search accepted the invitation to attend the pre-trial assessment, of which 42.4%
were randomised (supplementary table S2). The initial uptake (38.7%) was high compared with LDCT
screening trials, and probably due to our focus on COPD patients who might be more aware of
smoking-related risks and their chronic symptoms influenced their decision to enrol, compared with a
more general population. Older individuals were more likely to decline to participate in the trial (OR 1.92
for ⩾70 versus <50 years; p<0.0001). There was no association with sex, but there were geographical
differences (supplementary table S3).
Provision of sputum samples
In the first year (baseline), 89.8% provided sputum samples, but 36 were inadequate for assessment (so
85.2% provided an evaluable sample). Of those with adequate samples, 19.0% were abnormal for either
cytology or cytometry and the rate was lower in subsequent years (table 2). The percentage not providing
an adequate sputum sample increased from 14.8% at baseline up to 46.1% by year 5.
33.2% of all individuals in the screened arm had an abnormal sputum result at any time, of which 22.5%
had abnormal cytology and 12.6% had abnormal cytometry (1.9% (15 out of 785) had both abnormal
cytology and cytometry, 20.6% (162 out of 785) had abnormal cytology only, and 10.7% (84 out of 785)
had abnormal cytometry only). 82.4% (14 out of 17) of sputum-positive cancers were detected at an early
stage compared with 38.1% (eight out of 21) of sputum-negative cancers (p=0.01). Cytology, which used
morphological criteria alone, identified more cancers than image cytometry (12 versus five) among those
with abnormal sputum, so they appeared to be complementary. No cancer had both abnormal cytology
and cytometry. There was no discernible association between type of sputum test and histology,
particularly with having only few cases.
Primary end-point
78 lung cancers were identified (36 and 42 in the control and screened groups, respectively); the Kaplan–
Meier plot is given in supplementary figure S2. The median follow-up was 5 years, matching the planned
duration in the protocol for each participant.
Table 3 shows histology and cancer staging. Overall, 54.8% of screened individuals versus 45.2% of
controls, with known staging, were diagnosed at an early stage (similar to 59.4% versus 48.1% for nonsmall
cell lung cancer alone). Table 4 compares stage at diagnosis between the trial arms. The relative risk for
early-stage cancer detection was 1.21 (95% CI 0.75–1.95; one-sided exact p=0.24) or 0.82 (95% CI 0.52–1.31)
TABLE 1 Baseline characteristics of the randomised individuals
Controls Screened
Participants 783 785
Sex
Female 373 (48) 377 (48)
Male 410 (52) 408 (52)
Smoking status
Current smoker 435 (56) 439 (56)
Ex-smoker 348 (44) 346 (44)
COPD severity
Mild 195 (25) 196 (25)
Moderate 588 (75) 588 (75)
Missing/unknown 0 1
Source of participants
General practice 622 (79) 619 (79)
Pulmonary rehabilitation programme 95 (12) 94 (12)
Hospital outpatients 35 (4) 42 (5)
Lung function laboratory 31 (4) 30 (4)
Mean age at randomisation years 63 63
Mean age when started smoking years 16 16
Mean age when stopped smoking years 61 (n=348) 62 (n=346)
Mean cigarettes smoked per day n 24 24
Mean smoking duration years 45 45
Mean pack-years 53 54
Data are presented as n or n (%). COPD: chronic obstructive pulmonary disease.
https://doi.org/10.1183/13993003.00581-2019 5
LUNG CANCER | S.G. SPIRO ET AL.
TABLE 2 Sputum results in the screened group in each year
Baseline Year 2 Year 3 Year 4 Year 5
Cytology or cytometry result
#
785
¶
639
¶
560
¶
516
¶
447
¶
Normal 542 (81) 398 (87) 343 (94) 300 (89) 221 (92)
Abnormal
Low grade 111 (17) 51 (11) 18 (5) 33 (10) 17 (7)
High grade 16 (2) 6 (1) 2 (1) 4 (1) 3 (1)
Died or cancer diagnosed since last visit 19 22 24 32
No sputum result 116 (15)
+
184 (29)
+
197 (35)
+
179 (35)
+
206 (46)
+
Did not provide sample 68 131 155 157 195
Tried but unable to provide sample 12 10 3 8 5
Provided spontaneous sample
§
33 43 38 14 6
Provided induced sample
§
30100
Cytology result (where available) 604 400 301 285 198
Normal 503 (83) 358 (90) 289 (96) 269 (94) 191 (96)
Abnormal
Low grade 86 (14) 36 (9) 11 (4) 13 (5) 5 (3)
High grade 15 (2) 6 (2) 1 (<1) 3 (1) 2 (1)
Cytometry result (where available) 603 418 350 323 237
Normal 570 (95) 400 (96) 342 (98) 298 (92) 221 (93)
Abnormal
Low grade 32 (5) 18 (4) 7 (2) 22 (7) 15 (6)
High grade 1 (<1) 0 1 (<1) 3 (1) 1 (<1)
Data are presented as n or n (%); the percentages in brackets for normal or abnormal sputum are based
on the total number who had a sputum result as the denominators.
#
: in some cases only cytology or
cytometry results were available (not both) and so the result classification was based on the known result
if a repeat sputum sample was not done;
¶
: total number of individuals expected to provide sputum
samples in each year (i.e. excluding those who had an abnormal sputum result, died or were diagnosed
with cancer who were no longer expected to provide sputum samples);
+
: the percentage who did not
provide a sputum sample, out of the total expected;
§
: sample was inadequate for cytology and cytometry
assessment.
TABLE 3 Histology and stage of the lung cancers
Controls Screened
Cancers 36 42
Small cell 5 (14) 10 (24)
Adenocarcinoma 8 (22) 11 (26)
Squamous 9 (25) 14 (33)
Large cell 0 1 (2)
Other histology 9 (25) 5 (12)
Unknown 5 (14)
#
1 (2)
Nonsmall cell lung cancer 27
¶
32
¶
Stage I 11 16
Stage II 2 3
Stage III 6 4
Stage IV 7 9
Unknown 1
Small cell lung cancer 510
Limited disease 1 4
Extensive disease 4 6
Data are presented as n or n (%). The exit chest radiography found five cancers in the screened group
(these had no sputum samples or their sputum tests were normal throughout the trial: cancer stage was I
(n=2), II (n=1), IV (n=1) and limited disease (n=1)) and six cancers in the control group (stage was I (n=3), III
(n=1), IV (n=1) and missing (n=1)).
#
: diagnosed at nontrial sites (unknown or not set up for the trial so no
access to medical records; these cancers were notified through registries and we found staging for one of
the five cases);
¶
: includes one patient in each trial group where histology was unknown but stage was
available.
https://doi.org/10.1183/13993003.00581-2019 6
LUNG CANCER | S.G. SPIRO ET AL.
for advanced cancers. Hence, there was no clear stage shift. In the sensitivity analyses, the rate ratio was a
secondary analysis (not pre-specified in the trial protocol) and although the estimate for early-stage
disease made screening appear favourable (1.83, 95% CI 0.94–3.54), there was no corresponding reduction
in advanced cancers (1.24, 95% CI 0.65–2.39). Furthermore, the size of the absolute difference in stage
(either early or advanced) is not clinically important.
Screening performance
Table 5 summarises the findings of all three tests among the lung cancers in the screened group: 44.7%
had an abnormal sputum sample, but 55.3% (21 cases) had normal results for all samples.
Figure 2 summarises sensitivity and FPR for all three tests estimated only among individuals who actually
had the tests (labelled “direct”) and among all 785 individuals randomised to surveillance (labelled
“overall”) (see further description in the supplementary material). The measures for LDCT and AFB can
only be interpreted in the context of being second-stage tests, and do not represent performance for
population screening where everyone has the test(s).
In the screened group, the overall sensitivity for sputum was 40.5% and FPR was 32.8%. When examining
only those who had sputum results, the direct sensitivity for cytology/cytometry was 44.7% and the
corresponding FPR was 38.7% (figure 2). Hence, sputum testing did not detect many cases. The direct
FPR at baseline only was 18.7% and was lower in the subsequent year at 13.2%. Sputum testing had
insufficient screening performance.
188 individuals had an AFB at any time during the trial (an additional 73 declined or did not attend;
uptake 72.0%). Only 11 sputum-positive cancer cases had AFB and the direct sensitivity was 45.5%, with a
high FPR of 39.5% ( figure 2). Among participants with abnormal sputum, 38% had pre-invasive disease
(72 out of 188 mild to severe dysplasia or metaplasia); only three of these (two moderate dysplasia and
one squamous metaplasia) later developed lung cancer.
TABLE 4 Comparison of stage at diagnosis among those with lung cancer (in total there were 42 and 36 lung cancers in the
screened and control arms, respectively)
Early-stage disease (I/II for
nonsmall cell cancer and limited
disease for small cell cancer)
(primary outcome measure)
Advanced disease (III/IV for
nonsmall cell cancer and
extensive disease for small
cell cancer)
Screened Controls Screened Controls
Main analysis (cancer cases with known stage) 54.8% (23/42) 45.2% (14/31) 45.2% (19/42) 54.8% (17/31)
Relative risk 1.21
(95% CI 0.75–1.95; p=0.24)
Relative risk 0.82
(95% CI 0.52–1.31; p=0.24)
Sensitivity analyses
All cancers included in the denominators 54.8% (23/42) 38.9% (14/36) 45.2% (19/42) 47.2% (17/36)
Relative risk 1.41
(95% CI 0.86–2.30; p=0.09)
Relative risk 0.96
(95% CI 0.59–1.55; p=0.50)
Excluding cancers found by exit chest radiography
(n=5 screened; n=6 controls)
51.3% (19/37) 42.3% (11/26) 48.9% (18/37) 57.8% (15/26)
Relative risk 1.21
(95% CI 0.70–2.09; p=0.30)
Relative risk 0.84
(95% CI 0.53–1.35; p=0.30)
Cancer incidence expressed as person-years 6.8 per 1000 3.7 per 1000 5.6 per 1000 4.5 per 1000
Rate ratio 1.83
(95% CI 0.94–3.54; p=0.049)
Rate ratio 1.24
(95% CI 0.65–2.39; p=0.31)
Cancer incidence expressed as person-years and excluding
cancers found by exit chest radiography
5.7 per 1000 3.0 per 1000 5.4 per 1000 4.0 per 1000
Rate ratio 1.92
(95% CI 0.91–4.03; p=0.049)
Rate ratio 1.33
(95% CI 0.67–2.64; p=0.24)
Relative risk or rate ratio of >1 for early stage indicates that screening was effective (more early-stage disease found in the screened group).
Relative risk or rate ratio of <1 for advanced stage indicates that screening was effective (less advanced-stage disease found in the screened
group). Rate ratio, which uses person-years, might be less affected by overdiagnosis and unknown disease stage in the
denominators. All p-values are one-sided (specified in the protocol) because of interest only in finding more early-stage cancers in the
screened arm. LungSEARCH is not a definitive assessment of a screening policy, so it is analogous to phase II treatment trials that commonly
use one-sided statistical tests.
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LUNG CANCER | S.G. SPIRO ET AL.
239 individuals had LDCT at any time during the trial (an additional 22 declined or did not attend;
uptake 91.6%). 16 sputum-positive cancer cases had LDCT and the direct sensitivity (nodule size ⩾9 mm)
was 100%, with a FPR of 16.1% (figure 2).
Other cancers, mortality and smoking status
Supplementary table S4 summarises the end of trial status, including the number who had an exit chest
radiograph (430 screened and 486 controls, a difference that is unlikely to have materially biased the cancers
found). Other cancer types were balanced between the two groups. Lung cancer mortality (16 screened
versus 21 controls; hazard ratio 0.86; p=0.65), and all-cause mortality (hazard ratio 0.87; p=0.39) were similar
(supplementary figure S3). Among those who were current smokers at baseline (with known smoking status
at 5 years), 15.0% of controls and 17.7% of screened individuals had stopped completely during the trial.
Adverse events
In the surveillance group, one person had a COPD exacerbation possibly linked to AFB and another
committed suicide unrelated to study participation.
Discussion
We examined a sequential approach to only offer LDCT and AFB as second screening tests among
particularly high-risk individuals with abnormal sputum cytology/cytometry. Had we found a substantial
stage shift, a larger randomised trial of lung cancer mortality would overcome lead-time bias and
overdiagnosis. LungSEARCH complements LDCT trials [2, 6], including the only other randomised trial
of lung cancer screening conducted in the UK (the UK Lung Cancer Screening Trial) [33].
Although LungSEARCH preceded NLST and NELSON [5, 6], the concept that an effective, cheap and
easy initial test (sputum) could be considered for a wider group of smokers than is currently eligible for
LDCT remains valid. This is because current criteria exclude many high-risk individuals. Applying US
Preventive Services Task Force criteria [7], 25% of the LungSEARCH participants would be ineligible for
TABLE 5 Test findings among all 42 lung cancers in the screened group
Sputum result 38
Abnormal 17 (45)
Normal 21 (55)
No sputum or both cytology/cytometry inadequate 4
Cytology result 38
Abnormal 12 (32)
Normal 26 (68)
Cytometry result 38
Abnormal 5 (13)
Normal 33 (87)
Worst AFB result 11
Carcinoma 2 (18)
Moderate dysplasia 2 (18)
Squamous metaplasia 1 (9)
No abnormality 6 (55)
Sputum and LDCT results 42
No sputum samples (hence no LDCT) 4 (2)
#
Sputum normal throughout study (hence no LDCT) 21 (3)
#
Sputum abnormal, LDCT detected cancer directly afterwards
¶
8
Sputum abnormal, LDCT detected cancer at a later follow-up
+
7
Sputum abnormal, LDCT did not flag for cancer investigation
§
1
Sputum abnormal, but no LDCT done 1
Data are presented as n or n (%), unless otherwise stated. AFB: autofluorescence bronchoscopy; LDCT:
low-dose computed tomography.
#
: the numbers in brackets are lung cancers found by the exit chest
radiography at 5 years;
¶
: the abnormal sputum result led directly to an abnormal CT (i.e. a nodule ⩾9 mm)
and the individuals were referred for immediate diagnostic investigations;
+
: individuals had an abnormal
sputum and the abnormal CT that found the cancer was one of the later follow-up scans (in three cases,
the first CT with a nodule ⩾9 mm was some years before the cancer diagnosis but subsequent CT scans
indicated that the nodule had shrunk before the final CT that led to diagnostic investigations showed
nodule growth);
§
: the individual had normal annual CT scans during the trial (the cancer was found by a
CT scan given outside of the protocol when the person finished the study; a suspicious large nodule
⩾9 mm had appeared).
https://doi.org/10.1183/13993003.00581-2019 8
LUNG CANCER | S.G. SPIRO ET AL.
LDCT. We hoped, therefore, that our sequential approach could find many cancers without offering many
more LDCT scans.
We exceeded the target of 50% of lung cancers diagnosed at an early stage using our surveillance strategy
(observed 55%), but the lack of effect was driven by the high percentage of unscreened participants
diagnosed at early stage (45% observed instead of 15% expected when LungSEARCH was designed in 2006).
Prominent health campaigns have encouraged individuals with persistent cough to seek medical attention
sooner, explaining why more lung cancers are now diagnosed earlier, as seen in UK audit data [35].
Although we reached the target sample size and hence had power for the expected primary outcome
(50% versus 15% early-stage cancers), the observed small stage shift of 55% versus 45% is not worthwhile
clinically.
In LungSEARCH, 90% of those who attempted a sputum sample at baseline did so successfully. However,
an increasing number of individuals did not provide sputum over time and four lung cancers were among
participants who provided no samples. Hence, 60% of all lung cancers in the screened group did not have
the opportunity for earlier detection by LDCT. Furthermore, of the cancers with sputum samples, only
45% had abnormal results (referred for LDCT and AFB). This is lower than the expected 80% from a
study that had more males than LungSEARCH and 59% had moderate/severe cough, although in that
study the sensitivity of sputum decreased to 21% for stage I adenocarcinoma [21]. It is unclear why
sputum was not effective. Unlike cervical cancer screening, which involves active removal of cells in the
cervix, detecting lung cancer in sputum depends on cells naturally shed into the bronchi, which is
influenced by tumour location and histology. It could be that malignant cells in the early stages of lung
cancer are still anchored to the basement membrane and each other, so that not enough travel into the
lumen. Although sputum testing has the appeal of being conducted at home, avoiding travel to screening
clinics which is required by LDCT (especially from rural areas), the lower number of individuals who
provided samples from year 2 plus the fact that several samples were inadequate together makes sputum
testing less useful than LDCT, in which a result could be obtained in almost all cases who are scanned.
AFB uptake was not high (72%), because several participants informed us that they found AFB off-putting
or uncomfortable [36]. Systematic reviews of AFB show heterogeneous study designs and variable
Sputum
n=669 participants
AFB (sputum positives only)
n=188 participants
LDCT (sputum positives only)
n=239 participants
"Direct" performance
(only those who had the test)
No lung cancer: 631
Lung cancer: 38
Abnormal: 244
Normal: 387
Abnormal: 17
Normal: 21
FPR: 38.7% (244/631)
18.7% (118/631) first year only
13.2% (55/417) second year only
Sensitivity: 44.7% (17/38)
"Overall" performance based on all
randomised participants (n=785)
FPR: 32.8% (244/743)
15.9% (118/743) first year only
7.4% (55/743) second year only
Sensitivity: 40.5% (17/42)
No lung cancer: 223
Lung cancer: 16
Abnormal:
nodule ≥9 mm: 36
nodule ≥5 mm: 81
Abnormal:
nodule ≥9 mm: 16
FPR:
16.1% (36/223)
36.3% (81/223)
Sensitivity: 100% (16/16)
FPR:
4.8% (36/743)
10.9% (81/743)
Sensitivity: 38.1% (16/42)
No lung cancer: 177
Lung cancer: 11
Abnormal: 70
Normal: 107
Abnormal: 5
Normal: 6
FPR: 39.5% (70/177)
Sensitivity: 45.5% (5/11)
FPR: 9.4% (70/743)
Sensitivity: 11.9% (5/42)
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).
https://doi.org/10.1183/13993003.00581-2019 9
LUNG CANCER | S.G. SPIRO ET AL.
sensitivities (67–100%) [37–39]. While AFB has value for individuals presenting with symptomatic lung
problems, LungSEARCH suggests a limited role in screening. Improvements in the optics in
videobronchoscopes have also reduced the need for the fluorescence mode and the shift in the natural
history of lung cancer from central to more peripheral tumours further limits the utility of AFB.
Very few reports have examined lung cancer screening in COPD. The NLST substudy (in the NLST American
College of Radiology Imaging Network (ACRIN) cohort) indicated a shift towards early-stage cancer among
COPD participants who had LDCT compared with those who had chest radiography [40], but no reduction
in lung cancer deaths [41]. The Danish Lung Cancer Screening Trial hinted that COPD participants with
>35 pack-years might benefit from LDCT [42], whereas in a nonrandomised matched cohort study of
mild/moderate COPD, 80% of lung cancers in those who had LDCT were diagnosed at stage I versus 0%
among those without LDCT, with corresponding lung cancer deaths of one versus 12 (p=0.002) [43].
Our trial had limitations. As in all cancer screening trials, participants could not be blinded, hence the
potential for bias (e.g. controls were aware of the trial objectives possibly making them more alert to
symptoms and seeking medical advice sooner), which might contribute to the higher than expected
proportion of early-stage cancers. Similarly, participants who stopped having the screening tests earlier
might lead to a lower percentage diagnosed with early-stage cancer. We had no data on cancer treatments
nor retrieved histological specimens for central pathology review, as these required additional local
resources. Overdiagnosis bias is an established issue in studies examining stage shift. We found slightly
more lung cancers in the screened group (n=42) than controls (n=36) and the different denominators
(expected in screening studies) can influence the comparison of stage shift. Therefore, we allowed longer
time for cancer notifications from the registries and to arrange the exit chest radiographs in the controls.
Although we did not find a material difference in cancer stage in LungSEARCH, there is some evidence
that individuals with COPD tend to develop more aggressive lung cancers [44, 45]. The NLST trial
suggests that overdiagnosis from LDCT screening is only seen in individuals with normal lung function,
not in COPD, although this should be confirmed in other studies [40]. Finally, we did not know whether
some of the control group participants had LDCT during the trial, which might have reduced the effect of
our screening policy, although we expect this to be very few because LDCT is not recommended routinely.
LDCT screening can be made more efficient using risk algorithms (including age and smoking intensity),
where only those with a risk exceeding a specified cut-off are offered LDCT. Such models detect more lung
cancers with fewer false positives than current criteria [7]. Several risk calculators contain COPD as a
factor [46–48], and demonstration/pilot studies in the UK conclude that the Liverpool Lung Project risk
model and/or the PLCO
M2012
model (from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Trial) should be used to identify a high-risk population in screening programmes [49–52].
These recommendations are supported by LungSEARCH in which LDCT detected all lung cancers among
sputum positives (although we cannot tell how well LDCT would have performed in the sputum-negative
cases and our trial did not include individuals without COPD).
In conclusion, our sequential screening strategy did not show a stage shift in cancer diagnosis. Our trial
has implications for future research and practice. First, it provides evidence from a large randomised trial
that it is difficult to find ways of targeting LDCT screening to make it more efficient (other than
risk-based algorithms). LDCT should therefore be offered to all eligible individuals within planned
screening programmes. Second, our study was based on particularly high-risk individuals (smokers with
COPD) and many unscreened individuals (controls) were diagnosed at an early cancer stage, indicative of
them seeking medical attention sooner. This probably means that this group is more receptive to screening
and early detection than previously thought, such that the uptake of LDCT within organised programmes
could be high among these individuals. Third, LDCT detected all lung cancers among COPD patients in
our trial who were sputum positive, which is suggestive evidence that planned screening programmes
should consider sufficient inclusion of COPD.
Acknowledgements: We are indebted to all of the trial participants who kindly agreed to take part and be followed up.
We thank all of the supporting staff in radiology, pathology and data management at each of the recruiting sites. We
also thank the independent data monitoring committee: Marc Lipman (University College London and Royal Free
London NHS Foundation Trust, London, UK), Angshu Bhowmik (Homerton University Hospital NHS Foundation
Trust, London, London, UK) and Stephen Duffy (Queen Mary University of London, London, UK). Finally, we are
grateful to all of the general practitioners who participated.
Author contributions: The original study conception came from S.G. Spiro, and was developed with J. George, P.L. Shah,
R.C. Rintoul, M. Novelli, P. Shaw, G. Kocjan, C. Griffiths, M. Falzon, P. Rabbits and A. Hackshaw. Clinical leads at each
recruiting centre were P.L. Shah, R.C. Rintoul, J. George, S. Janes, M. Callister, R. Booton, N. Magee, M. Peake,
P. Dhillon and K. Sridharan. Central sputum testing was led by M. Novelli, G. Kocjan and M. Falzon. Radiology
oversight came from P. Shaw and S. Padley. M.N. Taylor and A. Ahmed performed the central radiology audit. Expertise
in general practice was led by C. Griffiths. Senior research nurses involved in recruitment and management were N.
https://doi.org/10.1183/13993003.00581-2019 10
LUNG CANCER | S.G. SPIRO ET AL.
Chinyanganya, V. Ashford-Turner and S. Lewis. N. Counsell did the statistical analyses with A. Hackshaw. Study
coordination and data management were done by Y. Ngai and J. Allen. S.G. Spiro had oversight of the study
organisation. All authors were involved in commenting on the manuscript and have approved the submitted version.
We also acknowledge Alison Mitchell, who was the research nurse in Cambridge/Papworth Hospital for several years.
The lead author had full access to the data and final responsibility to submit for publication.
Conflict of interest: S.G. Spiro has nothing to disclose. P.L. Shah has nothing to disclose. R.C. Rintoul has nothing to
disclose. J. George has nothing to disclose. S. Janes reports personal fees for advisory board work from BARD1, Achilles
Therapeutics and AstraZeneca, personal fees for conference travel from AstraZeneca, outside the submitted work.
M. Callister has nothing to disclose. M. Novelli has nothing to disclose. P. Shaw has nothing to disclose. G. Kocjan has
nothing to disclose. C. Griffiths has nothing to disclose. M. Falzon has nothing to disclose. R. Booton has nothing to
disclose. N. Magee has nothing to disclose. M. Peake reports personal fees for lectures from Roche Products Ltd, grants
and personal fees for lectures from MSD Ltd, personal fees for advisory board work from BMS and Pfizer Ltd, outside
the submitted work. P. Dhillon has nothing to disclose. K. Sridharan has nothing to disclose. A.G. Nicholson has
nothing to disclose. S. Padley has nothing to disclose. M.N. Taylor has nothing to disclose. A. Ahmed has nothing to
disclose. J. Allen has nothing to disclose. Y. Ngai has nothing to disclose. N. Chinyanganya has nothing to disclose.
V. Ashford-Turner has nothing to disclose. S. Lewis has nothing to disclose. D. Oukrif has nothing to disclose.
P. Rabbits has nothing to disclose. N. Counsell has nothing to disclose. A. Hackshaw has nothing to disclose.
Support statement: LungSEARCH was funded by Cancer Research UK (C5784/A17168). R.C. Rintoul was part funded
by the NIHR Cambridge BRC and CRUK Cambridge Centre. S. Janes is a Wellcome Trust Senior Fellow in Clinical
Science (WT107963AIA). This work was undertaken at UCLH/UCL who received a proportion of funding from the
Dept of Health’s NIHR Biomedical Research Centre’s funding scheme (A. Hackshaw and S. Janes). Auto-florescence
bronchoscopy (D-light) systems in some centres were kindly provided by Karl Storz (Tuttlingen, Germany). Cancer
Research UK (and its external expert review panel) reviewed and approved the trial and its design before funding the
study, after which it was not involved in the conduct, analysis or report writing. Funding information for this article has
been deposited with the Crossref Funder Registry.
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