The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.

BACKGROUND Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects. OBJECTIVES To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening. DESIGN A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years). SETTING Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. PARTICIPANTS Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. INTERVENTIONS A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. MAIN OUTCOME MEASURES Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling. RESULTS A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality. CONCLUSIONS The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols. FUTURE WORK The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation. TRIAL REGISTRATION Current Controlled Trials ISRCTN78513845. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.

[1]  C I Henschke,et al.  CT screening for lung cancer. , 2003, Radiologic clinics of North America.

[2]  H. Morgenstern,et al.  Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium. , 2012, European journal of cancer.

[3]  Feng Li,et al.  Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography. , 2007, Lung cancer.

[4]  Ugo Pastorino,et al.  Computed tomography screening and lung cancer outcomes. , 2007, JAMA.

[5]  H. D. de Koning,et al.  The impact of a lung cancer computed tomography screening result on smoking abstinence , 2010, European Respiratory Journal.

[6]  Linda C Gallo,et al.  The Relevance of Fatalism in the Study of Latinas’ Cancer Screening Behavior: A Systematic Review of the Literature , 2010, International journal of behavioral medicine.

[7]  C. von Wagner,et al.  Inequalities in participation in an organized national colorectal cancer screening programme: results from the first 2.6 million invitations in England. , 2011, International journal of epidemiology.

[8]  H. D. de Koning,et al.  Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial , 2010, European Respiratory Journal.

[9]  E. Kuipers,et al.  Unit costs in population-based colorectal cancer screening using CT colonography performed in university hospitals in The Netherlands , 2012, European Radiology.

[10]  Alona Muzikansky,et al.  Early palliative care for patients with metastatic non-small-cell lung cancer. , 2010, The New England journal of medicine.

[11]  P. Grenier,et al.  Computer-aided detection of solid lung nodules on follow-up MDCT screening: evaluation of detection, tracking, and reading time. , 2007, AJR. American journal of roentgenology.

[12]  H. D. de Koning,et al.  Informed participation in a randomised controlled trial of computed tomography screening for lung cancer , 2009, European Respiratory Journal.

[13]  S W Duffy,et al.  Clinical Studies , 1877, Journal of Psychological Medicine and Mental Pathology (London, England : 1875).

[14]  Antoine Flahault,et al.  Baseline results of the Depiscan study: a French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR). , 2007, Lung cancer.

[15]  John K Field,et al.  CT screening for lung cancer: countdown to implementation. , 2013, The Lancet. Oncology.

[16]  Anne-Marie Sykes,et al.  CT screening for lung cancer: five-year prospective experience. , 2005, Radiology.

[17]  C. Begg,et al.  Variations in lung cancer risk among smokers. , 2003, Journal of the National Cancer Institute.

[18]  J. Goo.  A Computer-Aided Diagnosis for Evaluating Lung Nodules on Chest CT: the Current Status and Perspective , 2011, Korean journal of radiology.

[19]  D. Lynch,et al.  The National Lung Screening Trial: overview and study design. , 2011, Radiology.

[20]  N. Waugh,et al.  The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews. , 2006, Health technology assessment.

[21]  R. V. van Klaveren,et al.  Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch–Belgian randomised controlled lung cancer screening trial , 2010, Thorax.

[22]  David F Yankelevitz,et al.  Definition of a Positive Test Result in Computed Tomography Screening for Lung Cancer , 2013, Annals of Internal Medicine.

[23]  Feng Li,et al.  Mass screening for lung cancer with mobile spiral computed tomography scanner , 1998, The Lancet.

[24]  B. Gordon,et al.  Hypogammaglobulinemia, Common variant in children responsive to therapy. , 1960, JAMA.

[25]  Rongwei Fu,et al.  Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation , 2013, Annals of Internal Medicine.

[26]  S. Duffy,et al.  Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer , 2012, Annals of Internal Medicine.

[27]  P. Bennett,et al.  The evolution of worry after breast cancer risk assessment: 6‐year follow‐up of the TRACE study cohort , 2010, Psycho-Oncology.

[28]  Paul Kind,et al.  UK population norms for EQ-5D , 1999 .

[29]  A. Dirksen,et al.  The Danish Randomized Lung Cancer CT Screening Trial—Overall Design and Results of the Prevalence Round , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[30]  Qiang Li,et al.  Recent progress in computer-aided diagnosis of lung nodules on thin-section CT , 2007, Comput. Medical Imaging Graph..

[31]  RAP Scott,et al.  The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial , 2002, The Lancet.

[32]  H. Morgenstern,et al.  Systematic Reviews and Meta-and Pooled Analyses Previous Lung Diseases and Lung Cancer Risk : A Pooled Analysis From the International Lung Cancer Consortium , 2012 .

[33]  J. Austoker,et al.  Diagnosed with breast cancer while on a family history screening programme: an exploratory qualitative study. , 2008, European journal of cancer care.

[34]  J Cuzick,et al.  Psychosocial influences on older adults' interest in participating in bowel cancer screening. , 2000, Preventive medicine.

[35]  Harry J de Koning,et al.  Management of lung nodules detected by volume CT scanning. , 2009, The New England journal of medicine.

[36]  H. D. de Koning,et al.  Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON) , 2009, British Journal of Cancer.

[37]  Eugenio Paci,et al.  Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. , 2009, Lung cancer.

[38]  J. Scholefield,et al.  Analysis of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer , 2010, Gut.

[39]  K. Kerr,et al.  Guidelines on the radical management of patients with lung cancer , 2010, Thorax.

[40]  C. von Wagner,et al.  Cancer Fatalism and Poor Self-Rated Health Mediate the Association between Socioeconomic Status and Uptake of Colorectal Cancer Screening in England , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[41]  R. V. van Klaveren,et al.  The Liverpool Statement 2005: priorities for the European Union/United States spiral computed tomography collaborative group. , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[42]  D. Mannino.  COPD as a disease of children: hype or hope for better understanding? , 2010, Thorax.

[43]  C Beigelman-Aubry,et al.  thorax - Évaluation de l’impact d’un système CAD sur la performance des radiologues pour la détection des nodules pulmonaires sur des examens scanographiques multicoupes du thorax , 2007 .

[44]  E. Gelmann,et al.  Quality of life and trial adherence among participants in the prostate, lung, colorectal, and ovarian cancer screening trial. , 2004, Journal of the National Cancer Institute.

[45]  Binsheng Zhao,et al.  Small pulmonary nodules: volumetrically determined growth rates based on CT evaluation. , 2000, Radiology.

[46]  C. von Wagner,et al.  Outcomes of the Bowel Cancer Screening Programme (BCSP) in England after the first 1 million tests , 2010, Gut.

[47]  D. Whynes.  Could CT screening for lung cancer ever be cost effective in the United Kingdom ? , 2008 .

[48]  Matthew B Schabath,et al.  A risk model for prediction of lung cancer. , 2007, Journal of the National Cancer Institute.

[49]  S. Duffy,et al.  Mammographic parenchymal patterns and risk of breast cancer at and after a prevalence screen in Singaporean women. , 2000, International journal of epidemiology.

[50]  Length and Lead Time Biases in Radiologic Screening for Lung Cancer , 1999, Respiration.

[51]  Arash Naeim,et al.  Cost-effectiveness of CT screening in the National Lung Screening Trial. , 2014, The New England journal of medicine.

[52]  O. Miettinen,et al.  Survival of Patients with Stage I Lung Cancer Detected on CT Screening , 2008 .

[53]  C. Earle,et al.  Lung cancer treatment costs, including patient responsibility, by disease stage and treatment modality, 1992 to 2003. , 2011, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[54]  Timothy R Church,et al.  Selection criteria for lung-cancer screening. , 2013, The New England journal of medicine.

[55]  S. Duffy,et al.  The contribution of risk prediction models to early detection of lung cancer , 2013, Journal of surgical oncology.

[56]  Colleen Bouzan,et al.  Cost-Effectiveness of Computed Tomography Screening for Lung Cancer in the United States , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[57]  H. Møller,et al.  Variation in incidence of breast, lung and cervical cancer and malignant melanoma of skin by socioeconomic group in England , 2008, BMC Cancer.

[58]  Yiding Jiang,et al.  An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost. , 2012, Health affairs.

[59]  S. Duffy,et al.  Comparison of discriminatory power and accuracy of three lung cancer risk models , 2010, British Journal of Cancer.

[60]  D. Whynes.  Economics of cancer screening programs , 2004, Expert review of pharmacoeconomics & outcomes research.

[61]  J. Austoker,et al.  The psychological impact of mammographic screening. A systematic review , 2005, Psycho-oncology.

[62]  E. Glatstein,et al.  CT Screening for Lung Cancer: Five-Year Prospective Experience , 2006 .

[63]  W. Heindel,et al.  Detection of pulmonary nodules at multirow-detector CT: effectiveness of double reading to improve sensitivity at standard-dose and low-dose chest CT , 2004, European Radiology.

[64]  Stephen Senn,et al.  Statistical Issues in Drug Development , 1997 .

[65]  Bernard Maitre,et al.  Screening by Chest Radiograph and Lung Cancer Mortality : The Prostate , Lung , Colorectal , and Ovarian ( PLCO ) Randomized Trial , 2022 .

[66]  David K Whynes,et al.  Cost-Effectiveness of Screening for Colorectal Cancer: Evidence from the Nottingham Faecal Occult Blood Trial , 2004, Journal of medical screening.

[67]  W J Kostis,et al.  Computer-aided diagnosis for lung cancer. , 2000, Radiologic clinics of North America.

[68]  S. Lam,et al.  Probability of cancer in pulmonary nodules detected on first screening CT. , 2013, The New England journal of medicine.

[69]  Michael J. Watson,et al.  The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer , 1999, British Journal of Cancer.

[70]  Dongfeng Wu,et al.  Sojourn time and lead time projection in lung cancer screening. , 2011, Lung cancer.

[71]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[72]  S. Duffy,et al.  Defining high-risk individuals in a population-based molecular-epidemiological study of lung cancer. , 2006, International journal of oncology.

[73]  K. Marten,et al.  Computer-assisted detection of pulmonary nodules: performance evaluation of an expert knowledge-based detection system in consensus reading with experienced and inexperienced chest radiologists , 2004, European Radiology.

[74]  T. Mizoue,et al.  Long-term prognosis of patients with lung cancer detected on low-dose chest computed tomography screening. , 2012, Lung cancer.

[75]  William Hazelton,et al.  Benefits and Harms of Computed Tomography Lung Cancer Screening Strategies: A Comparative Modeling Study for the U.S. Preventive Services Task Force , 2014, Annals of Internal Medicine.

[76]  M. Peake,et al.  An evaluation of the impact of large-scale interventions to raise public awareness of a lung cancer symptom , 2014, British Journal of Cancer.

[77]  V. Saliba,et al.  Public Health in England. , 1988, Public health.

[78]  C. Berg,et al.  Targeting of low-dose CT screening according to the risk of lung-cancer death. , 2013, The New England journal of medicine.

[79]  P. Engstrom,et al.  Mammography adherence and psychological distress among women at risk for breast cancer. , 1993, Journal of the National Cancer Institute.

[80]  M. Provencio,et al.  Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine. , 2011, Journal of thoracic disease.

[81]  Xiping Xu,et al.  A case-control study of cytochrome P450 1A1, glutathione S-transferase M1, cigarette smoking and lung cancer susceptibility (Massachusetts, United States) , 1997, Cancer Causes & Control.

[82]  Harlan M Krumholz,et al.  Participation in cancer clinical trials: race-, sex-, and age-based disparities. , 2004, JAMA.

[83]  M. Diefenbach,et al.  Beliefs and attitudes about lung cancer screening among smokers. , 2012, Lung cancer.

[84]  J. Peres.  Lung cancer screening gets risk-specific. , 2013, Journal of the National Cancer Institute.

[85]  G Z Brett,et al.  Earlier diagnosis and survival in lung cancer , 1969, British medical journal.

[86]  A. Dirksen,et al.  CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT , 2012, Thorax.

[87]  R. Hubbard,et al.  Using socio-demographic and early clinical features in general practice to identify people with lung cancer earlier , 2013, Thorax.

[88]  M. Holmes-Rovner,et al.  Patient Satisfaction with Health Care Decisions , 1996, Medical decision making : an international journal of the Society for Medical Decision Making.

[89]  J. Parton.  Smoking and Drinking , 1886, Hall's journal of health.

[90]  N. Paul,et al.  Thoracic and Cardiac Imaging / Imagerie cardiaque et imagerie thoracique Assessing the Impact of Incidental Findings in a Lung Cancer Screening Study by Using Low-dose Computed Tomography , 2010 .

[91]  Ugo Pastorino,et al.  Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial , 2012, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[92]  H. D. de Koning,et al.  Lung cancer screening by spiral CT. What is the optimal target population for screening trials? , 2002, Lung cancer.

[93]  G. Silvestri,et al.  Attitudes towards screening for lung cancer among smokers and their non-smoking counterparts , 2007, Thorax.

[94]  Angela Boland,et al.  Population screening for lung cancer using computed tomography, is there evidence of clinical effectiveness? A systematic review of the literature , 2007, Thorax.

[95]  R. Souhami,et al.  Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  J. Brodersen,et al.  Psychosocial consequences of allocation to lung cancer screening: a randomised controlled trial , 2012, BMJ Open.

[97]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[98]  M. Spitz,et al.  An Expanded Risk Prediction Model for Lung Cancer , 2008, Cancer Prevention Research.

[99]  M. Mascalchi,et al.  Screening of lung cancer with low dose spiral CT: results of a three year pilot study and design of the randomised controlled trial ''Italung-CT''. , 2005, La Radiologia medica.

[100]  H. D. de Koning,et al.  European randomized lung cancer screening trials: Post NLST , 2013, Journal of surgical oncology.

[101]  J. Rathmell,et al.  Results of the two incidence screenings in the National Lung Screening Trial. , 2013, The New England journal of medicine.

[102]  Leah Blau,et al.  Statistical Models In Epidemiology , 2016 .

[103]  D. Parkin.  2. Tobacco-attributable cancer burden in the UK in 2010 , 2011, British Journal of Cancer.

[104]  B. Kramer,et al.  Overdiagnosis in low-dose computed tomography screening for lung cancer. , 2014, JAMA internal medicine.

[105]  Bernard Rachet,et al.  Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004–2007 , 2013, Thorax.

[106]  Matthijs Oudkerk,et al.  Prospects for population screening and diagnosis of lung cancer , 2013, The Lancet.

[107]  Yiding Jiang,et al.  A Cost-Utility Analysis of Lung Cancer Screening and the Additional Benefits of Incorporating Smoking Cessation Interventions , 2013, PloS one.

[108]  J. Weissfeld,et al.  Anxiety, Fear of Cancer, and Perceived Risk of Cancer following Lung Cancer Screening , 2008, Medical decision making : an international journal of the Society for Medical Decision Making.

[109]  S. Rowan.  Trends in cancer incidence by deprivation, England and Wales, 1990-2002. , 2007, Health statistics quarterly.

[110]  Federico Cappuzzo,et al.  Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. , 2008, Lung cancer.

[111]  J. Sosna,et al.  Cost-effectiveness of baseline low-dose computed tomography screening for lung cancer: the Israeli experience. , 2013, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[112]  C. Seale,et al.  Attitudes to participation in a lung cancer screening trial: a qualitative study , 2011, Thorax.

[113]  J. Wardle,et al.  Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact , 2004, BJOG : an international journal of obstetrics and gynaecology.

[114]  Elisabeth Brambilla,et al.  The IASLC Lung Cancer Staging Project: Proposals for the Revision of the T Descriptors in the Forthcoming (Seventh) Edition of the TNM Classification for Lung Cancer , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[115]  N. Müller,et al.  Lung nodule enhancement at CT: multicenter study. , 2000, Radiology.

[116]  Anthony J. Sherbondy,et al.  Pulmonary nodules on multi-detector row CT scans: performance comparison of radiologists and computer-aided detection. , 2005, Radiology.

[117]  J. Mulshine,et al.  Early detection of lung cancer. , 1993, Seminars in oncology.

[118]  L. Cardinale,et al.  Clinical implications and added costs of incidental findings in an early detection study of lung cancer by using low-dose spiral computed tomography. , 2013, Clinical lung cancer.

[119]  John K Field,et al.  Measurement Methods and Algorithms for the Management of Solid Nodules , 2012, Journal of thoracic imaging.

[120]  Kurt Straif,et al.  Preventable exposures associated with human cancers. , 2011, Journal of the National Cancer Institute.

[121]  G Scott Gazelle,et al.  Adopting helical CT screening for lung cancer , 2008, Cancer.

[122]  S. Duffy,et al.  Lung cancer screening: the way forward , 2008, British Journal of Cancer.

[123]  John K Field,et al.  The UK Lung Screen (UKLS): Demographic Profile of First 88,897 Approaches Provides Recommendations for Population Screening , 2014, Cancer Prevention Research.

[124]  Robert J Cerfolio,et al.  Survival of patients with true pathologic stage I non-small cell lung cancer. , 2009, The Annals of thoracic surgery.

[125]  John K. Gohagan,et al.  The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial , 2000 .

[126]  Darren R. Brenner,et al.  Previous Lung Diseases and Lung Cancer Risk: A Systematic Review and Meta-Analysis , 2011, PloS one.

[127]  N J Wald,et al.  UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer , 2011, Thorax.

[128]  A. Leung,et al.  Computer-aided detection (CAD) of lung nodules in CT scans: radiologist performance and reading time with incremental CAD assistance , 2010, European Radiology.

[129]  W. D. Ray.  4. Modelling Survival Data in Medical Research , 1995 .

[130]  G. Huston.  The Hospital Anxiety and Depression Scale. , 1987, The Journal of rheumatology.

[131]  Stephen J. Swensen,et al.  Estimating long-term effectiveness of lung cancer screening in the Mayo CT screening study. , 2008, Radiology.

[132]  S. Duffy,et al.  Translation of research results to simple estimates of the likely effect of a lung cancer screening programme in the United Kingdom , 2014, British Journal of Cancer.

[133]  J. Mulshine,et al.  An actuarial approach to comparing early stage and late stage lung cancer mortality and survival. , 2010, Population health management.

[134]  Cancer,et al.  Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial , 2010, The Lancet.

[135]  F. Fazio,et al.  Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results , 2003, The Lancet.

[136]  B. Brunekreef,et al.  Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). , 2013, The Lancet. Oncology.

[137]  M. Prokop,et al.  British Thoracic Society guidelines for the investigation and management of pulmonary nodules: accredited by NICE , 2015, Thorax.

[138]  Yu-Chung Wu,et al.  Time Trends of Overall Survival and Survival after Recurrence in Completely Resected Stage I Non-small Cell Lung Cancer , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[139]  C. Catalano,et al.  Volumetric evaluation of therapy response in patients with lung metastases. Preliminary results with a computer system (CAD) and comparison with unidimensional measurements , 2006, La radiologia medica.