ESR/ERS white paper on lung cancer screening

The NLST is the first randomised, controlled lung cancer screening trial in current and former smokers (> 30 pack-years) aged between 55 and 74 years to show a significant reduction in lung-cancer-specific mortality [6]. The computed tomography (CT) screening arm of the trial involved 26,722 participants who received three yearly screening rounds of LDCT. The control arm involved 26,732 participants who received three yearly screening rounds using chest radiographs. After a follow-up period of approximately 6.5 years, participants in the CT screening arm were 20 % less likely to die from lung cancer than those in the control arm. A 6 % reduction in overall mortality was also observed within the 6.5-year period. In the CT screening arm, 356 participants died from lung cancer, whereas the number in the corresponding radiography arm was 443 [6]. In an additional evaluation 1 year later, these numbers had increased to 469 in the CT arm and 552 in the radiography arm, which corresponds to a 15 % reduction [7]. These results suggest that LDCT finds more cancers, most of them being in stage IA (>50 %) and approximately 10 % in stage IB [8]. Still, 43 % (469 out of 1089) of those patients who developed lung cancer died of lung cancer. The overall screening effort meant that 320 participants had to be screened to prevent one lung cancer death within the 6.5-year follow-up period [6].

The Dutch−Belgian NELSON trial is the largest European randomised controlled trial with at-risk participants based on age and smoking history randomly selected from population registries. The first outcome data are expected in 2016. The trial involves 7577 participants in the CT screening arm and compares them to 7871 participants in the control arm [9]. Apart from a smoking cessation programme, no intervention was offered in the control arm. Published results are available from smaller randomised controlled trials from Denmark (DLST) and Italy (Italung, DANTE and MILD). These trials involved approximately 1000–2000 patients in each arm [10]. Published results suggest no advantage for lung cancer screening. In fact, DLST and MILD even found a trend towards higher mortality in the yearly CT screening arms [11, 12]. Other current randomised controlled trials are the German Lung Screening and Intervention (LUSI) trial and the UK Lung Screening (UKLS) trial [13, 14].

There is a wide range of acceptance of the general lung cancer screening algorithm using LDCT across the globe; however, different degrees of modification from the NLST algorithm seem to be required (Table 1) [5].

From February 2012, the Lung Cancer Screening Panel of the National Comprehensive Cancer Network (NCCN) in the USA recommended annual LDCT screening of all high-risk individuals between the age of 55 and 74 years, as defined in the NLST [15]. However, the NCCN guidelines expanded the NLST criteria based on non-randomised studies and observational data. Individuals 50 years of age or older with a tobacco smoking history of 20 or more pack-years and one additional risk factor should be screened annually. The suggested additional risk factors were history of cancer, history of lung disease [chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis], family history of lung cancer, radon exposure and occupational exposure. The NCCN currently does not advise screening of individuals at moderate and low risk for lung cancer, or for individuals with exposure to second-hand smoke [16].

A collaborative initiative of the American Cancer Society [17], the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology [18], and the NCCN published a review of LDCT screening for lung cancer, together with clinical practice guidelines, in May 2012 [10]. They adopt the NLST eligibility criteria, but note that the duration and frequency of screening remain undetermined [18]. In June 2012, guidelines for lung cancer screening were issued by the American Association for Thoracic Surgery (AATS) [19], expanding the criteria beyond the NLST. The AATS guidelines consider the amount of tobacco exposure and age to be the most important risk factors, and therefore do not restrict screening to patients who quit smoking in the previous 15 years. Since the risk of lung cancer does not decrease after 3 years of screening, the AATS recommends annual LDCT screening for high-risk patients from age 55 to 79 years. They consider that level 2 evidence is enough to advise screening for smokers 50–79 years of age with a 20 pack-year smoking history or other factors that produce a cumulative ≥ 5 % risk of developing lung cancer over the following 5 years. Based on AATS consensus opinion (level 3 evidence), patients treated for primary bronchogenic carcinoma who have completed 4 years of radiographic surveillance without evidence for recurrence should also be screened. In January 2013, the American Cancer Society published guidelines that recommend annual lung screening by LDCT based on the NLST eligibility criteria until the age of 74 years [20]. In May 2013, the ACCP published its third edition guidelines of diagnosis and management of lung cancer, including a recommendation concerning lung cancer screening [21, 22]. Annual screening with LDCT for individuals who meet the NLST eligibility criteria is recommended (grade 2B; weak recommendation, moderate level of evidence).

In December 2013, the United States Preventive Services Task Force (USPSTF) developed their recommendation statement [23], which was published in March 2014 [24], supporting LDCT lung cancer screening for healthy adults between 55 and 80 years of age with a smoking history of 30 pack-years or more and who have smoked within the previous 15 years. The number of years needed for screening is not specified, but screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits the life expectancy or the ability or willingness to have curative lung surgery (grade B recommendation). Under the Affordable Care Act [25], any procedure that receives a grade B recommendation from the US Preventive Services Task Force (USPSTF) has to be covered by private insurers without co-payment. Most insurers in the USA follow the recommendations of the task force, and pay for those services. In April 2014, the US federal agency Center for Medicare and Medicaid services (CMS) advisory panel voted against covering lung cancer screening [26]. Key concerns were the high false-positive rate of CT screening, indication creep outside of the intended screening population, inability to assure quality scans with low radiation dose, and consistent interpretation and diagnostic work-up in routine practice. In February 2015, in contrast to the recommendations of the agency’s advisory board, Medicare announced its decision to start covering annual lung cancer screening once per year for long-time smokers at high risk for the disease [27]. CMS experts require that screening candidates are between ages 55 and 77 years, have no signs or symptoms of lung disease, have tobacco smoking history of at least 30 pack-years and are current smokers or ex-smokers who have quit smoking within the previous 15 years. For the initial screen, the beneficiary must receive a written order for LDCT lung cancer screening obtained during a “lung cancer screening counselling and shared decision-making visit” from a physician, physician assistant, nurse practitioner or clinical nurse specialist. CMS also gives details for that visit, radiologist eligibility criteria and imaging centre eligibility criteria [27]. In Europe, there are no lung cancer screening recommendations or reimbursed screening programmes so far.

Tobacco smoking is a major risk factor for lung cancer, as shown by many epidemiological studies. Other less important risk factors are passive (second-hand) smoking, occupational exposure, environmental exposure, residential radon exposure, presence of COPD and family history of lung, head and neck cancer. A meta-analysis of ten case−control studies including 7609 cases and 10,431 controls shows an increase of the relative risk of lung cancer in the European population with active smoking (versus ex-smokers), with duration and amount of smoking and the cumulative dose of pack-years [28]. The recommendations for the NELSON trial are based on data from the Cancer Prevention Study II (CPS II) [29]. According to this data, a smoking history of 30 years or more in individuals older than 55 years and a consumption of at least one pack of cigarettes a day correspond to a lung cancer incidence of at least 300 per 100,000. The rate of lung cancer diagnosed for those selected populations in recent randomised trials by LDCT are summarised in Table 2.

More data from other cohorts are described in the systematic review published by Bach et al. [10]. The rate of lung cancer diagnosed ranges between 0.8 and 2.2 % initially and between 2.4 % and 4.7 % in 34−78 months of follow-up. Those figures can be taken as the pre-test probability.

Risk models help to increase pre-test probability and reduce overdiagnosis. They improve the patient selection in order to define populations with higher pre-test probabilities: the Liverpool Lung Project (LLP) risk prediction model is used in the UKLS screening trial; the PLCO2012 (Prostate, Lung, Colorectal, and Ovarian) randomised trial and the NLST trial. The former two studies predict lung cancer detection, while the latter predicts death by lung cancer (Table 3).

Recently, de Koning et al. [39] published a study estimating the harms and benefits of lung cancer screening for efficient lung cancer screening policies. They used five separately developed micro-simulation models calibrated to the two largest randomised, controlled trials on lung cancer screening [17, 39]. Those models were independently developed at five institutions: Erasmus Medical Center (Rotterdam), Fred Hutchinson Cancer Research Center (Seattle), Massachusetts General Hospital (Boston), Stanford University (Stanford), and University of Michigan (Ann Arbor). All account for the individual’s age-specific, smoking-related risk for lung cancer, date and stage of lung cancer diagnosis, the corresponding lung cancer mortality and the individual’s life expectancy in the presence and absence of screening. The most advantageous strategy identified is the annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. That approach would lead to 50 % of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14 % reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7 % of all cases of lung cancer).

Thus far, there are no good risk predictors for nonsmokers and no convincing data to recommend screening. Lung cancer in never smokers is the seventh leading cause of cancer mortality, and therefore is a significant cause of death worldwide. The main risk factors include age, environmental tobacco exposure, cooking fumes, inherited genetic susceptibility, occupational and environmental exposure to carcinogens, hormonal factors, pre-existing lung disease and oncogenic viruses [40]. Nonsmall cell lung cancer (NSCLC) in never smokers is clinically characterised by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced stage patients [41]. Even though those factors are known, there is no beneficial screening programme for lung cancer among this population.

With modern multidetector CT, pulmonary nodules are detectable at a size of less than 2 mm. Small nodules are extremely common, but the vast majority of these nodules are benign. Given this fact, the definition of a positive screening result determines the number of false-positive results. On average, about 25 % of the thoracic surgical procedures performed during the various randomised controlled lung cancer screening trials were done for benign nodules [21]. If there are fewer false-positive nodules, there is less need for further workup and lower risk of complications, especially from invasive diagnostic examinations including surgery.

The definition of a positive screening result differed substantially between the NLST and most European trials. The NLST defined any non-calcified nodule with a maximum diameter ≥ 4 mm as a positive screening result [6]. As a consequence, the number of false-positive scans was high: 27 % of scans in the first two screening rounds, of which 96 % were false-positive. According to the NLST nodule management algorithm, these suspicious nodules needed further work-up: either a follow-up LDCT for nodules of 4–10 mm, or a referral to a pulmonologist for nodules > 10 mm in maximum diameter [6].

The NELSON and some other European trials used a threshold of approximately 10 mm diameter (50 mm³ volume) for a positive screening result, but also established an indeterminate group of nodules measuring 5–10 mm in diameter (50–500 mm³ volume) that required earlier follow-up than the yearly screening interval [42]. Only if significant growth (> 25 % volume change) was found, were these nodules considered a positive screening result. By using this approach, the number of scans with positive screening results was reduced from 27 % in the NLST to 2.7 % in the NELSON, and the false-positives could be reduced substantially from > 95 % in the NLST to approximately 50 % in the NELSON [8, 43].

Recently, new criteria for the follow-up of pulmonary nodules, such as LungRADS and LU-RADS, have been presented in order to increase the positive predictive value in CT screening with minimum effect on sensitivity for the detection of malignancy [44, 45].

The size of a nodule was measured in most screening trials, like the NLST, as the largest diameter of a pulmonary nodule [6]. This approach suffers from a substantial inter-reader and intra-reader variability, which can be reduced by applying volumetric techniques, as used in the NELSON and other more recent trials. Non-actionable nodules were defined as those with benign morphology (e.g., calcification), small size (< 50 mm³), and lack of or very slow growth of the solid component of a nodule with a volume doubling time (VDT) > 600 days. Indeterminate nodules were defined as nodules with a volume of the solid component between 50 and 500 mm³, sub-solid nodules with a diameter of the ground glass component > 10 mm, or solid nodules with a VDT between 400 and 600 days. Actionable nodules were defined as solid components > 500 mm³, more than 20 % growth in diameter of a ground glass component, or VDT < 400 days of a solid component [42]. Non-actionable, reportable nodules were kept on regular (yearly) follow-up, indeterminate nodules were put on a more rapid follow-up of 3–6 months, while actionable nodules led to direct medical workup.

Increasing knowledge about the CT phenotypes of screen-detected pulmonary nodules with different biologic behaviours will lead to a better estimation of their probability of malignancy, and help to decrease the amount of additional follow-up scans and workup examinations [46], e.g., perifissural nodules were demonstrated to have a high likelihood of being benign [47, 48].

For the invasive diagnostic work-up of small nodules, the value of white light fibrebronchoscopy is very limited [49], but newer diagnostic endoscopic techniques, such as endobronchial ultrasound-guided biopsy with mini probe or electromagnetic navigation bronchoscopy, might be more promising. For some peripheral nodules (> 1 cm), transthoracic CT-guided biopsy or primary resection by video-assisted thoracoscopic surgery for diagnostic and therapeutic reasons may be recommended [50]. The risk of serious complications (pneumothorax requiring drainage, cardiorespiratory complications during anaesthesia, infection or haemorrhage) not only relates to the invasiveness of the diagnostic procedure itself, but also to the patient’s functional status [51]. Subjects eligible for LDCT screening will present themselves mostly with a high comorbidity risk, due to COPD or chronic cardiovascular disease [46, 52].

Adhering to a certified high quality radiology plan for LDCT screening will minimise radiation exposure for screening participants. Further, the adherence to a pulmonary nodule management plan based on nodule diameter, volume and growth rate will help to increase safety for lung cancer screening participants, mostly by decreasing the total amount of diagnostic investigations they will need to undergo in order to determine the nature of their screen-detected lung nodules. Moreover, a lower amount of false-positive lesions with a decreased number of additional diagnostic investigations may finally help to decrease participant’s anxiety and psychological stress during lung cancer screening [53].

The vast majority of lung cancer screening trials were designed more than a decade ago. The LDCT protocols were simply achieved by reducing the fixed tube load of diagnostic CT from typically 100–300 mAs to 10–40 mAs. A CT dose index (CTDI_vol) of 2–3 mGy was used as a target for NLST [54, 55]. Similar values were used in the NELSON and the various other European trials. The resulting effective dose is roughly 40 % of these values for males and 50 % for females, resulting in 1–1.3 mSv for a CTDI_vol of 2.5 mGy. The organ dose (mSv) to the lung or to the breast can be roughly estimated using 1.5 × CTDI_vol. Precise numbers vary depending on scanner type, and in particular on the pre-filtering of the X-ray spectrum.

With recent improvements in detector technology, automated exposure control techniques and iterative image reconstruction, a further substantial decrease in radiation exposure of 80 % to a level around 0.2 mSv is possible without impairing image quality [56]. However, radiation exposure will always have to be higher in obese individuals than in normal weight individuals because of the difference in X-ray absorption. Excessive reduction of radiation dose will lead to image quality degradation with either high image noise or loss of image details, which will especially affect sub-solid lesions. These are the limiting factors for further dose reduction.

Radiation risk in the age range of 40 to 60 years is mainly determined by the organ dose to the lungs. Apart from the breast in premenopausal women, other organs have a much lower contribution to excess cancer risk [57]. Radiation exposure and smoking appear to have an additive effect on cancer risk [58]. This means that the excess risk for developing radiation-induced lung cancer may be twice as high in smokers as in never-smokers [59].

Given an effective dose of 1.3 mSv for women and 1.0 mSv for men, the excess lifetime cancer risk was estimated to be 0.02 % in male smokers and 0.05 % in female smokers if three yearly screening rounds were performed [60]. Risks did not change whether the starting age for screening was 30, 40 or 50 years. This implies that radiation risk becomes important only if the pre-test risk for lung cancer is small. Given a baseline cancer risk of 0.8–2.2 % in the various screening trials, the risk−benefit ratio is very favourable. Even if the number of screening examinations increases from three to 24, the excess lifetime cancer risk induced by radiation remains below the baseline cancer risk, but it increases with age [38].

Radiation risk grows strongly if follow-up scans are performed using standard clinical protocols (old equipment 4–18 mSv, new equipment 2–4 mSv [61]) instead of screening with LDCT settings (new equipment 0.2 mSv [56]). For this reason, the work-ups of screen-detected nodules should remain within the screening programme as long as possible [62].

The cost-effectiveness of the screening intervention is one of the major considerations for those who are responsible for screening guidelines, practice measures and insurance coverage [63]. Varying results on the cost-effectiveness of lung cancer screening have been reported [64‐67]. In their recent publication, the NLST reports reasonable cost-effectiveness of LDCT screening of lung cancer [68]. LDCT screening as performed in the NLST trial costs $81,000 per quality-adjusted life year (QALY) gained (95 % CI $52,000–186,000). Screening trials that cost less than $100,000 per QALY are considered cost-effective. Incremental cost effectiveness ratio (ICER) is the ratio of the change in costs to incremental benefits of a therapeutic intervention or treatment [69]. The NLST ICER was $52,000 (95 % CI $34,000–106,000). However, the ICER results of the NLST were highly sensitive to base-case assumptions. For example, if the reduction in mortality from causes other than lung cancer was included in the calculation, the QALY fell to $54,000. QALY increased to more than $100,000 when the cost of future care was increased. Moreover, estimated cost-effectiveness varied in the subgroup analysis. Screening with LDCT was much more cost-effective in women than in men and among the groups with a higher risk of lung cancer. Whether screening performed in different countries in Europe will be cost-effective depends on exactly how the screening will become implemented [68], and on which respective cost structures and reimbursement policies will be used.

Expectation management is crucial for a successful CT screening programme. It is important for three main reasons: 1) giving participants the ability to understand the benefits and potential harms, 2) reducing anxiety in case a nodule is found and 3) reducing litigation and its chances for success. Screening is very likely to reduce a participant’s risk of dying from lung cancer. However, a substantial group of participants will still die from lung cancer. Most cancers found will be in a treatable stage (60–80 % stage I) – but not all [8, 70]. Some cancers may grow so slowly that they will not be life-limiting and treating them may be unnecessary (overdiagnosis) [39]. Screening is known to miss nodules present on LDCT [71]. The annual screening programme will pick up nodules missed on earlier scans, which reduces the risk of missed nodules developing into untreatable cancer. As small nodules are extremely common, it is very likely that a nodule will be found. LDCT is not optimally suited for the detection and diagnosis of many other chest diseases. However, incidental findings leading to unnecessary workup, costs and complications may occur.

Information given to participants, clinicians not involved in screening and the public should be clearly understandable. Informed consent is important because of the dangers of undetected cancers, overdiagnosis or complications due to work-up or treatment of screen-detected lesions. The participants should be aware of the incidental finding policy of the screening programme.