Lung cancer accounts for 28% of all cancer deaths in Europe. For about 70% of lung cancer patients, diagnosis comes too late: with the disease already at an advanced stage, only 15% of patients diagnosed will survive five years. For both men and women, lung cancer is the leading cause of cancer-related death.

Each year, lung cancer claims more lives than colon, prostate, ovarian, and breast cancer combined. In 2018, there were nearly 1,000 lung cancer deaths each day in the EU, or 338,000 people lost to lung cancer yearly. With numbers this high, it is no surprise that one in three people are affected by lung cancer, whether they themselves or a loved one has the disease. And it isn’t going anywhere — 2018 also saw the diagnosis of a further 470,000 new cases of lung cancer. It is expected that in the period 2015-2040, the incidence of lung cancer will increase by 37% (46% for men and 24% for women).

Screening for lung cancer is performed with low-dose Computed Tomography (CT). CT is a non-invasive imaging technology which can be used to detect possible lung cancer nodules, which are the earliest signs of lung cancer. This technology provides the opportunity for more effective treatments, better disease control, and better care.

The likelihood of lung cancer nodules being malignant is assessed by measuring the time it takes for a nodule to double in volume (volume doubling time) of a nodule between the baseline (or first) scan and follow-up scans.

Lung cancer screening is a preventive method that aims to reduce lung cancer mortality. When lung cancer is caught and diagnosed at earlier stages, treatment options are more effective and survival rates increase. This diagnosis is done through regular computed tomography (CT) scans, which can detect nodules in the lungs that may become cancers and allow them to be monitored. Though 85% of lung cancers can be attributed to smoking, and smoking cessation is considered the most effective preventive method for halting deterioration in current smokers, quitting smoking only decreases the risk of developing lung cancer; half of all lung cancers currently diagnosed are in former smokers, who can be at high risk for decades after they quit [4]. Screening with low-dose CT scans is therefore crucial for former smokers as well.

Even as smoking prevalence declines, US estimates indicate that the rate of smoking-related lung cancer mortality will remain high for decades. Despite tobacco control interventions, there will continue to be current smokers and ex-smokers who meet the eligibility criteria for lung cancer screening in the coming decades [5]. The smoking patterns of men and women in Europe compared with the US suggest that not only will this also happen in Europe, it will last longer. In Europe, lung cancer causes the deaths of more people than breast, colorectal, and cervical cancer combined [1]. While all EU countries have some form of breast cancer and cervical cancer screening, and most have begun implementing colorectal cancer screening, the full potential of lung cancer screening is still yet to be realised. This is in part because the current level of implementation of personalised screening and prevention by healthcare systems is still low, and lung cancer screening programmes will need to be personalised to target high risk populations and discount the never smokers. Through the high-quality implementation of a cost-effective, risk-based CT lung cancer screening programme in Europe, between 60.000 and 80.000 lives could be saved every year — more than any other single cancer screening programme that currently exists.

There have been many studies done on exploring the potential of lung cancer screening, but only two large studies have had enough statistical power to show mortality effects: the NLST [6] and the NELSON study [9]. The US-based NLST study from 2002 showed a lung cancer mortality reduction of 20%, with 23.3% of screenings returning false-positives. The EU-based NELSON study presented its final results in 2020; it showed a mortality reduction of 24% in men, with 1,2% of all screenings returning false positives. With a false positive screening, the participant receives a positive screening result, but further diagnostic procedures ultimately show that there is no cancer. In a screening programme, high false positive rates are undesirable — they cause stress and psychological burden for the participants and unnecessary costs for health care systems.

In 1999, a US study called ELCAP showed that low-dose CT scans greatly improved the detection of lung nodules, the potential earliest stage of lung cancer [7]. Following these results, the National Lung Screening Trial (NLST) was initiated in the US in 2002. The NLST enrolled more than 53,000 participants who were current or former heavy smokers and were aged 55 to 74. The trial randomly assigned people to receive lung screening either by low-dose helical CT scans or chest X-rays. The trial was sponsored by the National Cancer Institute. In 2011, the results showed a lung cancer mortality reduction of 20% for participants assigned to CT scans when compared with participants assigned to chest X-rays, and a 6,7% all-cause mortality reduction. This study provided the first results demonstrating the efficacy of low-dose CT screening for lung cancer [6]. The downside of the NLST was the large number of false positive results. In the NLST, 23.3% of all screenings performed returned false positives.

Unlike the NLST, the NELSON study used a unique method of volumetric measurements of nodules and their growth between the screening intervals, whereas the NLST solely observed the diameter and used this to determine nodule growth across annual screenings. Furthermore, the NELSON study applied screening intervals instead of annual screening; CT screening was performed at increasing intervals of 1, 2, and 2.5 years [8].  The trial was performed in four hospitals in the Netherlands and Belgium, where 7,557 participants underwent screening with a low-dose CT scan in the period of 2003–2008.

The highly anticipated NELSON results on lung cancer related mortality reduction showed a mortality reduction of 39–59% in women and 24% in men and a significant reduction in false positives (only 1,2%).

A variety of cost-effectiveness studies on lung cancer screening have been performed, using several specific clinical studies as inputs and accounting for a range of scenarios. Most publications demonstrate that lung cancer screening can be cost-effective, based on country-specific thresholds for cost-effectiveness. Generally, studies agree that lung cancer screening is costly but worth the cost in terms of health-benefits gained.

Results of cost-effectiveness analyses are expressed as the Incremental Cost-Effectiveness Ratio (ICER), which reflects net costs per Quality-Adjusted Life-Year (QALY) or Life-Year (LY) gained. Most publications demonstrate that lung cancer screening can be cost-effective, with country-specific thresholds for cost-effectiveness (e.g., <$50,000 per QALY, as sometimes used in the USA). The ICERs for lung cancer screening ranged between $15,000 and $100,000 per QALY gained and between $20,000 and $62,000 per LY gained.

Both annual and biennial lung cancer screening programmes were found to be potentially cost-effective. Goffin et al. (10) specifically compared the annual and biennial strategies and concluded biennial screening used fewer resources, gained fewer life-years, but resulted in very similar QALYs gained when estimated over a time horizon of 20 years. They estimated the ICER of annual compared with biennial lung cancer screening was between $54,000–$4,8 million/QALY gained, respectively, making biennial screening more cost-effective. Ten Haaf et al. (11) concluded that annual lung cancer screening was more cost-effective but that less intensive screening with longer intervals could also be cost-effective.

The final publication of the NELSON trial warrants new cost-effectiveness analyses to assess the implications of volumetric screening (12), particularly given that the presentation at WCLC 2018 demonstrated an increased mortality reduction with a low false positive rate (13). The increased availability of both lung cancer-related and lung cancer screening-related data will make future cost-effectiveness analyses more robust, and therefore better suited to assist decision makers in designing and introducing lung cancer screening in national programmes.

There are several related topics in addition to the primary outcomes of lung cancer screening which are of interest: the ‘Big 3’ smoking-induced diseases (lung cancer, COPD, coronary heart disease), smoking cessation, and gender differences.

The Big 3 smoking-induced diseases measured in a single CT imaging examination: lung cancer, coronary heart disease, and COPD.
Like lung cancer, coronary heart disease (CHD), and chronic obstructive pulmonary disease (COPD) also have high 1) incidence and mortality rates, 2) are related to smoking, and 3) are measurable through imaging biomarkers. These biomarkers are 1) the volume doubling time (VDT) of lung nodules for lung cancer, 2) coronary artery calcium for CHD, and 3) emphysema for COPD, as measured by chest Computed Tomography (CT) imaging.

For these Big 3 diseases, early treatment has been shown to delay or stop progression and allow therapy at a treatable stage in a large number of patients. Currently, treatment for these diseases is mostly initiated at a relatively late stage, often after the first clinical symptoms have been observed. The impact on disease burden can be significantly less if the diseases are caught at a subclinical stage. Therefore, the prevention and/or early treatment of all these diseases is of growing importance.

Smoking cessation
Participants in lung cancer screening programmes have higher smoking cessation rates than the non-screened smoking population. For smoking cessation services, this could be used as an additional tool to motivate individuals to quit [14]. Smoking cessation has an impact on more than just lung cancer; it also affects a wide spectrum of smoking-related health problems, including CHD and COPD [15]. The combination of lung cancer screening and a smoking cessation programme could substantially reduce lung cancer mortality [16], as well as impacting these other comorbidities. Similar results were found in a modelling study [17].

Gender differences
The biological sex of lung cancer screening participants has a large differential effect on the results; both the NLST and NELSON studies showed that screening is more effective for women than it is for men [18, 19]. There are also sex-based differences in the biological characteristics of lung cancer, including histology and aggressiveness. These differences provide further opportunities to improve lung cancer screening by taking biological sex into account.

Gender differences can be expected to influence the recruitment process, the CT screening and the screening test result, the health seeking behaviour of the participants, and whether participants commit to health behavioural changes (smoking cessation). However, there is at present a lack of evidence about gender differences in lung cancer screening. To optimise future lung cancer screening, the full effect of gender needs to be understood in order to enhance autonomous informed decisions about screening uptake, healthcare seeking behaviour, and treatment.

Though many questions regarding lung cancer screening have been answered, there is still plenty of room for optimisation. We at iDNA have made it our mission to ensure the best practices are available for implementation, while endeavouring to contribute further innovations to lung cancer screening:

Selecting the optimal target group for screening remains a highly debated subject. Defining the eligibility criteria of a screening programme greatly influences the selectivity, specificity, and cost-effectiveness of a screening programme. iDNA has experts in every area related to lung cancer screening and can provide assistance and guidance with any questions regarding these matters.

The same goes for selecting an optimal screening interval. Currently, guidelines agree on annual screening as the standard, but recent evidence suggests biennial screening has the potential to be just as effective in certain risk groups, while also greatly reducing implementation costs.

Without effective and timely treatment following the early detection of cancer, the effects on mortality reduction and quality of life will be limited. Many universities and companies are investing heavily in improving surgical intervention technologies, radiotherapy applications, and pharmaceuticals that localize and target cancerous lung nodules. One of our goals at iDNA is to help set up (clinical) research to further innovate and improve treatment opportunities for early stage lung cancer.

The NELSON study proved that lung cancer screening is effective, which is why iDNA, together with our consortium of scientific partners, are funded by the EU to run lung cancer screening pilot programmes in five European countries. This new trial is branded the ‘4-IN-THE-LUNG-RUN’, and started January 1st, 2020. Please see here for more information.

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