Interstitial Lung Disease Within a Lung Cancer Screening
Conditions: Interstitial Lung Disease
Sponsor: Manchester University NHS Foundation Trust

1 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
 
 
 
 
Interstitial lung disease within a lung cancer 
screening programme 
 
 
 
IRAS Project ID: 233809 
 
 
Sponsor: Manchester University NHS Foundation Trust 
 
Chief Investigator: Dr Nazia Chaudhuri 
 
 
 
 
 
 
Protocol version history 
Original protocol 
Version 1.0   23th August 2017 
 
 
 
 
 
 

2 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
Study contacts 
 
Role 
Name 
Contact details 
Chief Investigator 
Dr Nazia Chaudhuri 
Consultant in Respiratory Medicine, 
Joint Clinical Lead in ILD 
and Honorary Senior Lecturer 
Manchester University NHS Foundation 
Trust. 
nazia.chaudhuri@nhs.net 
Co-Investigator 
Professor Janelle Yorke 
Lead for Christie Patient Centred Research 
Group, The Christie NHS Foundation Trust, 
Wilmslow Road, Manchester M20 4BX 
janelle.yorke@manchester.ac.uk 
Co-investigator 
Dr Haval Balata 
Clinical Research Fellow 
Manchester University NHS Foundation Trust 
haval.balata@MFT.ac.uk 
Co-investigator 
Dr Phil Crosbie 
Consultant in Respiratory Medicine  
and Honorary Senior Lecturer 
Manchester University NHS Foundation 
Trust. 
philip.crosbie@manchester.ac.uk 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
Contents 
1 
Background ..................................................................................................................................... 5 
1.1 
Interstitial Lung Disease .......................................................................................................... 5 
1.2 
Lung Cancer ............................................................................................................................. 5 
1.3 
Low dose CT screening for lung cancer ................................................................................... 6 
1.3.1 
Optimising screening participation ................................................................................. 6 
1.3.2 
Defining the threshold for screening .............................................................................. 6 
1.4 
ILD and lung cancer screening ................................................................................................ 7 
2 
Rational for study ............................................................................................................................ 7 
3 
Aims and Objectives ........................................................................................................................ 8 
3.1 
Objectives................................................................................................................................ 8 
3.1.1 
Primary Objectives .......................................................................................................... 8 
3.1.2 
Secondary Objectives ...................................................................................................... 8 
3.2 
Outcome Measures ................................................................................................................. 8 
3.2.1 
Primary Measures ........................................................................................................... 8 
3.2.2 
Secondary Measures ....................................................................................................... 8 
4 
Patient Selection Criteria ................................................................................................................ 9 
4.1 
Inclusion criteria ...................................................................................................................... 9 
4.2 
Exclusion criteria ..................................................................................................................... 9 
5 
Study Design.................................................................................................................................. 10 
4.1 Screening service: ....................................................................................................................... 10 
4.2 Screening LDCT scans: ................................................................................................................. 10 
4.3 ILD MDT: ...................................................................................................................................... 10 
4.4 Study population: ........................................................................................................................ 10 
6 
Data storage and analysis ............................................................................................................. 11 
7 
Adverse events .............................................................................................................................. 11 
8 
Quality assurances ........................................................................................................................ 11 
9 
Ethical considerations ................................................................................................................... 12 
9.1 
Patient protection ................................................................................................................. 12 
9.2 
Subject confidentiality .......................................................................................................... 12 
9.3 
Informed consent .................................................................................................................. 12 
10 
Administrative responsibilities.................................................................................................. 12 

4 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
10.1 
Amendments ......................................................................................................................... 12 
10.2 
Reporting............................................................................................................................... 13 
11 
Study sponsorship and insurance ............................................................................................. 13 
12 
Publication policy ...................................................................................................................... 13 
 
List of abbreviations 
BTS 
 
British Thoracic Society 
COPD 
 
Chronic obstructive pulmonary disease 
CXR 
 
Chest x-ray 
FSS 
 
Fatigue Severity Scale 
HADS 
 
Hospital Anxiety and Depression score 
HRQoL  
Health related quality of life 
ILA 
 
Interstitial lung abnormalities 
ILD 
 
Interstitial lung disease 
IPF 
 
Idiopathic pulmonary fibrosis 
K-BILD  
Kings Brief Interstitial Lung Disease 
LCQ 
 
Leicester Cough Questionnaire 
LDCT 
 
Low dose computed tomography 
LHC 
 
Lung health check 
MDT 
 
Multidisciplinary team 
MFT 
 
Manchester University NHS Foundation Trust 
NHS 
 
National health service 
NLST 
 
National lung screening trial 
NSCLC  
Non-small cell lung cancer 
PI 
 
Principle investigator 
PIS 
 
Patient information sheet 
PLCO 
 
Prostate, lung, colorectal and ovarian study 
QoL 
 
Quality of life 
RCTs 
 
Randomised controlled trials 

5 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
UCSD-SBQ 
University of California San Diego Shortness of Breath Questionnaire 
VAS 
 
Visual Analogue Scale 
1 Background 
 
1.1 
Interstitial Lung Disease 
Interstitial lung disease (ILD) represents a heterogeneous group of diseases of either known or unknown 
aetiology with different pathogenesis and prognosis. Idiopathic pulmonary fibrosis (IPF) is a chronic 
progressive fibrotic lung disease and the most common form of ILD. It is characterised by an irreversible loss of 
lung function with the development of debilitating breathlessness that ultimately leads to death. The 
prognosis of IPF is worse than most cancers with an average life expectancy of three to five years 1. For 
decades immunosuppression with a combination of corticosteroids and azathioprine was the standard 
treatment; however it was subsequently shown that this regimen was actually associated with increased 
mortality 2. Until recently there has been a dearth of evidence-based treatment options available for managing 
IPF.  Over the last 5 years, disease modifying anti-fibrotic agents have been developed which have been shown 
to slow the progression of the disease 3,4. As a consequence, earlier diagnosis through a specialist 
multidisciplinary team (MDT) has become an essential step in the management of ILD 5. However, patients 
with IPF often report significant delays before receiving the correct diagnosis 6. The British Thoracic Society 
(BTS) IPF registry demonstrates that patients often have symptoms for over 12 months and have a significant 
disease burden before presenting to a specialist 7. With the availability of disease modifying management 
strategies it is important to identify patients early in their disease course to have maximal impact on the 
natural progression of ILDs specifically IPF. Lung cancer screening strategies provide a unique opportunity to 
identify patients with previously undiagnosed ILDs. 
1.2 
Lung Cancer 
Lung cancer is the world’s leading cause of cancer-related death (1.6 million deaths/year) 8. The main risk 
factor is smoking 9. Prevention through smoking cessation is paramount 10-12, however unaided quit rates are 
<5% at 12 months 13. There are 9 million smokers in England 13, smoking-related morbidity and mortality will 
remain a major public health burden for many years to come 14. In the UK, 45,500 people are diagnosed with 
lung cancer each year. Most patients (≈70%) present with advanced incurable disease, often as an emergency 
15. Survival is poor (1-yr 32%, 5-yr 9.5%) 16,17 and lower than other equivalent nations 18,19. Manchester has the 
highest rate of premature death in the country and lung cancer is the leading cause, responsible for more 
deaths than all other cancers combined 20. Detection and radical treatment of early stage disease is associated 
with long-term survival. However, early stage lung cancer is often clinically silent or associated with non-
specific symptoms, therefore the window for curative treatment is frequently lost. More effective diagnosis of 
symptomatic lung cancer through awareness campaigns, e.g. ‘Be Clear on Cancer’, is valuable but this 
approach alone is unlikely to transform outcomes, as symptoms are most commonly associated with advanced 
disease 21.  

6 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
1.3 
Low dose CT screening for lung cancer 
Numerous observational 22-24 and randomised controlled trials (RCTs) 25-30, in asymptomatic at risk populations, 
have demonstrated the efficacy of low dose computed tomography (LDCT) to detect early stage non-small cell 
lung cancer (NSCLC), the most common pathological subtype (≈88%). The largest study, the National Lung 
Screening Trial (NLST, n=53,454), demonstrated a reduction in lung cancer specific (20%) and overall mortality 
(6.7%) with annual LDCT screening compared to chest x-ray (CXR) 26. The US Preventative Services Task Force 
now recommends individuals aged 55-80 with a smoking exposure compatible with NLST be offered annual 
LDCT screening 31. Recently, the UK Lung Cancer Screening Pilot (UKLS) confirmed the benefit of screening 
high-risk smokers with LDCT in a UK setting 28. Most cancers detected were early stage (85.7%, n=36/42) and 
83.3% underwent surgical resection (national resection rate 16%) 32. Estimated cost effectiveness was £8,466 
per quality adjusted life year (QALY) 28, well below the NICE threshold for UK implementation (£20-
30,000/QALY). Mortality data from the European NELSON randomised trial (n=15,822) is awaited 25. Several 
important issues that remain unresolved include optimisation of identification of high-risk individuals for 
screening, embedding smoking-cessation in screening programmes, ensuring participation in ‘hard to reach' 
at-risk populations 33,34, and understanding how best to deal with additional non-lung cancer findings. 
 
1.3.1 Optimising screening participation 
Current smoking and lower socio-economic status (SES) were associated with reduced participation in UKLS 35, 
this participation bias has been reported in other RCTs 36,37 and inequalities in uptake according to SES is 
common to other screening programmes 38,39. Several studies report differences in attitudes to screening 
between current and never smokers 40-42; how best to identify and engage this ‘hard-to-reach’ population 
remains a critical issue 43-45 and a priority area for implementation 46,47. Travel was the most common reason 
for non-participation in UKLS 48, therefore the Manchester Early Detection of Lung Disease Pilot used a mobile 
CT scanner located in convenient community settings to improve accessibility, an approach that has been 
effective in breast cancer screening 49. 
 
1.3.2 Defining the threshold for screening 
Retrospective analysis of NLST, after stratification according to lung cancer risk, demonstrated that the 
majority of cancers (88%) were detected in the three highest risk quintiles and only 1% in the lowest 50. The 
number needed to screen (NNS) to save 1 life was 161 in the highest risk group and 5,276 in the lowest; higher 
lung cancer risk was also associated with lower screening-related harms 51. The more precise selection of 
higher risk smokers may improve screening efficacy, but the optimal method to select participants is unclear. 
In UKLS, screening was offered if 5-year lung cancer risk was ≥5%, as calculated by the Liverpool Lung Project 
model (LLPv2) 52. Another model (PLCOm2012), developed using the much larger Prostate, Lung, Colorectal, 

7 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
Ovarian RCT (PLCO, n= 154,901) 53, performed significantly better than NLST selection criteria (sensitivity 83% 
vs. 71%) and 41.3% fewer cancers were missed 54. Further analysis indicated that the mortality benefit of LDCT 
screening was evident only above a 6-year lung cancer risk threshold of 1.5% when NNS to prevent one LC 
death was lower than NLST (NNS: PLCO 255 vs. NLST 320) 55.  
 
1.4 
ILD and lung cancer screening 
Several common features in the pathogenesis of ILD and lung cancer have been determined. There is evidence 
to suggest an association between various forms of ILD and lung cancer 56. Several studies have published data 
on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening. A 
trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 
participants 22. An Irish trial identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who 
underwent low-dose CT screening for lung cancer 57. Sverzellati et al evaluated 692 participants in the 
Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 
(15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial 
pneumonia in 26 (3.8%) 58. The National Lung Screening Trial reported that the frequency of “clinically 
significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%. A retrospective 
analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities (ILA) in 86 
participants (9.7%) 59. These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic 
in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884. Follow-up CT at 2 years in this trial 
demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, 
while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were 
more common in those who currently smoked and in those with more pack-years of cigarette smoking. These 
trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung 
disease in this at-risk population which is important for prognosis and subsequent management. Interstitial 
lung abnormalities progression on CT has been shown to be associated with increased rate of pulmonary 
function decline and increased mortality 60. No direct comparison has been made between ILD patients 
diagnosed through a screening programme and those diagnosed through a ‘standard’ non-screening pathway 
and the impact this may have on long term outcomes. 
 
2 Rational for study 
A number of lung cancer screening programmes are underway in the UK with the aim of establishing a national 
screening programme in the future. As well as identifying early stage lung cancer, these programmes also 
provide a unique opportunity to diagnose other prevalent respiratory diseases, including ILD, at an early 
asymptomatic stage. Early detection of ILD through these programmes provides an opportunity to diagnose 
and establish treatment early and potentially have a significant impact on disease progression and 
symptomatic burden. 

8 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
3 Aims and Objectives 
 
3.1 
Objectives 
3.1.1 Primary Objectives 
To determine the prevalence of ILD in a community-based lung cancer screening programme. 
 
3.1.2 Secondary Objectives 
To compare patients diagnosed with ILD in a lung cancer screening programme to those diagnosed through 
routine care, assessing a number of parameters: 
1. Quality of life, symptoms and psychological burden at diagnosis. 
2. MDT agreed type and radiological pattern of disease as depicted by ATS/ERS ILD criteria 61. 
3. Lung function (Forced vital capacity (FVC) and transfer factor (DLCO) at diagnosis. 
4. Treatment strategies 
 
3.2 
Outcome Measures 
3.2.1 Primary Measures 
The prevalence and incidence of ILD in participants of a community-based lung cancer screening programme. 
 
3.2.2 Secondary Measures 
 
 
Symptom burden and duration as per standardised clinical history proformas. 
 
Quality of life and symptom burden using the following questionnaires: 
o 
SF-36: a widely used validated non-disease-specific questionnaire to assess QoL in multiple 
diseased populations 62. The SF-36 is a generic HRQoL instrument, comprising 36 items, 
grouped into eight domains: physical functioning, role-physical, bodily pain, general health, 
vitality, social functioning, role emotional, and mental health. Scores are converted into a 
100-point scale, higher scores indicating better QoL. The SF-36 has been validated for use in 
ILD groups including IPF 63.  
o 
Kings Brief Interstitial Lung Disease (K-BILD) 64: developed and validated for specific use in 
ILD patients. It comprises 3 domains (psychological, breathlessness and activities, chest 
symptoms and a total score). Scores range from 0-worst to 100-best.  
o 
The University of California San Diego Shortness of Breath Questionnaire (UCSD-SBQ): a 24-
item dyspnea questionnaire that asks respondents to rate themselves from 0 (“Not at all”) to 

9 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
5 (“Maximally or unable to do because of breathlessness”) in two areas: 1) how short of 
breath they are while performing various activities (21 items); and 2) how much shortness of 
breath, fear of hurting themselves by over exerting, and fear of shortness of breath limit 
them in their daily lives (3 items). Scores range from 0–120, with higher scores indicating 
greater dyspnea has demonstrated validity in ILDs trials 65,66. 
o 
Leicester Cough Questionnaire (LCQ) 67 : is a 19-item questionnaire exploring the impact of 
cough severity across three domains: physical (eight items), psychological (seven items) and 
social (four items). The total severity score ranges from 3 to 21, with a lower score indicating 
greater impairment of health status due to cough. The LCQ has been used as an outcome 
measure in clinical trial including ILD patients 68. 
o 
Fatigue Severity Scale (FSS) 69: contains nine items developed to assess disabling fatigue. 
Item responses are measured on a seven-point Likert type scale ranging from strongly 
disagree to strongly agree. The nine items are combined into a total score; a lower total 
score indicates less effect of fatigue on everyday life. The FSS scale has been used in ILD 
populations 70.  
o 
Visual Analogue Scale (VAS) 71: a single item scale for each symptom - patients are asked to 
mark cough, breathlessness and fatigue severity on a linear 100 mm visual analogue scale for 
the past 2 weeks. The extremes of each scale are marked from 'no cough' to 'worst 
cough'/’no breathlessness’ to ‘worst breathlessness’ and ‘no fatigue’ to ‘worst fatigue’.  
 
 
Diagnosis and radiological pattern through clinical MDT proformas 
 
Full pulmonary function tests 
 
Shuttle walk tests: distance walked and oxygen saturation (pre and immediately post test) 
 
Initiated treatments 
 
4 Patient Selection Criteria 
 
4.1 
Inclusion criteria 
 
Age 50-80 
 
Ever-smokers (current or previous) 
 
MDT diagnosis of ILD detected through lung cancer screening or through a non-screening pathway 
 
Attending the regional ILD clinic 
 
4.2 
Exclusion criteria 
 
Unable to complete self-report questionnaire measures e.g. due to cognitive impairment or English 
not first language  

10 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
Unable to provide written informed consent. 
 
Individuals who do not consent to participation in this study will not be disadvantaged in anyway. They will 
continue to receive ILD clinic assessment, treatment and follow-up as per standard practice. 
 
5 Study Design 
 
4.1 Screening service: Invitation letters, endorsed by GPs to improve participation 46,72,73, were sent to all 
individuals (n=16, 402), age 55-74, registered at participating GP practices (n=14), asking ever smokers to 
attend a community-based Lung Health Check (LHC). The LHC, which took place in supermarket carparks in 
deprived areas of Manchester, assessed symptoms, lung cancer risk (PLCOm2012) and measured spirometry. All 
participants with a 6-year lung cancer risk >1.5% were offered entry into the screening programme (n=1,450), 
which involved a non-contrast low dose CT scan at baseline and 12 months later. The first screening round was 
in 2016 and the second and final screening round in 2017.  
 
4.2 Screening LDCT scans: All LDCT scans (Optima 660, GE Healthcare) use helical acquisition of axial 
images from lung apices to the costophrenic angles. Imaging is performed without intravenous contrast, in 
suspended maximal inspiration, with the patient supine and arms above head (scan time 5-10 seconds). 
Acquisition parameters (kVp and mAs) vary with body weight to achieve a CT dose index below 3.0 
millisieverts. Images are reconstructed at 1.25 mm thickness and at 1.25 mm increments. Most CT scans are 
reported within 2 weeks by practising National Health Service (NHS) Consultant Radiologists with a specific 
interest in thoracic radiology.  
 
4.3 ILD MDT: Any ILAs detected on screening LDCT scans were highlighted in the CT report and referred to 
the regional ILD MDT for review and discussion. The MDT consisted of three ILD respiratory physicians, a 
thoracic radiologist with an interest in ILD, two specialist ILD nurses and an MDT co-ordinator. Once discussed 
at the MDT, those deemed to have changes suggestive of significant ILD have been referred to the regional ILD 
service for assessment in the clinic. 
 
4.4 Study population: Individuals attending the regional ILD clinic as a ‘new referral’ will be invited to 
participate. Inclusion and exclusion criteria will be evaluated and suitable participants will be provided with a 

11 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
patient information sheet (PIS) prior to written consent being obtained for enrolment into the study. We will 
recruit patients from two groups:  
 
Group 1: ILD diagnosed through the Manchester early detection of lung disease pilot (lung cancer 
screening programme) and  
 
Group 2: age and sex matched individuals with ILD diagnosed through standard non-screening 
pathway. 
Participation at the clinic will involve collection of demographic information, medical history including co-
morbidities and medication history, full lung function tests (within 6 weeks), shuttle-walk test (within 6 weeks), 
MDT outcome proforma, clinic visit outcome including initiation of any treatments and completed 
questionnaires.  
 
6 Data storage and analysis 
Data will be stored on a specially designed research database and analysed using SPSS. The original signed 
consent form and completed questionnaire are stored within a secured location accessible only to the 
research team at MFT. Statistical significance will be set at <0.05. Clinical and demographic data analyses will 
be descriptive. Questionnaire scores will be calculated according to corresponding scoring algorithms, and 
mixed-modelling will used to examine the changes in the various scores between the three time-points, 
explore factors associated with HRQOL and differences between Group 1 and Group 2. 
 
7 Adverse events 
It is not anticipated that any adverse outcomes will occur; direct study participation will only be on the day of 
clinic visit. 
 
8 Quality assurances 
Data entry will be the responsibility of all members of the research team who will check data control as a 
matter of standard practice. 
 
 
 

12 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
9 Ethical considerations 
 
9.1 
Patient protection 
The principal investigator (PI) will ensure that this study is conducted in agreement with the Guidelines for 
Good Clinical Practice after appropriate ethical review and approval. 
 
9.2 
Subject confidentiality 
Each participant’s completed questionnaire and consent form will be stored in a locked filing cabinet in a 
secure location in the North West Lung Centre at Manchester University NHS Foundation Trust (MFT). This is 
where the regional ILD clinic is held. Patients recruited to the study have a unique study number. Data both 
clinical and laboratory will be coded according to the unique study number and not linked directly to patient 
identifiable information. The research database is hosted on a secure MFT network with access limited to the 
research team. 
 
9.3 
Informed consent 
All participants will be asked to provide written informed consent (signed and personally dated by the patient) 
to study participation. This will take place during their first visit to the regional clinic. Patient data collected as 
part of the study is kept strictly confidentiality, but medical records may be reviewed for study purposes by 
authorized individuals other than their treating physician.  
 
10 Administrative responsibilities 
The study will be administered by the research team directly with oversight from the R+D department at MFT. 
 
10.1 Amendments 
Ethical approval covers only the information contained in the protocol. It does not include extensions or 
amendments to the study. All amendments need to be signed by the PI. Amendments will be communicated to 
the patients within the scope of the patient information / informed consent. 
 
 

13 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
10.2 Reporting 
The final evaluation and reporting will be done after completion of the study. All information in that report is 
strictly confidential. 
11 Study sponsorship and insurance 
The study sponsor will be the Manchester University NHS Foundation Trust; the study is covered by standard 
NHS indemnity. 
 
12 Publication policy 
The PI will be responsible for determining the final publication or public presentation of data. Protection of 
data from subjects and participating physicians must be guaranteed in all publications. Publication will be 
aimed at peer-reviewed scientific journals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

14 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
 
 
References 
1. 
Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk 
factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997;155:242-8. 
2. 
Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, King TE, Jr., Lasky JA, 
Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 
2012;366:1968-77. 
3. 
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med 2014;370:2071-82. 
4. 
King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients 
with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92. 
5. 
Idiopathic pulmonary fibrosis in adults: diagnosis and management. 2013. at 
https://www.nice.org.uk/guidance/cg163.) 
6. 
Oldham JM, Noth I. Idiopathic pulmonary fibrosis: early detection and referral. Respir Med 
2014;108:819-29. 
7. 
The British Thoracic Society Interstitial Lung Disease Registry Programme - Annual Report 
2015/16. 2016. (Accessed 02/08/2017, at https://www.brit-thoracic.org.uk/document-library/audit-
and-quality-improvement/lung-disease-registry/bts-ild-registry-annual-report-201516/.) 
8. 
Global Burden of Disease Cancer C, Fitzmaurice C, Dicker D, et al. The Global Burden of 
Cancer 2013. JAMA Oncol 2015;1:505-27. 
9. 
Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. Br Med J 1950;2:739-
48. 
10. 
Pirie K, Peto R, Reeves GK, Green J, Beral V, Million Women Study C. The 21st century 
hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. 
Lancet 2013;381:133-41. 
11. 
Pastorino U, Boffi R, Marchiano A, et al. Stopping Smoking Reduces Mortality in Low-Dose 
Computed Tomography Screening Participants. J Thorac Oncol 2016;11:693-9. 
12. 
Carter BD, Abnet CC, Feskanich D, et al. Smoking and mortality--beyond established causes. 
N Engl J Med 2015;372:631-40. 
13. 
West R, May S, West M, Croghan E, McEwen A. Performance of English stop smoking 
services in first 10 years: analysis of service monitoring data. BMJ 2013;347:f4921. 
14. 
Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-related mortality in the 
United States. N Engl J Med 2013;368:351-64. 
15. 
Elliss-Brookes L, McPhail S, Ives A, et al. Routes to diagnosis for cancer - determining the 
patient journey using multiple routine data sets. Br J Cancer 2012;107:1220-6. 
16. 
O'Dowd EL, McKeever TM, Baldwin DR, et al. What characteristics of primary care and 
patients are associated with early death in patients with lung cancer in the UK? Thorax 2015;70:161-
8. 
17. 
2016. (Accessed 5th May 2016, May 2016, at http://www.cancerresearchuk.org/health-
professional/cancer-statistics/statistics-by-cancer-type/lung-cancer/survival - heading-Zero.) 
18. 
Walters S, Maringe C, Coleman MP, et al. Lung cancer survival and stage at diagnosis in 
Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004-2007. 
Thorax 2013;68:551-64. 
19. 
Holmberg L, Sandin F, Bray F, et al. National comparisons of lung cancer survival in England, 
Norway and Sweden 2001-2004: differences occur early in follow-up. Thorax 2010;65:436-41. 
20. 
2016. at http://healthierlives.phe.org.uk/topic/mortality.) 

15 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
21. 
Ironmonger L, Ohuma E, Ormiston-Smith N, Gildea C, Thomson CS, Peake MD. An evaluation 
of the impact of large-scale interventions to raise public awareness of a lung cancer symptom. Br J 
Cancer 2015;112:207-16. 
22. 
Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic 
experience. Radiology 2003;226:756-61. 
23. 
Miller DL, Mayfield WR, Luu TD, et al. Community-Based Multidisciplinary Computed 
Tomography Screening Program Improves Lung Cancer Survival. Ann Thorac Surg 2016;101:1864-9. 
24. 
Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall 
design and findings from baseline screening. Lancet 1999;354:99-105. 
25. 
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. 
26. 
National Lung Screening Trial Research T, Aberle DR, Adams AM, et al. Reduced lung-cancer 
mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. 
27. 
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. 
28. 
Field JK, Duffy SW, Baldwin DR, et al. UK Lung Cancer RCT Pilot Screening Trial: baseline 
findings from the screening arm provide evidence for the potential implementation of lung cancer 
screening. Thorax 2016;71:161-70. 
29. 
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. 
30. 
Ashraf H, Saghir Z, Dirksen A, et al. Smoking habits in the randomised Danish Lung Cancer 
Screening Trial with low-dose CT: final results after a 5-year screening programme. Thorax 
2014;69:574-9. 
31. 
Moyer VA, Force USPST. Screening for lung cancer: U.S. Preventive Services Task Force 
recommendation statement. Ann Intern Med 2014;160:330-8. 
32. 
LUCADA. National Lung Cancer Audit annual report 2015 (for the audit period 2014)2015. 
33. 
Field JK, Smith RA, Aberle DR, et al. International Association for the Study of Lung Cancer 
Computed Tomography Screening Workshop 2011 report. Journal of thoracic oncology : official 
publication of the International Association for the Study of Lung Cancer 2012;7:10-9. 
34. 
Field JK, Devaraj A, Duffy SW, Baldwin DR. CT screening for lung cancer: Is the evidence 
strong enough? Lung Cancer 2016;91:29-35. 
35. 
McRonald FE, Yadegarfar G, Baldwin DR, et al. The UK Lung Screen (UKLS): demographic 
profile of first 88,897 approaches provides recommendations for population screening. Cancer Prev 
Res (Phila) 2014;7:362-71. 
36. 
National Lung Screening Trial Research T, 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. 
37. 
Hestbech MS, Siersma V, Dirksen A, Pedersen JH, Brodersen J. Participation bias in a 
randomised trial of screening for lung cancer. Lung Cancer 2011;73:325-31. 
38. 
von Wagner C, Baio G, Raine R, et al. Inequalities in participation in an organized national 
colorectal cancer screening programme: results from the first 2.6 million invitations in England. Int J 
Epidemiol 2011;40:712-8. 
39. 
Lang SJ, Abel GA, Mant J, Mullis R. Impact of socioeconomic deprivation on screening for 
cardiovascular disease risk in a primary prevention population: a cross-sectional study. BMJ Open 
2016;6:e009984. 
40. 
Silvestri GA, Nietert PJ, Zoller J, Carter C, Bradford D. Attitudes towards screening for lung 
cancer among smokers and their non-smoking counterparts. Thorax 2007;62:126-30. 

16 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
41. 
Patel D, Akporobaro A, Chinyanganya N, et al. Attitudes to participation in a lung cancer 
screening trial: a qualitative study. Thorax 2012;67:418-25. 
42. 
Delmerico J, Hyland A, Celestino P, Reid M, Cummings KM. Patient willingness and barriers 
to receiving a CT scan for lung cancer screening. Lung Cancer 2014;84:307-9. 
43. 
Vander Weg MW, Howren MB, Cai X. Use of routine clinical preventive services among daily 
smokers, non-daily smokers, former smokers, and never-smokers. Nicotine Tob Res 2012;14:123-30. 
44. 
Hayton C, Clark A, Olive S, et al. Barriers to pulmonary rehabilitation: characteristics that 
predict patient attendance and adherence. Respir Med 2013;107:401-7. 
45. 
Dalton AR, Bottle A, Okoro C, Majeed A, Millett C. Uptake of the NHS Health Checks 
programme in a deprived, culturally diverse setting: cross-sectional study. J Public Health (Oxf) 
2011;33:422-9. 
46. 
Quaife SL, Ruparel M, Beeken RJ, et al. The Lung Screen Uptake Trial (LSUT): protocol for a 
randomised controlled demonstration lung cancer screening pilot testing a targeted invitation 
strategy for high risk and 'hard-to-reach' patients. BMC Cancer 2016;16:281. 
47. 
Field JK, Duffy SW. Lung cancer CT screening: is annual screening necessary? Lancet Oncol 
2016. 
48. 
Ali N, Lifford KJ, Carter B, et al. Barriers to uptake among high-risk individuals declining 
participation in lung cancer screening: a mixed methods analysis of the UK Lung Cancer Screening 
(UKLS) trial. BMJ Open 2015;5:e008254. 
49. 
Reuben DB, Bassett LW, Hirsch SH, Jackson CA, Bastani R. A randomized clinical trial to 
assess the benefit of offering on-site mobile mammography in addition to health education for older 
women. AJR Am J Roentgenol 2002;179:1509-14. 
50. 
Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to 
the risk of lung-cancer death. N Engl J Med 2013;369:245-54. 
51. 
Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for lung cancer: a 
systematic review. JAMA 2012;307:2418-29. 
52. 
Raji OY, Duffy SW, Agbaje OF, et al. Predictive accuracy of the Liverpool Lung Project risk 
model for stratifying patients for computed tomography screening for lung cancer: a case-control 
and cohort validation study. Ann Intern Med 2012;157:242-50. 
53. 
Oken MM, Hocking WG, Kvale PA, et al. Screening by chest radiograph and lung cancer 
mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 2011;306:1865-
73. 
54. 
Tammemagi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N 
Engl J Med 2013;368:728-36. 
55. 
Tammemagi MC, Church TR, Hocking WG, et al. Evaluation of the lung cancer risks at which 
to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 
2014;11:e1001764. 
56. 
Archontogeorgis K, Steiropoulos P, Tzouvelekis A, Nena E, Bouros D. Lung cancer and 
interstitial lung diseases: a systematic review. Pulm Med 2012;2012:315918. 
57. 
MacRedmond R, Logan PM, Lee M, Kenny D, Foley C, Costello RW. Screening for lung cancer 
using low dose CT scanning. Thorax 2004;59:237-41. 
58. 
Sverzellati N, Guerci L, Randi G, et al. Interstitial lung diseases in a lung cancer screening 
trial. Eur Respir J 2011;38:392-400. 
59. 
Jin GY, Lynch D, Chawla A, et al. Interstitial lung abnormalities in a CT lung cancer screening 
population: prevalence and progression rate. Radiology 2013;268:563-71. 
60. 
Araki T, Putman RK, Hatabu H, et al. Development and Progression of Interstitial Lung 
Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 2016;194:1514-22. 
61. 
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care 
Med 2011;183:788-824. 

17 
Protocol v2 20.05.2019 
 
IRAS Project ID: 233809 
62. 
Ware JE. How to score Version 2 of the SF-36 Health Survey (Standard and Acute forms). 3 
ed: Lincon RI: QualityMetric; 2000. 
63. 
Swigris JJ, Gould MK, Wilson SR. Health-related quality of life among patients with idiopathic 
pulmonary fibrosis. Chest 2005;127:284-94. 
64. 
Patel AS, Siegert RJ, Brignall K, et al. The development and validation of the King's Brief 
Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax 2012;67:804-10. 
65. 
Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary 
fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760-9. 
66. 
Swigris JJ, Yorke J, Sprunger DB, et al. Assessing dyspnea and its impact on patients with 
connective tissue disease-related interstitial lung disease. Respir Med 2010;104:1350-5. 
67. 
Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom 
specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). 
Thorax 2003;58:339-43. 
68. 
Scholand MB, Wolff R, Crossno PF, et al. Severity of cough in idiopathic pulmonary fibrosis is 
associated with MUC5 B genotype. Cough 2014;10:3. 
69. 
Michielsen H DVJ, Ven Heck GL, et al. Examination of the dimensionality of fatigue: The 
construction of the Fatigue. European Journal of Psychological Assessment 2004;20:39-48. 
70. 
Swigris JJ, Fairclough DL, Morrison M, et al. Benefits of pulmonary rehabilitation in idiopathic 
pulmonary fibrosis. Respir Care 2011;56:783-9. 
71. 
Gould D ea. Visual Analogue Scale (VAS). Journal of Clinical Nursing 2001;10:697-706. 
72. 
Hewitson P, Ward AM, Heneghan C, Halloran SP, Mant D. Primary care endorsement letter 
and a patient leaflet to improve participation in colorectal cancer screening: results of a factorial 
randomised trial. Br J Cancer 2011;105:475-80. 
73. 
Cole SR, Young GP, Byrne D, Guy JR, Morcom J. Participation in screening for colorectal 
cancer based on a faecal occult blood test is improved by endorsement by the primary care 
practitioner. J Med Screen 2002;9:147-52.