Screening for early stage lung cancer and its correlation with lung nodule detection.

Currently, the most effective way of reducing lung cancer mortality is early diagnosis of lung cancer. The National Lung Screening Trial has proved the efficacy of lung cancer screening using low-dose computed tomography to reduce lung cancer mortality. However, many questions remain surrounding lung cancer screening implementation, among which include how to select the optimal risk population, the personalized screening interval based different levels of risk, methods to improve diagnostic discrimination between malignant and benign disease in detected lung nodules, and the roles of biomolecular markers in stratifying risk and in guiding the management of indeterminate nodules. This review concentrates on the latest developments of lung cancer screening and provides an overview of the main unanswered questions on lung nodule detection.

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

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

[3]  H. Koning,et al.  Should Never-Smokers at Increased Risk for Lung Cancer Be Screened? , 2015 .

[4]  B. Kramer,et al.  Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. , 2016, The Lancet. Oncology.

[5]  Xiaohong Wu,et al.  Value of quantitative analysis of circulating cell free DNA as a screening tool for lung cancer: a meta-analysis. , 2010, Lung cancer.

[6]  M. Mascalchi,et al.  Dose exposure in the ITALUNG trial of lung cancer screening with low-dose CT. , 2012, The British journal of radiology.

[7]  Larry D. Lynd,et al.  Cost-Effectiveness Analyses of Lung Cancer Screening Strategies Using Low-Dose Computed Tomography: a Systematic Review , 2016, Applied Health Economics and Health Policy.

[8]  C. Berg,et al.  Applying the National Lung Screening Trial eligibility criteria to the US population: what percent of the population and of incident lung cancers would be covered? , 2012, Journal of medical screening.

[9]  M. Tammemägi Application of risk prediction models to lung cancer screening: a review. , 2015, Journal of thoracic imaging.

[10]  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.

[11]  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.

[12]  E. Katilius,et al.  Development of a Protein Biomarker Panel to Detect Non–Small‐Cell Lung Cancer in Korea , 2017, Clinical lung cancer.

[13]  D. Tang,et al.  Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer , 2013, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[14]  P. Prorok,et al.  Conceptualizing overdiagnosis in cancer screening. , 2015, Journal of the National Cancer Institute.

[15]  H. D. de Koning,et al.  Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial , 2013, European Respiratory Journal.

[16]  P. V. van Ooijen,et al.  Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval , 2016, Thorax.

[17]  Malik Yousef,et al.  Gene expression profiles in peripheral blood mononuclear cells can distinguish patients with non-small cell lung cancer from patients with nonmalignant lung disease. , 2009, Cancer research.

[18]  M. Paci,et al.  Circulating plasma DNA as diagnostic biomarker in non-small cell lung cancer. , 2009, Lung cancer.

[19]  E. Kazerooni,et al.  Performance of Lung-RADS in the National Lung Screening Trial , 2015, Annals of Internal Medicine.

[20]  G. Wallstrom,et al.  Comparative Study of Autoantibody Responses between Lung Adenocarcinoma and Benign Pulmonary Nodules , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[21]  E. Kroh,et al.  Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma , 2011, Proceedings of the National Academy of Sciences.

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

[23]  M. Melamed,et al.  Lung cancer screening results in the National Cancer Institute New York Study , 2000, Cancer.

[24]  F. Fischbach,et al.  Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness , 2003, European Radiology.

[25]  S. Armato,et al.  Lung cancers missed at low-dose helical CT screening in a general population: comparison of clinical, histopathologic, and imaging findings. , 2002, Radiology.

[26]  A. Miller,et al.  Cost-effectiveness of Lung Cancer Screening in Canada. , 2015, JAMA oncology.

[27]  A. Fiorelli,et al.  Circulating Tumor Cells in Diagnosing Lung Cancer: Clinical and Morphologic Analysis. , 2015, The Annals of thoracic surgery.

[28]  D. Parkin,et al.  Czech study on lung cancer screening , 2000, Cancer.

[29]  Fenghai Duan,et al.  Projected outcomes using different nodule sizes to define a positive CT lung cancer screening examination. , 2014, Journal of the National Cancer Institute.

[30]  M. Huang,et al.  Combined Detection of CEA, CK-19 and c-met mRNAs in Peripheral Blood: A Highly Sensitive Panel for Potential Molecular Diagnosis of Non-Small Cell Lung Cancer , 2006, Oncology.

[31]  L. Humphrey,et al.  Patient-Centered Outcomes among Lung Cancer Screening Recipients with Computed Tomography: A Systematic Review , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[32]  Massimo Bellomi,et al.  Diagnostic Performance of Low-Dose Computed Tomography Screening for Lung Cancer over Five Years , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[33]  D. Berry,et al.  Benefits and harms of CT screening for lung cancer: a systematic review. , 2012, JAMA.

[34]  J. Brodersen,et al.  Psychosocial consequences in the Danish randomised controlled lung cancer screening trial (DLCST). , 2015, Lung cancer.

[35]  J. Reich A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening , 2008, Thorax.

[36]  J. Habbema,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) , 2007, International journal of cancer.

[37]  T. Molina,et al.  Morphological analysis of circulating tumour cells in patients undergoing surgery for non‐small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method , 2012, Cytopathology : official journal of the British Society for Clinical Cytology.

[38]  Y. Miller,et al.  Validation of a Multiprotein Plasma Classifier to Identify Benign Lung Nodules , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[39]  Caroline Dive,et al.  Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  T. Molina,et al.  Preoperative Circulating Tumor Cell Detection Using the Isolation by Size of Epithelial Tumor Cell Method for Patients with Lung Cancer Is a New Prognostic Biomarker , 2010, Clinical Cancer Research.

[41]  Chiang-Ching Huang,et al.  Genomic variations in plasma cell free DNA differentiate early stage lung cancers from normal controls. , 2015, Lung Cancer.

[42]  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.

[43]  A. Gazdar,et al.  Lung cancer in never smokers — a different disease , 2007, Nature Reviews Cancer.

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

[45]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[46]  Sanjib Basu,et al.  Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer , 2010, Clinical Cancer Research.

[47]  Nicola Sverzellati,et al.  Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen , 2016, European Radiology.

[48]  C. la Vecchia,et al.  Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  M. Okumura,et al.  Novel approach for detection of isolated tumor cells in pulmonary vein using negative selection method: morphological classification and clinical implications. , 2011, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[50]  Marta Di Nicola,et al.  microRNAs Derived from Circulating Exosomes as Noninvasive Biomarkers for Screening and Diagnosing Lung Cancer , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[51]  C. Dooms,et al.  Detection of Lung Cancer through Metabolic Changes Measured in Blood Plasma , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[52]  R. Catarino,et al.  Circulating DNA: Diagnostic Tool and Predictive Marker for Overall Survival of NSCLC Patients , 2012, PloS one.

[53]  Jonathan W. Uhr,et al.  Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but not in Healthy Subjects or Patients With Nonmalignant Diseases , 2004, Clinical Cancer Research.

[54]  J. Herman,et al.  Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum , 2016, Clinical Cancer Research.

[55]  Timothy R. Church,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 , 2014, PLoS medicine.

[56]  Marius Ilie,et al.  “Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease , 2014, PloS one.

[57]  Ash A. Alizadeh,et al.  An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage , 2013, Nature Medicine.

[58]  Ugo Pastorino,et al.  MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer , 2011, Proceedings of the National Academy of Sciences.

[59]  R. Passariello,et al.  CAD (computed-aided detection) and CADx (computer aided diagnosis) systems in identifying and characterising lung nodules on chest CT: overview of research, developments and new prospects , 2010, La radiologia medica.

[60]  Kyle J Myers,et al.  Noncalcified lung nodules: volumetric assessment with thoracic CT. , 2009, Radiology.

[61]  S. Friberg,et al.  On the growth rates of human malignant tumors: Implications for medical decision making , 1997, Journal of surgical oncology.

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

[63]  V. Moyer Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement , 2014, Annals of Internal Medicine.

[64]  Y. Hwang,et al.  Panels of tumor-derived RNA markers in peripheral blood of patients with non-small cell lung cancer: their dependence on age, gender and clinical stages , 2016, Oncotarget.

[65]  Ugo Pastorino,et al.  Plasma DNA quantification in lung cancer computed tomography screening: five-year results of a prospective study. , 2009, American journal of respiratory and critical care medicine.

[66]  M. Oudkerk,et al.  Slow-growing lung cancer as an emerging entity: from screening to clinical management , 2013, European Respiratory Journal.

[67]  H. D. de Koning,et al.  Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. , 2014, The Lancet. Oncology.

[68]  Wenjun Chang,et al.  Development of Autoantibody Signatures as Novel Diagnostic Biomarkers of Non–Small Cell Lung Cancer , 2010, Clinical Cancer Research.

[69]  G. Byrnes,et al.  Screening for lung cancer. , 2004, The Cochrane database of systematic reviews.

[70]  Noor B. Dawany,et al.  Peripheral Immune Cell Gene Expression Predicts Survival of Patients with Non-Small Cell Lung Cancer , 2012, PloS one.

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

[72]  K. Doi,et al.  Computer-aided detection of peripheral lung cancers missed at CT: ROC analyses without and with localization. , 2005, Radiology.

[73]  Massimo Bellomi,et al.  miR-Test: a blood test for lung cancer early detection. , 2015, Journal of the National Cancer Institute.

[74]  P. Prorok,et al.  Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial. , 2013, Lung cancer.

[75]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

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

[77]  Harry J de Koning,et al.  Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. , 2014, The Lancet. Oncology.

[78]  M. Scorsetti,et al.  Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. , 2015, American journal of respiratory and critical care medicine.

[79]  H. Koning,et al.  Overdiagnosis in lung cancer screening: why modelling is essential , 2015 .

[80]  P. Boyle,et al.  Clinical validation of an autoantibody test for lung cancer , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[81]  H. Rusinek,et al.  Lung Adenocarcinoma: Correlation of Quantitative CT Findings with Pathologic Findings. , 2016, Radiology.

[82]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[83]  Matthew P. Goetz,et al.  NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY , 2019 .

[84]  D. Aberle,et al.  Results of initial low-dose computed tomographic screening for lung cancer. , 2013, The New England journal of medicine.

[85]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[86]  T. Molina,et al.  Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non‐small‐cell lung carcinoma: comparison of the efficacy of the CellSearch Assay™ and the isolation by size of epithelial tumor cell method , 2011, International journal of cancer.

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

[88]  Asger Dirksen,et al.  Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. , 2016, American journal of respiratory and critical care medicine.

[89]  Richard B. Lanman,et al.  Costs of Diagnostic Assessment for Lung Cancer: A Medicare Claims Analysis , 2017, Clinical lung cancer.

[90]  S. Duffy,et al.  66 UK Lung Cancer Screening trial (UKLS): Prevalence data at baseline , 2014 .

[91]  Vanathi Gopalakrishnan,et al.  A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals Found to be Cancer-Free by CT Screening , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[92]  A. Devaraj Missed cancers in lung cancer screening – more than meets the eye , 2014, European Radiology.

[93]  P C Prorok,et al.  Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. , 2000, Journal of the National Cancer Institute.

[94]  U. Pastorino,et al.  Quantification of free circulating DNA as a diagnostic marker in lung cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[96]  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.

[97]  M. R. Armstrong,et al.  ACR CT Accreditation Program and the Lung Cancer Screening Program Designation. , 2016, Journal of the American College of Radiology : JACR.

[98]  B. Levy,et al.  Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer. , 2016, The oncologist.

[99]  Sofia Agelaki,et al.  Circulating Biomarkers in Non-Small-Cell Lung Cancer: Current Status and Future Challenges. , 2016, Clinical lung cancer.

[100]  Ahmedin Jemal,et al.  Annual number of lung cancer deaths potentially avertable by screening in the United States , 2013, Cancer.

[101]  Caroline Dive,et al.  Analysis of Circulating Tumor Cells in Patients with Non-small Cell Lung Cancer Using Epithelial Marker-Dependent and -Independent Approaches , 2012, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[102]  Rebecca M. Lindell,et al.  5-year lung cancer screening experience: growth curves of 18 lung cancers compared to histologic type, CT attenuation, stage, survival, and size. , 2009, Chest.

[103]  H. D. de Koning,et al.  Performance and Cost-Effectiveness of Computed Tomography Lung Cancer Screening Scenarios in a Population-Based Setting: A Microsimulation Modeling Analysis in Ontario, Canada , 2017, PLoS medicine.

[104]  S. Armato,et al.  Lung cancer: performance of automated lung nodule detection applied to cancers missed in a CT screening program. , 2002, Radiology.

[105]  Edmund A Franken,et al.  Satisfaction of search from detection of pulmonary nodules in computed tomography of the chest. , 2013, Academic radiology.

[106]  H. D. de Koning,et al.  DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: argument for maximum screening interval of 2 years , 2016, Journal of Clinical Pathology.

[107]  Henrik Zetterberg,et al.  Identification of tissue-specific cell death using methylation patterns of circulating DNA , 2016, Proceedings of the National Academy of Sciences.

[108]  C. White,et al.  Missed lung cancer on chest radiography and computed tomography. , 2012, Seminars in ultrasound, CT, and MR.

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

[110]  J. Crowley,et al.  The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.