policy review european position statement on lung cancer ... · policy review european position...

www.thelancet.com/oncology Published online November 27, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30861-6 1

Policy Review

European position statement on lung cancer screeningMatthijs Oudkerk, Anand Devaraj, Rozemarijn Vliegenthart, Thomas Henzler, Helmut Prosch, Claus P Heussel, Gorka Bastarrika, Nicola Sverzellati, Mario Mascalchi, Stefan Delorme, David R Baldwin, Matthew E Callister, Nikolaus Becker, Marjolein A Heuvelmans, Witold Rzyman, Maurizio V Infante, Ugo Pastorino, Jesper H Pedersen, Eugenio Paci, Stephen W Duffy, Harry de Koning, John K Field

Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm³, and new lung nodules greater than 200 mm³, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.

IntroductionLung cancer screening with low-dose CT can save lives, and this method will probably be embraced by national health organisations throughout Europe in the future. The results from the US National Lung Cancer Screening Trial (NLST)1 on reduced lung cancer mortality and from seven pilot trials 2–8 within Europe on other aspects of low-dose CT screening have provided sufficient evidence for Europe to start planning for lung cancer screening while mortality data from the NELSON trial2 are awaited.

This European Union (EU) position statement describes the current status of lung cancer screening and sets out the essential elements needed to ensure the development of effective European screening programmes. The EU position statement expert group comprises individuals from eight European countries who have been actively engaged in the planning and execution of randomised controlled screening trials in Europe,9 who are involved in the clinical management of patients with lung cancer and lung nodules, and who have developed relevant clinical practice guidelines on smoking cessation, recruitment of high risk participants, patient information literature, as well as CT screening protocols, CT scan radiology reporting, and the clinical management of CT-detected nodules. These experts represent all the specialties and professions involved in delivering successful lung cancer screening programmes in Europe. The emphasis of this EU position statement focuses on the actual implementation of CT lung cancer screening programmes in Europe by radiologists, supported by epidemiologists, pulmonologists, and thoracic surgeons, in the full context of clinical lung cancer diagnosis and treatment. These individuals comprise the core membership of the EU Lung cancer CT Screening Implementation Group (EU-LSIG) and have prepared this EU position statement. We did a

comprehensive literature search for papers on lung cancer screening and, through in-depth discussions, developed this EU position statement consensus.

The structure of this document not only reflects the available evidence that addresses the major questions concerning the delivery of a successful screening intervention, but also highlights any issues that still need to be resolved for successful implementation. Contributions to this EU position statement were provided by a team of clinicians and scientists expert in CT as the method of choice for lung cancer screening. The requirement for an EU position statement stems from the need to provide European recommendations on CT screening that will assist the EU Commission and national health agencies in beginning to plan the implementation of lung cancer screening within the next 2 years, and to avoid opportunistic and uncontrolled screening. Moreover, since the publication of the NLST results in 2011,1 an EU position statement on the value of CT screening for lung cancer is now a crucial necessity.

The focus of this EU position statement is restricted to lung cancer screening with low-dose CT and the early detection of lung nodules before clinical work-up, and does not address the entirety of work-up and treatment choices. Since new randomised controlled trials of low-dose CT screening that are powered to allow conclusions about mortality reduction are highly unlikely, our recommendations are based on the current available data. Data provided by several studies2,6,8 are sufficient to make recommendations concerning the minimisation of false positive results in both screen-detected and non-screen detected nodules. The need for non-contrast-enhanced low-dose interval imaging should not be considered a false-positive test because the individual is not undergoing an invasive clinical work-up and therefore the risk of physical harm is very low. Furthermore, evidence10,11

Lancet Oncol 2017

Published Online November 27, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30861-6

Center for Medical Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands (Prof M Oudkerk MD, R Vliegenthart MD, M A Heuvelmans MD); Department of Radiology, Royal Brompton Hospital, London, UK (A Devaraj MD); Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (T Henzler MD); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna General Hospital, Vienna, Austria (H Prosch MD); Translational Research Unit and Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik, Heidelberg University, Heidelberg, Germany (C P Heussel MD); Translational Lung Research Centre Heidelberg, German Centre for Lung Research, Heidelberg, Germany (C P Heussel); Department of Diagnostic and Interventional Radiology, University-Hospital Heidelberg, Heidelberg, Germany (C P Heussel); Department of Diagnostic and Interventional Radiology Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain (G Bastarrika MD); Radiology, Department of Medicine and Surgery, University of Parma, Parma, Italy (Prof N Sverzellati MD); Department of Clinical and Experimental Biomedicine, University of Florence, Florence, Italy (M Mascalchi MD); Division of Radiology (Prof S Delorme MD) and Division of Cancer Epidemiology

2 www.thelancet.com/oncology Published online November 27, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30861-6

Policy Review

(Prof N Becker PhD), German Cancer Research Center,

Heidelberg, Germany; Respiratory Medicine Unit,

David Evans Research Centre, Nottingham University

Hospitals, Nottingham, UK (Prof D R Baldwin MD);

Department of Respiratory Medicine, Leeds Teaching

Hospitals, St James’s University Hospital, Leeds, UK

(M E Callister MD); Department of Thoracic Surgery, Medical

University of Gdańsk, Gdańsk, Poland (Prof W Rzyman MD);

Thoracic Surgery Department, University and Hospital Trust—

Azienda Ospedaliera Universitaria Integrata, Verona,

Italy (M V Infante MD); Department of Thoracic

Surgery, Istituto Nazionale Tumori, Milan, Italy

(U Pastorino MD); Department of Cardiothoracic Surgery,

Rigshospitalet, University of Copenhagen, Copenhagen,

Denmark (J H Pedersen MD); ISPO Cancer Research and

Prevention Institute Tuscany Region, Florence, Italy

(Prof E Paci MD); Wolfson Institute of Preventive

Medicine, Barts and The London School of Medicine and

Dentistry, London, UK (Prof S W Duffy PhD);

Department of Public Health, Erasmus MC, Rotterdam,

Netherlands (Prof H J de Koning MD); and

Roy Castle Lung Cancer Research Programme,

Department of Molecular and Clinical Cancer Medicine,

University of Liverpool, Liverpool, UK (Prof J K Field PhD)

Correspondence to: Prof John K Field, Roy Castle Lung

Cancer Research Programme, Department of Molecular and

Clinical Cancer Medicine, University of Liverpool,

Liverpool L7 8TX, UK [email protected]

shows that the psychological distress caused is transient and smoking cessation rates increase among those who require interval imaging.

This position statement represents a balance of the available data and therefore reflects which approaches are supported by good evidence, where further evidence is needed to implement effective screening programmes, and where practical implications for lung cancer screening can already be drawn from the available knowledge.

Diagnostic tests for lung cancer detectionCT has progressed to be the best method for lung cancer screening. Previous lung cancer screening trials in the 1980s using chest x-rays with and with out sputum cytology showed no significant survival advantage,12,13 which led to inactivity in this field of research for more than two decades. The first publication on lung CT screening in 199914 ignited interest in this field again. Other diagnostic methods might have a future potential in lung cancer screening but no trials are yet available to support clinical use.15

Earlier trials using CT as a screening method provided evidence not only on the effectiveness of lung cancer screening, but also on the natural history of the disease. The debate continued on the ability of CT screening to reduce mortality until the NLST was published,1 in which 53 454 patients were randomly assigned to receive either low-dose CT or a chest x-ray for screening. This trial had its results reported 1 year earlier than

planned because the stop criteria of a 20% reduction in lung cancer mortality rate with low-dose CT had been reached in a periodic planned interim analysis compared with that achieved by chest x-ray. The trial also showed a 6·7% reduction in all-cause mortality with low-dose CT screening (1877 deaths in the low-dose CT group compared with 2000 deaths in the radiography group).1

There is increasing evidence of the effectiveness of CT screening from several pilot trials in Europe and from the NELSON trial publications2,16,17 (table). However, we need to remain aware of the implications and problems associated with the work-up of suspicious nodules (ie, the invasiveness of biopsies, waiting time until a final decision).

The high false-positive rates both in the initial screening and subsequent screening rounds, as reported in the NLST, need to be reduced to ensure that harmful effects on participants are kept to a minimum. This reduction is best achieved by accurate interval imaging with the latest and most precise methods, particularly semi-automated volumetric analysis rather than manual measurement of maximum diameter, as already implemented by several trials.2,7,8 Furthermore, the definition of false positives also has a major bearing on how we interpret false-positive data. The NELSON,16 MILD,3 and UKLS8 trials defined false positives using baseline data as patients who required a referral to the pulmonologist and who required a further diagnostic investigation (3·5%), but who subsequently did not

Recruitment period

Recruitment criteria Screening methods

Randomised controlled trials

NLST1 2002–04 Age 55–75 years, ≥30 PY smoker, quit smoking <15 years earlier Annual low-dose CT vs chest x-ray for 3 years

MILD3 2005–11 Age >49 years, ≥20 PY smoker, quit smoking <10 years earlier, no cancers within past 5 years

Three groups: no screen, annual screen, and biennial low-dose CT for 5 years

ITALUNG4 2004–06 Age 55–69 years, ≥20 PY smoker Annual low-dose CT for 4 years vs no screen

DANTE5 2001–06 Age 60–75 years, ≥20 PY smoker, quit smoking <10 years earlier, male

Annual low-dose CT for 4 years vs no screen

DLCST6 2004–06 Age 50–70 years, ≥20 PY smoker, quit smoking <10 years earlier, FEV1 ratio >30%, able to climb two flights of stairs without pausing

Annual low-dose CT vs usual care for 5 years

NELSON2 2003–06 Age 50–75 years, smoker or quit smoking ≤10 years earlier, >15 cigarretes per day for >25 years or >ten cigarretes per day for >30 years

Low-dose CT in year 1, year 2, year 4, and year 6·5 vs no screen

LUSI7 2007–11 Age 50–69 years, heavy smoking history Annual low-dose CT and smoking cessation for 5 years vs smoking cessation alone

UKLS8 2011–14 Age 50–75 years, ≥5% of 5-year lung cancer risk as calculated by LLPv2 scores

Wald single low-dose CT screen design vs no screen

Other studies

I-ELCAP14 1993–2006 Age >60 years, ≥10 PY smoker Annual low-dose CT and chest x-ray for 5 years

Mayo LDCT trial18 1999 Age >50 years, 20 PY smoker, quit smoking <10 years earlier Annual low-dose CT for 5 years

PANCAN19 2008–11 Age 50–75 years, ≥2% of 3-year lung cancer risk as calculated by PLCO score

Low-dose CT in year 1, year 2, and year 4

COSMOS20 2000–01 Age >50 years, ≥20 PY smoker Annual low-dose CT for 10 years

PY=pack-year. FEV=forced respiration volume. LLPv2=Liverpool Lung Project risk model, version 2. PLCO=Prostate, Lung, Colorectal, and Ovarian trial risk model.

Table: European pilot trials for lung cancer low-dose CT screening


Policy Review

have lung cancer. This definition differs from that used in the NLST, in which every individual who had an additional CT scan before a repeat annual screen was considered positive (a nodule with a diameter of 4 mm or more). This amounted to 24% of participants, of which 96% were false positive with unnecessary CT examinations and a related radiotherapy burden. Since the publication of NLST, the NELSON study21 has shown that nodules with a volume smaller than 100 mm³ (or <5 mm in diameter) do not confer an increased risk of malignancy at baseline.

Although no other technology is available that could replace CT screening, emerging technologies need to undergo the same scrutiny that has been applied to CT screening to ensure robustness and validity in its use. However, if a new emerging technology is considered, it should be compared with CT screening in a randomised controlled trial, and should show a negative predictive value of almost 100% and a positive predictive value higher than that of CT screening. In the future, some technologies might be applied as an adjunct to CT screening, of which more is discussed later on in this paper.

Outcomes of lung cancer screening trialsThe outcomes of various lung cancer screening trials provide insight into how to implement lung cancer screening in differing countries in Europe, as well as the optimal set-up for a population and screening at a single centre. We have learnt much about each stage of the lung cancer CT screening pathway and the management decisions that are required.22 Ongoing trials2–8 have provided insight into risk assessment, CT screen nodule manage ment, multidisciplinary team work-up, and surgical interventions, as well as psychological effects on parti cipants and the cost-effectiveness of the screening process.

Several nationally funded randomised studies have already been undertaken in Europe to assess the feasibility of lung cancer screening. These include DANTE,5 DLCST,6 ITALUNG,4 LUSI,7 MILD,3,23 NELSON,2 and UKLS.8,22 Their results, individually and when pooled, will contribute to the implementation of CT screening in Europe. The only European fully powered randomised controlled trial that will provide mortality and cost-effectiveness data is the NELSON trial, but we do have sufficient data to start planning before the full results are available. The results from NLST alone have been sufficient for low-dose CT screening to start in the USA and Canada.

The incorporation of the coronary artery calcification score and emphysema assessment on low-dose CT imaging might enhance the cost-effectiveness and attractiveness of low-dose CT lung cancer screening.24 Chronic obstructive pulmonary disease (COPD) and emphysema are the strongest lung cancer risk predictors and, together with cardiovascular disease, all three imaging biomarkers have substantial effects on

morbidity but also have independent effects on overall mortality.25,26

Lung cancer risk prediction modellingThe concept of clearly defining a target population for lung cancer screening is gaining importance.19,27 Selection on the basis of age alone, as in most other cancer screening disease settings (eg, breast and colon), is insufficient in lung cancer because of other powerful risk factors, the most important of which is exposure to tobacco smoke. Other major risk factors, which are also taken into account, include a history of respiratory diseases (COPD, emphy sema, bronchitis, pneumonia, and tuberculosis), pre vious malignancy, family history of lung cancer (first-degree relative diagnosed at age 60 years or younger), and exposure to asbestos. Several multivariable risk prediction models have been published,28,29 but only two (the modified Liverpool Lung Project [LLPv2] and Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial [PLCO] models27,30) have been used so far to select patients for screening in a clinical trial. Risk prediction models, including the US Preventive Services Task Force (USPSTF) recommen-dations, have been tested in the NLST dataset, showing that the NLST selection criteria could have been improved if a risk prediction model had been implemented.30–32 The LLPv2 is the only risk model that has been used so far to select patients for a lung cancer screening randomised controlled trial.8 In this trial, a higher percentage of participants were diagnosed with lung cancer at baseline than those in the NLST and NELSON trials. The LLPv2 model cutoff of 5% over 5 years is being validated in the Liverpool Healthy Lung Project.27,33,34 The original LLP model has compared favourably with the Spitz and Bach models.35 The LLP model was validated in the UK with the use of data from a population-based prospective cohort study,33 with an area under the curve (AUC) of 0·82 (95% CI 0·80–0·85).33 The Bach, Spitz, LLP, and modified PLCO (PLCOm2012) risk models were externally validated in the German EPIC cohort study36 of 20 700 ever-smokers. The PLCOm2012 model showed the best performance in external validation (C index 0·81, 95% CI 0·76–0·86) and the highest sensitivity, specificity, and positive predictive value compared with the other three models. However, the superiority of the PLCOm2012 model over the Bach and LLP models was considered modest by the authors.36

Five different risk models have been compared with one another by use of the PLCO and NLST trial datasets.37

Although several sophisticated models have used a range of risk variables (ie, family history, previous malignancy, previous respiratory disease, exposure to asbestos), the Bach model had a good sensitivity and specificity,28 even though it only used age and smoking history for cal culating risk score, emphasising the importance of these two risk factors. The PLCOm2012 model also provided good results,


Policy Review

but this model was developed using the PLCO dataset, so there might be issues of overfitting. However, all the models compared were superior to the NLST selection criteria and the USPSTF recommendations. The PLCOm2012 risk model was also used to calculate the predicted risk of lung cancer from baseline data from 95 882 ever-smokers aged 45 years or more in the Australian 45 and Up Study (2006–09).38 The results showed good discrimination (AUC 0·80, 95% CI 0·78–0·81) and excellent calibration. Thus, the use of risk prediction models is essential in the selection of patients for lung cancer screening. Cost-effectiveness was also increased in the high-risk groups38 meaning that risk prediction should also reduce costs per life saved. There is no information on related cost-effectiveness.37 We recognise that the aforementioned risk prediction models were based on European populations and that lung cancer risk predictions might be affected by regional differences. This EU position statement does not recommend any specific risk prediction model, but either the PLCOm2012 or the LLPv2 would suffice if screening were to be implemented immediately.

We need to be aware of the different European health care systems and the issues concerning the use of a risk stratification approach (such as in Germany, in which all individuals have a legal right of access to the available diagnostic and therapeutic techniques). However, it should be argued that screening low-risk patients would be unethical because of harm-to-benefit considerations.

The risk profile of those targeted for screening is a valuable and cost-effective tool to identify those with preclinical disease who are eligible for screening.8,30 The integration of the risk profile with one or more biomarkers or susceptibility genes could improve the selection of high-risk patients for screening, the manage-ment of disease, or both.39,40 Predictive biomarkers, such as microRNA markers, are potentially effec tive tools for the identification of susceptible patients and future lung cancer cases,41–43 while a bronchial airway gene-expression classifier could improve the diagnostic per formance of bronchoscopy.42 Breath tests for lung cancer should be considered a strong possibility for screening and are being tested in clinical trials.43,44

The identification of new biomarkers for screening will be a reason to implement cooperative research. The availability of large, high-quality biobanks embedded in screening trials together with radiomic analysis is a future opportunity that should be explored further in a lung cancer screening context.

Harms and benefits associated with lung cancer screeningThe harms associated with lung cancer screening, such as overdiagnosis, surgery for benign lesions, psychological harm, and radiation exposure, need to be acceptable before the implementation of screening. Minimising harm is essential to maximise the clinical effectiveness of the intervention.

Physical harms can be reduced by ensuring that only patients with a sufficiently high risk of developing lung cancer are screened, by reducing screening radiation dose to a minimum, and by the effective management of atypical findings, including nodules, suspected lung cancers, and incidental findings. These measures re-quire a high degree of clinical expertise to be available so that all aspects of CT screening and management are completed to the highest standards. Thus, lung cancer screening should only be undertaken according to protocol, and at screening units and centres that are able to guarantee rigorous quality control.

According to the guidelines of the European Society for Medical Oncology (ESMO)45 and the European Society of Thoracic Surgeons,46 low-dose CT screening can be done outside a clinical trial setting if it is offered within a screening programme with quality control and in a centre with CT screening experience, extensive thoracic oncology activity, multidisciplinary management of suspicious findings, and a well-developed programme of minimally invasive thoracic surgery. Psychological harms

80 mm3A

B

5·35 mm

5·35 mm

5·78 mm

8·0 mm

10·0 mm

100 mm3

268 mm3 524 mm3

5·78 mm

8 mm 10 mm

Figure 1: Comparative visualisation demonstrating the advantage of using volume instead of diameter when assessing CT-detected lung nodules(A) A volume growth of 25%, defined as growth by NELSON criteria, is hardly appreciable by diameter measurement (8% diameter increase, which is no growth according to existing criteria). (B) A 25% diameter increase (ie, the threshold for growth definition) reflects almost a doubling in volume (95%), highlighting the insensitivity of diameter measurement for growth. Reproduced with permission from Field and colleagues.22


Policy Review

can be reduced by providing information about CT screening in a language that is understood by those who are screened, including details about atypical findings, with accurate information about the probability of cancer, especially where findings are likely to be benign.

The potential physical harms of screening should be provided to attendees in a clear manner, including harm from radiation exposure47 and the harms from a biopsy or resection of a benign lesion. However, the radiation risk is likely to be overestimated and will decrease in the future with the arrival of the latest CT platforms, with ultra low-dose CT technology. All European trials will provide data that will allow a direct quantification of overdiagnosis. The proportion of benign resections in clinical trials varies from 10% to at least 25% of all operations.3,8 Our consensus indicates that a prevalence of 10% or lower for lung cancer should be reached, but an optimal percentage has not been established yet. It should be noted that the dynamic between patient and physician is altered in a lung cancer screening setting when compared with settings where symptomatic individuals present them selves to health-care institutions.

Effective implementation of lung cancer screening programmes also includes recognition of the benefits of maximising smoking cessation within CT screening programmes. Smokers should be informed of the dangers of continuing to smoke for their own general health and should be offered suitable support to help quit.48–50

CT methodologies for early lung cancer detectionIn the NLST trial, a CT screen was regarded as positive if it showed any non-calcified nodule of at least 4 mm in diameter. The American College of Radiology set up a Lung Cancer Screening Committee subgroup to develop Lung-RADS,51,52 a quality assurance tool with which to standardise the reporting of lung cancer CT screening and to inform management recommendations. The rationale behind this initiative was that it would assist in the interpretation of nodule findings.

A comparison of Lung-RADS performance with NLST data53 showed that Lung-RADS substantially reduced the false-positive result rate, but also reduced screening sensitivity. Mehta and colleagues54 have suggested that the Lung-RADS system needs to be revised, and they faulted the system on the basis that it has never been studied in a prospective manner. Additionally, Li and colleagues55 have analysed the effect of the so-called rounding method used in Lung-RADS on the frequency of positive results and on the growth assessment of pulmonary nodules. The authors con cluded that rounding up the mean nodule diameter in Lung-RADS increased the frequency of positive results, leading to a detrimental effect on the efficiency of lung cancer screening. Furthermore, Lung-RADS does not provide guidance on risk prediction models. The Brock score provides a more accurate estimate of a nodule’s risk of malignancy than baseline Lung-RADS criteria.56,57

An alternative method is to determine nodule volume using a software for semi-automated segmentation, which enables an accurate estimation of nodule size after

0 50–100 100–200 200–300 300–400 400–500Nodule volume categories (mm3)

0

2

4

6

8

* *

*

****

10

12

14

Mea

n ax

ial d

iam

eter

(mm

)

Figure 2: Range in mean axial nodule diameter per nodule categoryNodules with a mean diameter of 8–10 mm (coloured zone) are represented in each nodule volume category. These nodules represent the group with the highest uncertainty about nodule nature. The data in this figure are based on intermediate-sized baseline nodules only. Adapted with permission from Heuvelmans and colleagues .58

<100 mm³ volume or <5 mm diameter

Volumetric analysis (or diameter measurement ifvolumetry not available or not technically possible)

100 to <300 mm³ volumeor 5 to <10 mm diameter

≥300 mm³ volume or ≥10 mm diameter

Further work-up and consideration of definitive management

Next round of screeningaccording to protocol

CT scan 3 months afterbaseline

VDT ≤600 days?No Yes

Management accordingto category at 3 months

Yes

No

Solid non-calcified nodule at baseline CT

Clear features of benign disease?

Figure 3: Nodule management protocol for screen-detected solid nodules at baselineFor nodules with a volume-doubling time (VDT) of 400–600 days (intermediate cancer risk of about 4%), a second repeat CT scan in 3 months should be considered as an initial work-up option.


Policy Review

three-dimensional reconstruction (figure 1). Volumetric analysis of CT-detected nodules was initially recommended by Henschke and colleagues14 in 1999, and has been further developed and validated in the NELSON and the UKLS trials. A comparative analysis58 of both diameter and volume was done with baseline data from participants of the NELSON trial, of which 2240 non-calcified nodules of intermediate size were identified. Diameter within a single nodule varied by a median of 2·8 mm, which is larger than the LungRADS cutoff for nodule growth (>1·5 mm increase in mean diameter). Nodules with a diameter of 8–10 mm were represented in each of the five nodule volume categories (figure 2).59

The recommendation for the future management of solid nodules detected with CT screening is that semi-automatically derived volume and volume-doubling time should be used in preference to diameter measurements, which should only be used where volumetry is not technically possible.

Prerequisites for lung cancer population screeningThe accreditation awarded to institutions and radiologists participating in lung cancer CT screenings should

include training in the implementation of quality assurance processes.

The establishment of central national registries for participants would ensure that inclusion criteria are met. In this registry, results from different screening modalities, such as CT manufacturer dose, together with work-up results, should be collected to ensure that previous screens are available and quality control can be assured. The institutions providing a lung cancer screening service should be registered, have access to a participant registry that includes information from previous screens, should use a certified nodule evaluation software, and should deliver screening results and recommendations to a central participant registry. We recommend that the European lung cancer community develop national registries, which could be linked on a hub-and-spoke model, to enable international quality con trol and the use of collected data to improve the provision of lung cancer screening throughout Europe over time.

National quality assurance boards should be set up to monitor the adherence to minimum technical standards and to standardise diagnostic criteria for screen-detected lung nodules, similar to the UK and European breast

Newly identified solid non-calcified nodulenot present on the previous CT screening

Clear features of benign disease?Yes

<30 mm³ volume or <4 mm diameter

Volumetry (or diameter measurement if volumetryis not available or not technically possible)

30 to <200 mm³ volumeor 4 to <8 mm diameter

≥200 mm³ volumeor ≥8 mm diameter

Further work-up andconsideration ofdefinitive management

CT scan 3 months after detection

No

Next round of screeningaccording to protocol

Nodule resolution, benigncalcification, or significantlydecreased size

Stable size on basis of volumetry or two-dimensional non-automated diameter value

VDT >600 days and<200 mm³ volume or<8 mm diameter

VDT ≤600 days or ≥200 mm³ volume or ≥8 mm diameter

Next round of screening according to protocol

Management according to category at 3 months

Figure 4: Nodule management protocol for screen-detected incidental solid nodules at follow-upVDT=volume doubling time.


Policy Review

screening programmes.60–62 Such national quality assurance boards should be entitled to advise or intervene whenever basic requirements are not met. The lung cancer community should consider following the example of the Dutch breast cancer screening service by organising so-called central reading centres of all CT screening programmes across the country.62 This ap proach is favoured over a local reading of CT scans as the latter could have a major effect on routine radiology service delivery. This approach would also enable ongoing national quality assurance control and the introduction of the forefront automated pulmonary nodule reading software.

Institutions participating in screening programmes require multidisciplinary teams to represent all relevant specialities (including a pulmonologist, thoracic surgeon, radiologist, lung cancer nurse, and so on) in which suspicious screening results can be discussed. These institutions should regularly demonstrate to a quality as-surance board that they continue to meet basic standards similar to those proposed by the Radiological Society of North America.63

Lung nodule management at baseline CT screeningThe management of prevalent lung nodules should mostly depend on size criteria. Volumetry is essential, but

diameter cutoffs need to be provided for cases in which segmentation is not possible. Minimum standards for CT acquisition parameters in lung cancer screening need to be met to ensure the standardisation of volumetric analysis (ie, protocol regarding slice thickness, recon-struction interval, and image reconstruction algorithm [kernel]), and to clearly define the low radiation dose.

The management of screen-detected lung nodules should be based on the evidence from screening trials that have used volumetry, such as the NELSON trial. In the original NELSON nodule management protocol,2 volume cutoffs for negative and positive screen results were less than 50 mm³ for negative and more than 500 mm³ for positive results. Nodules with a volume of 50–500 mm³ were classified as indeterminate. These cutoffs could be optimised on the basis of lung cancer probability results of the first two screening rounds from the NELSON trial.21 For example, for solid nodules with a volume of less than 100 mm³, the patient should return for an annual screen; for nodules with a volume of 100–300 mm³, the patient should return for a repeat screen in 3 months; for volumes greater than 300 mm³, the patient should be referred to a multi disciplinary team.21 Figure 364 shows the recom mended nodule management protocol for screen-detected solid nodules at baseline, figure 464 for screen-detected incidental

Baseline volumetric analysis (or diameter measurement ifvolumentric is not available or not technically possible)

5–6 mm diameter ≥80 mm³ volume or≥6 mm diameter

CT scan 3 monthsafter baseline

VDT ≥400 days or clearevidence of growth

CT scan 1 year afterbaseline

No Yes

Stable on basis of two-dimensional non-automated diameter value

Stable size on basis of volumetry

VDT >600 days VDT 400–600 days VDT ≤400 days or clearevidence of growth

CT scan 2 years afterbaseline

VDT assessment andmanage according toVDT category at 1 year;discharge if stable

Discharge Consider discharge (onlyif based on volumetry)or ongoing CTsurveillance dependingon patient preference

Consider biopsy orfurther CT surveillancedepending on patientpreference

Further work-up andconsideration ofdefinitive management

Figure 5: Nodule management protocol for clinically detected solid nodules according to British Thoracic Society guidelinesVDT=volume doubling time. Reproduced with permission from Callister and colleagues.64


Policy Review

nodules at follow-up, figure 5 for clinically detected solid nodules according to British Thoracic Society (BTS) guidelines, and figure 6 for sub-solid nodules for both screen-detected and clinically detected nodules. Detailed risk profiles for the probability of lung cancer over 2 years are shown in figure 7.21 Data to inform this figure have been provided by the NELSON group for both nodule volume and volume-doubling time (<400 days and 400–600 days—an increased risk, described in figure 3; >600 days, no substantially increased risk), which provides guidance to the future follow-up interval for specific participants. In 2017, a study65 provided in-vivo evidence for the growth patterns of screen-detected lung cancers, showing an exponential growth pattern that can be described by the volume-doubling time. Acknowledging that software packages give different estimates of solid nodule volume, commonly around 20% of difference (corresponding to a non-measurable 7% error in nodule diameter; absolute 0·4 mm error),66 there might be merit in decreasing the nodule volume threshold for a repeat screen at 3 months to 80 mm³ if the software is not phantom validated (a calibration process for quality assurance of different CT scanners; figure 5).

For sub-solid nodules, surveillance should be favoured over intervention to avoid overdiagnosis. For all pure ground glass nodules and most partial solid nodules, a return to annual screening is recommended (figure 6).67

Knowledge and data from ongoing lung cancer screening projects will also be important for the future optimisation and refinement of nodule management protocols.

Morphology assessment should also play a part in the management of solid nodules, such as clustered, ill-defined nodules, which are more consistent with inflammatory aetiologies, or smooth peri-fissural nodules or intrapulmonary lymph nodes, which require management not based purely on size criteria.68 There are several alternative work-up methods for screen-detected suspicious nodules with volumes larger than 300 mm³ at baseline, such as core needle biopsy, PET or CT scans, and primary resection.

The management of a patient should be done ac-cording to their risk of malignancy. Low-risk nodules, such as those with a risk of malignancy lower than 10%, can be followed up with interval imaging, but high-risk nodules need further work-up if it is agreeable to the patient after an informed discussion. As the risk of

Sub-solid nodule on CT

Nodule <5 mm, patient unfit for anytreatment or stable over 4 years?

Previous imaging?

Repeat thin section CT at 3 months

Resolved Stable

Assess risk of malignancy(Brock model†, morphology‡),patient fitness, and patient preference

Low risk of malignancy(approximately <10%)

Higher risk of malignancy(approximately >10%) or concerningmorphology‡, discussoptions with patient

Growth or altered morphology*

Assess interval change; if stable overless than 4 years, assess risk of malignancy as below

No

Yes

Yes

Discharge Thin section CT 1, 2, and 4 yearsfrom baseline

Image-guided biopsy Favour resection or non-surgicaltreatment

No

Figure 6: Management protocol for sub-solid nodules for both screen-detected and clinically detected nodules according to British Thoracic Society guidelinesReproduced with permission from Callister and colleagues.64 *Change in mass or a new solid component. †The Brock model can underestimate the risk of malignancy in sub-solid nodules that persist at 3 months. ‡The size of the solid component in part-solid nodules, pleural indentation, and bubble-like appearance.


Policy Review

malignancy increases, management options broadly include further surveillance, biopsy, or treatment.

ESMO guidelines published in 201745 indicate that the cornerstone of treatment of potentially resectable lung cancer is the surgical removal of the tumour. For patients who are not willing to accept the risks of surgery, or for whom surgery is a high-risk option, non-surgical therapy should be offered. This option could be either stereo-tactic ablative radiotherapy, hypofraction ated high-dose radiotherapy or image-guided ablative therapy.45

Incident screening roundsAlthough incident screening rounds will constitute much of the work in the early detection of lung cancer, until recently research did not focus on incident nodules and their definition, which has varied widely between low-dose CT lung cancer screening trials.8,64,69,70 Incident nodules detected in high-risk individuals after baseline screening had either been missed in a previous scan or had developed de novo in the time interval since the previous scan. In the event of a missed nodule, calculation of the volume-doubling time is advised for further risk stratification. However, patients with newly developed nodules are a specific group that is distinct from patients that have had nodules detected at baseline. With an annual incidence of between 3% and 13% of participants, these newly developed nodules are regularly encountered in low-dose CT lung cancer screening.71–74 Unlike baseline nodules, which could have been present for years before detection, new incident nodules are potentially fast-growing.17,75–77 This potential is reflected in a high cancer risk of 2–8% for participants with a new incident nodule.17,71,72,74 Because these nodules have less time to grow before detection than those nodules detected previously, baseline cutoff values are not applicable.17 This formerly theoretical concept, which led to an adjustment of cutoff values for new incident nodules in several trials,53,72,77 has been supported for new solid incident nodules by the results of the NELSON trial.17 Because a large proportion (37–57%) of new incident nodules are very small (<50 mm³ in volume),17,71,74 volume measure-ments should be preferred, since diameter measurements are much less precise and reproducible. Data from the NELSON trial suggest that new solid incident nodules should be categorised in three groups: nodules smaller than 27 mm³ in volume (<1% lung cancer probability) represent a low-risk group, and these patients could return to the annual screen schedule (based on an annual screening programme); patients with new solid incident nodules of 27–207 mm³ in volume (3% lung cancer probability) form an intermediate-risk group requiring a repeat low-dose CT in 3 months; and patients with new non-calcified solid incident nodules equal or greater than 208 mm³ in volume (17% lung cancer probability) form a high-risk group requiring referral to a multidisciplinary team.17 We suggest simplifying these categories to volumes smaller than 30 mm³, 30–200 mm³, and equal or

greater than 200 mm³ (figure 4). The existing data indicate that the majority (68–86%) of lung cancers found in new incident nodules during lung cancer screening are detected at stage I.17,72 Therefore, volume-doubling time assessment at follow-up scans appears appropriate, as outlined in the BTS guidelines.64 However, the available evidence regarding new incident nodules is insufficient, and a more standardised approach to reporting, such as strictly separating baseline and incident nodules, could simplify the recommended routine clinical management of patients with newly detected incident nodules. If a CT scan is done less than 2 years before screening is available, recommendations for new inci dence nodules detected during screening could be extrapolated to routine clinical practice in a high-risk patient population, similar to that done in the NELSON trial. This recommendation has now been adopted by the BTS guidelines on nodule management,78 and by the BTS Quality Standard on lung nodule management. In a low-risk population, the management of patients should follow BTS guidelines.

Clinical work-up of CT-detected lung nodules in clinical practiceIncidentally detected lung nodules are an increasingly common clinical problem arising from the increased use of cross-sectional imaging in clinical practice. The BTS has undertaken the in-depth task of developing guide lines on the management of pulmonary nodules in a clinical context, separate from the context of population screening.64 This work has been based on an extensive

700

3%

5%

600

500

400

300

200

7% 10% 15% 20% 30% 50%100

00 100 200 300 400 500

Volu

me d

oubl

ing

time

(day

s)

Volume of largest nodule (mm3)

Figure 7: Contour plot of the effect of the combined effect of nodule volume and volume-doubling times on the 2-year probability of lung cancer The risk isolines represent the percentage of NELSON participants that will be diagnosed with lung cancer within 2 years according to the volume of their largest nodule and volume-doubling time of the fastest growing nodule inthe 50–500 mm3 range. Reproduced with permission from Horeweg and colleagues.21


Policy Review

review of the literature, which included publications from several lung cancer CT screening trials, and an in-depth analysis of the data. The guideline development group used methods compliant with the AGREE Collaboration criteria and standards set by NHS Evidence. The evidence review was comprehensive, done in November, 2012, and updated in June, 2014. The guidelines provide four management algorithms and two malignancy prediction tools:64 the Brock risk prediction tool to calculate malignancy in solid pul monary nodules equal or larger than 5 mm in volume, which are unchanged at 3 months,56 and the Herder prediction tool to be used after PET/CT.79 Furthermore, volumetry has been recommended by BTS

as the preferred measurement for CT-detected nodules. The guidelines also provide recommendations for the management of nodules with extended volume-doubling times.

The BTS guidelines provide recommendations on the use of further imaging and PET/CT information that can be incorporated into pulmonary risk models (Herder model), and advice on biopsy and the threshold for treatment without histological confirmation. BTS also provides advice on the information that should be given to patients about the management of pulmonary nodules in a non-screening context. This EU position statement recommends keeping a database of all nodules that can facilitate a future refinement of nodule management in line with new evidence.

Optimal timing of lung cancer screening intervalsThe USPSTF on CT screening has recommended annual screening from age 55 years to 80 years.80 In a NELSON publication,81 a 2·5-year screening interval resulted in a significant increase in in terval cancers in the fourth screening round, providing evidence against using this interval in a future screening programme. There were also significantly more interval cancers in a 2·5-year timeframe, and a trend towards more cancers detected at a later stage. A detailed analysis of the cost-effectiveness of various screening scenarios showed that almost all approaches increase cost-effectiveness when screens are annual.82 However, half of the participants included in the NELSON trial had no pulmonary nodules detected, and the 2-year probability of participants developing lung cancer was 0∙4%, indicating that a screening interval of up to 2 years could be considered for similar individuals in future screening programmes, in a risk-stratified approach. The only trial to test annual and biennial screening was the MILD trial,83 in which no difference was found in terms of mortality when comparing these two screening intervals.

Screening intervals have been modelled by both the UKLS trial84 and the International Early Lung Cancer Action Program.85 Duffy and colleagues84 acknowledged the risk of increasing the number of screening intervals but also acknowledged that it could potentially provide a more cost-effective approach. Yankelevitz and colleagues85

argued that we should move beyond hypothesis testing and onto quantification. We need to learn how the length of the interval between screens affects the diagnostic distribution before we consider changing annual screening intervals.

So far, we only have trial evidence for annual screening. Studies have shown that previous negative screening results might provide directions for further risk stratification.86,87 Future decisions regarding interval timing should be based on risk, psychosocial effects,88 cost-effectiveness, and the feasibility of implementation,89 but these areas require further investigation. However, with new ultra-low-dose CT techniques, the radiation

Panel 1: European Union (EU) position statement recommendations

We recommend the following actions to begin implementation of lung cancer screening in Europe:1 Low-dose CT is the only evidence-based method for the early detection of lung cancer

shown to provide a mortality reduction. On the basis of this evidence from randomised controled trials, the EU position statement recommends that we start to plan for the implementation of lung cancer screening in Europe while cognisant of future publications that include the awaited NELSON trial data on mortality and cost-effectiveness and data from the six smaller European studies for developing implementation strategies in each of their own countries.

2 Future lung cancer low-dose CT programmes should use a validated risk stratification approach so that only individuals deemed to be at high enough risk are screened. In the near future, incorporation of potential biomarkers and susceptibility genes into lung cancer risk models should be considered to improve the accuracy of risk stratification models.

3 All future screenees entering into early detection programmes for lung cancer should be provided with carefully constructed participant information on the potential benefits and harms of screening to enable them to make an informed decision as to whether they wish to participate or not. Smoking cessation advice should be offered to all active smokers.

4 Future management of screen-detected solid nodules should utilise semi-automatically derived volume measurements and volume-doubling time, and should be quality assured.

5 National quality assurance boards should be set up by professional bodies to ensure adherence to all minimum technical standards, including semi-automated volumetry, and to standardise diagnostic criteria for screen-detected lung nodules, including radiation exposure limits.

6 Management of prevalent lung nodules in CT screening programmes, lung nodules at incident screening (newly detected), and CT-detected lung nodules in clinical practice should be managed with different protocols because of different pretest lung cancer probabilities.

7 Although only evidence for annual low-dose CT lung cancer screening is available, recent research suggests the possibility of using a more personalised approach to lung cancer screening with a risk-based approach on the results of baseline and first screening rounds.

8 Management of lung nodules by lung cancer multidisciplinary teams should be done according to the EU position statement recommendations with the aim of minimising harm and ensuring patients receive the most appropriate treatment.

9 The EU position statement expert group recommends that the planning for low-dose CT screening should be started throughout Europe because low-dose CT lung cancer screening has the potential to save lives.


Policy Review

dose for repeated CT screenings over a 30-year period might not be a major issue for participants. New developments, such as deep machine learning, will assist in the automation of pulmonary nodule management in lung cancer screening.90

In the future, we think that, with implementation of ultra-low-dose CT screening, there will be no obstacles in tailoring the frequency of screening of high-risk individuals over a 25-year period. We should be considering precision medicine in the field of lung cancer screening, and whether an individual who has had a negative baseline and a negative 1-year scan should be moved into biennial screening until their risk profile changes. As lung cancer screening is still in an embryonic stage of implementation in Europe, we have an op-portunity to plan the development of an optimal lung cancer low-dose CT screening strategy.91

ConclusionThis EU position statement describes the current status of lung cancer screening in Europe. Through consensus discussions with experts from the eight European countries undertaking randomised controlled trials of lung cancer CT screening, we have developed nine recommendations to guide the implementation of lung cancer screening in Europe (panel 1). Some specific areas still require further development and consideration, such as the integratation of smoking cessation into lung cancer screening programmes and the selection of the appropriate target screening population. However, evidence clearly shows that Europe must start planning for implementation within the next 18 months, as outlined here (panel 2). During this planning period, each country will need to focus on deciding the best risk prediction method for the identification and recruitment of high-risk populations and on setting up the required infrastructure for quality-controlled CT scans that use volumetric analysis. This EU position statement has provided detailed recommendations on the management of lung nodules by

lung cancer multidisciplinary teams, with the aim of minimising harm and ensuring that patients receive the optimal diagnosis and therapy.ContributorsMO and JKF developed the concept and design of the EU position statement on lung cancer screening. All authors contributed equally to the development of the EU position statement.

Declaration of interestsGB has received personal fees from Bayer, General Electric, and Siemens Healthcare. DRB has received personal fees from AstraZeneca. SD has received grants from the German Research Foundation and from the Dietmar Hopp Foundation. JKF has received grants from HTA funding for the UKLS trial, grants and other funding from Liverpool CCG, and other research funding from Epigenomics and Vision Gate. CPH has received consultation and personal fees from Pfizer, Boehringer Ingelheim, Novartis, Gilead, MSD, Intermune, and Fresenius; research funding from Siemens, Pfizer, and Boehringer Ingelheim; and lecture fees from Gilead, MSD, Pfizer, Intermune, Novartis, Basilea, and Bayer. MVI reports personal fees from Exact Sciences. HdK reports grants and other non-financial support from the NELSON trial, a grant for health technology assessment for CT lung cancer screening in Canada by Cancer Care Ontario, and a grant from the University of Zurich to assess the cost-effectiveness of CT lung cancer screening in Switzerland; HdK took part in a 1-day advisory meeting on biomarkers organised by MD Anderson/Health Sciences during the 16th World Conference on Lung Cancer. MO reports grants from the Royal Dutch Academy of Sciences, from the Netherlands Organisation of Scientific Research, and from the Netherlands Organisation for Health Research and Development. NS reports personal fees from Roche, Boehringer Ingelheim, Parexel, and Bayer. WR reports a patent of a protein marker signature of early lung cancer pending, and a patent of a miRNA signature of early lung cancer. AD, RV, TH, HP, MM, MEC, MAH, NB, UP, JHP, EP, and SWD declare no competing interests.

References1 National Lung Screening Trial Research Team, Aberle DR,

Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409.

2 van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009; 361: 2221–29.

3 Sverzellati N, Silva M, Calareso G, et al. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. Eur Radiol 2016; 26: 3821–29.

4 Paci E, Puliti D, Lopes Pegna A, et al. Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax 2017; 72: 825–31.

5 Infante M, Cavuto S, Lutman FR, et al. Long-term follow-up results of the DANTE trial, a randomized study of lung cancer screening with spiral computed tomography. Am J Respir Crit Care Med 2015; 191: 1166–75.

6 Wille MM, Dirksen A, Ashraf H, et al. Results of the randomized danish lung cancer screening trial with focus on high-risk profiling. Am J Respir Crit Care Med 2016; 193: 542–51.

Panel 2: A call for action

Europe needs to set a timeline for implementing lung cancer screening:• Publish recommendations for implementation with

quality assurance measures (6 months)• Plan health service requirements and their delivery

(12 months)• Plan phased implementation in high-risk regions while

awaiting mortality data from the NELSON trial (18 months)• Plan to set up a European registry of images and data

(18 months)• Evaluate implementation after the first 12 months and

review delivery strategy (36 months)• Expand lung cancer screening to all regions within Europe

(48 months)

Search strategy and selection criteria

Data for this European Union position statement were identified through searches of PubMed, MEDLINE, and references from relevant articles using search terms “lung cancer CT screening trial”, “lung screen detected nodules”, “lung cancer CT screening recommendations”, and “lung cancer CT screening cost effectiveness”. Identified abstracts and reports from meetings were included only when they related directly to previously published work. Only articles published in English between 1999 and 2017 were included.


Policy Review

7 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: 890–96.

8 Field JK, Duffy SW, Baldwin DR, et al. The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer. Health Technol Assess 2016; 20: 1–146.

9 Field JK, van Klaveren R, Pedersen JH, et al. European randomized lung cancer screening trials: Post NLST. J Surg Oncol 2013; 108: 280–86.

10 Van den Bergh KA, Essink-Bot ML, Bunge EM, et al. Impact of computed tomography screening for lung cancer on participants in a randomized controlled trial (NELSON trial). Cancer 2008; 113: 396–404.

11 Van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON). Br J Cancer 2010; 102: 27–34.

12 Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR. Lung cancer screening: the Mayo program. J Occup Med 1986; 28: 746–50.

13 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.

14 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.

15 Biederer J, Ohno Y, Hatabu H, et al. Screening for lung cancer: does MRI have a role? Eur J Radiol 2017; 86: 353–60.

16 Horeweg N, van der Aalst CM, Vliegenthart R, et al. Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 2013; 42: 1659–67.

17 Walter JE, Heuvelmans MA, de Jong PA, et al. Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial. Lancet Oncol 2016; 17: 907–16.

18 Marcus PM, Bergstralh EJ, Fagerstrom RM, et al. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 2000; 92: 1308–16.

19 Tammemagi MC, Schmidt H, Martel S, et al. Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study. Lancet Oncol 2017; 18: 1523–31.

20 Veronesi G, Bellomi M, Mulshine JL, et al. Lung cancer screening with low-dose computed tomography: a non-invasive diagnostic protocol for baseline lung nodules. Lung Cancer 2008; 61: 340–49.

21 Horeweg N, van Rosmalen J, Heuvelmans MA, 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. Lancet Oncol 2014; 15: 1332–41.

22 Field JK, Oudkerk M, Pedersen JH, Duffy SW. Prospects for population screening and diagnosis of lung cancer. Lancet 2013; 382: 732–41.

23 Infante M, Sestini S, Galeone C, et al. Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials. Eur J Cancer Prev 2016; 26: 324–29.

24 Cressman S, Peacock SJ, Tammemagi MC, et al. The cost-effectiveness of high-risk lung cancer screening and drivers of program efficiency. J Thorac Oncol 2017; 12: 1210–22.

25 Gonzalez J, Marin M, Sanchez-Salcedo P, Zulueta JJ. Lung cancer screening in patients with chronic obstructive pulmonary disease. Ann Transl Med 2016; 4: 160.

26 Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197–223.

27 Cassidy A, Myles JP, van Tongeren M, et al. The LLP risk model: an individual risk prediction model for lung cancer. Br J Cancer 2008; 98: 270–76.

28 Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst 2003; 95: 470–78.

29 Spitz MR, Hong WK, Amos CI, et al. A risk model for prediction of lung cancer. J Natl Cancer Inst 2007; 99: 715–26.

30 Tammemagi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013; 368: 728–36.

31 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.

32 Katki HA, Kovalchik SA, Berg CD, Cheung LC, Chaturvedi AK. Development and validation of risk models to select ever-smokers for CT lung cancer screening. JAMA 2016; 315: 2300–11.

33 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.

34 Field JK, Gaynor ES, Duffy SW, et al. Liverpool healthy lung project: a primary care initiative to identify hard to reach individuals with a high risk of developing lung cancer. AACR Annual Meeting; Washington, DC, USA; April 1–5, 2017. 4220.

35 Field JK, Marcus M, Maroni R, et al. Liverpool Healthy Lung project. 2017. http://www.liverpoolccg.nhs.uk/health-and-services/healthy-lungs/ (accessed June 9, 2017).

36 Li K, Husing A, Sookthai D, et al. Selecting high-risk individuals for lung cancer screening: a prospective evaluation of existing risk models and eligibility criteria in the german EPIC cohort. Cancer Prev Res (Phila) 2015; 8: 777–85.

37 Ten Haaf K, Jeon J, Tammemagi MC, et al. Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study. PLoS Med 2017; 14: e1002277.

38 Weber M, Yap S, Goldsbury D, et al. Identifying high risk individuals for targeted lung cancer screening: Independent validation of the PLCOm2012 risk prediction tool. Int J Cancer 2017; 141: 242–53.

39 Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452: 633–37.

40 Amos CI, Dennis J, Wang Z, et al. The OncoArray consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol Biomarkers Prev 2017; 26: 126–35.

41 Sestini S, Boeri M, Marchiano A, et al. Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening. Oncotarget 2015; 6: 32868–77.

42 Silvestri GA, Vachani A, Whitney D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Engl J Med 2015; 373: 243–51.

43 Broza YY, Kremer R, Tisch U, et al. A nanomaterial-based breath test for short-term follow-up after lung tumor resection. Nanomedicine 2013; 9: 15–21.

44 Owlstone Medical. LuCID: a multi-centre prospective trial for lung cancer screening. 2016. https://www.owlstonemedical.com/clinical-pipeline/lucid/ (accessed July 1, 2017).

45 Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl 4): iv1–iv21.

46 Pedersen JH, Rzyman W, Veronesi G, et al. Recommendations from the European Society of Thoracic Surgeons (ESTS) regarding computed tomography screening for lung cancer in Europe. Eur J Cardiothorac Surg 2017; 51: 411–20.

47 Rampinelli C, De Marco P, Origgi D, et al. Exposure to low dose computed tomography for lung cancer screening and risk of cancer: secondary analysis of trial data and risk-benefit analysis. BMJ 2017; 356: j347.

48 Tammemagi MC, Berg CD, Riley TL, Cunningham CR, Taylor KL. Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst 2014; 106: dju084.

49 Ashraf H, Tonnesen P, Holst Pedersen J, Dirksen A, Thorsen H, Dossing M. Effect of CT screening on smoking habits at 1-year follow-up in the Danish Lung Cancer Screening Trial (DLCST). Thorax 2009; 64: 388–92.

50 Brain K, Carter B, Lifford KJ, et al. Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial. Thorax 2017; 72: 912–18.

51 Fintelmann FJ, Bernheim A, Digumarthy SR, et al. The 10 pillars of lung cancer screening: rationale and logistics of a lung cancer screening program. Radiographics 2015; 35: 1893–908.


Policy Review

52 McKee BJ, Regis SM, McKee AB, Flacke S, Wald C. Performance of ACR lung-RADS in a clinical CT lung screening program. J Am Coll Radiol 2016; 13 (suppl 2): R25–R29.

53 Pinsky PF, Gierada DS, Black W, et al. Performance of lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med 2015; 162: 485–91.

54 Mehta HJ, Mohammed TL, Jantz MA. The American College of Radiology lung imaging reporting and data system: potential drawbacks and need for revision. Chest 2017; 151: 539–43.

55 Li K, Yip R, Avila R, Henschke CI, Yankelevitz DF. Size and growth assessment of pulmonary nodules: consequences of the rounding. J Thorac Oncol 2016; 12: 657–62.

56 McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013; 369: 910–19.

57 van Riel SJ, Ciompi F, Jacobs C, et al. Malignancy risk estimation of screen-detected nodules at baseline CT: comparison of the PanCan model, Lung-RADS and NCCN guidelines. Eur Radiol 2017; 27: 4019–29.

58 Heuvelmans MA, Walter JE, Vliegenthart R, et al. Disagreement of diameter and volume measurements for pulmonary nodule size estimation in CT lung cancer screening. Thorax 2017; published online Oct 22. DOI: 10.1136/thoraxjnl-2017-210770.

59 Heuvelmans M, Vliegenthart R, van Ooijen P, et al. Nodule size is poorly represented by nodule diameter in low–dose CT lung cancer screening. IASLC 17th world conference on lung cancer; Vienna, Austria; Dec 4–7, 2016. P1.03–042.

60 Public Health England. Breast screening: programme consolidated standards. London: Public Health England, 2017.

61 Perry N, Broeders M, de Wolf C, Tornberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition—summary document. Ann Oncol 2008; 19: 614–22.

62 LCRB Dutch breast cancer—focus on early disease. 2017. http://www.lrcb.nl/en/breast-cancer/audit/ (accessed May 15, 2017).

63 CT Volumetry Technical Committee. Lung nodule assessment in CT screening profile. 2017. QIBA. http://qibawiki.rsna.org/images/f/fb/QIBA_CT_Vol_LungNoduleAssessmentInCTScreening_2017.07.rev15.pdf (accessed Aug 01, 2017).

64 Heuvelmans MA, Vliegenthart R, de Koning HJ, et al. Quantification of growth patterns of screen-detected lung cancers: the NELSON study. Lung Cancer 2017; 108: 48–54.

65 de Hoop B, Gietema H, van Ginneken B, Zanen P, Groenewegen G, Prokop M. A comparison of six software packages for evaluation of solid lung nodules using semi-automated volumetry: what is the minimum increase in size to detect growth in repeated CT examinations. Eur Radiol 2009; 19: 800–08.

66 Scholten ET, de Jong PA, Jacobs C, et al. Interscan variation of semi-automated volumetry of subsolid pulmonary nodules. Eur Radiol 2015; 25: 1040–47.

67 Chung K, Jacobs C, Scholten ET, et al. Lung-RADS category 4X: does it improve prediction of malignancy in subsolid nodules? Radiology 2017; 284: 264–71.

68 Midthun DE, Jett JR. Screening for lung cancer: the US studies. J Surg Oncol 2013; 108: 275–79.

69 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.

70 Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015; 70 (suppl 2): ii1–ii54.

71 Henschke CI, Naidich DP, Yankelevitz DF, et al. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001; 92: 153–59.

72 Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–71.

73 Wilson DO, Weissfeld JL, Fuhrman CR, et al. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan. Am J Respir Crit Care Med 2008; 178: 956–61.

74 Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002; 165: 508–13.

75 Henschke CI, Yankelevitz DF, Yip R, et al. Lung cancers diagnosed at annual CT screening: volume doubling times. Radiology 2012; 263: 578–83.

76 Carter D, Vazquez M, Flieder DB, et al. Comparison of pathologic findings of baseline and annual repeat cancers diagnosed on CT screening. Lung Cancer 2007; 56: 193–99.

77 Xu DM, Yip R, Smith JP, Yankelevitz DF, Henschke CI, Investigators IE. Retrospective review of lung cancers diagnosed in annual rounds of CT screening. AJR Am J Roentgenol 2014; 203: 965–72.

78 Cancer Research UK. Pulmonary nodule risk. 2017. https://itunes.apple.com/gb/app/pulmonary-nodule-risk/id1142255949?mt=8 (accessed May 15, 2017).

79 Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest 2005; 128: 2490–96.

80 US Preventive Services Task Force. Final Update Summary: Lung Cancer: Screening. 2015. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/lung-cancer-screening (accessed July 26, 2017).

81 Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax 2017; 72: 48–56.

82 Ten Haaf K, Tammemagi MC, Bondy SJ, 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. PLoS Med 2017; 14: e1002225.

83 Pastorino U, Rossi M, Rosato V, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012; 21: 308–15.

84 Duffy SW, Field JK, Allgood PC, Seigneurin A. Translation of research results to simple estimates of the likely effect of a lung cancer screening programme in the United Kingdom. Br J Cancer 2014; 110: 1834–40.

85 Yankelevitz D, Henschke C. Lung cancer: low-dose CT screening—determining the right interval. Nat Rev Clin Oncol 2016; 13: 533–34.

86 Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Risk stratification based on screening history: the NELSON lung cancer screening study. Thorax 2017; 72: 819–24.

87 Patz EF Jr, Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. 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. Lancet Oncol 2016; 17: 590–99.

88 Dunn CE, Edwards A, Carter B, Field JK, Brain K, Lifford KJ. The role of screening expectations in modifying short-term psychological responses to low-dose computed tomography lung cancer screening among high-risk individuals. Patient Educ Couns 2017; 100: 1572–79.

89 Field JK, Duffy SW, Devaraj A, Baldwin DR. Implementation planning for lung cancer screening: five major challenges. Lancet Respir Med 2016; 4: 685–87.

90 Ciompi F, Chung K, van Riel SJ, et al. Towards automatic pulmonary nodule management in lung cancer screening with deep learning. Sci Rep 2017; 7: 46479.

91 Field JK. Perspective: the screening imperative. Nature 2014; 513: S7.

policy review european position statement on lung cancer ... · policy review european position...

Documents