1. Enrollment criteria for screening and cost effectiveness

A major conclusion of the two recent studies [3, 4] on lung cancer screening in China was the emphasis on deliberately selecting candidates for screening. According to a study published by Katki et al. [11] in 2016, several screening effectiveness and efficiency metrics (e.g., number needed to screen to prevent one lung cancer death) could be optimized in the US with a “risk-based approach” for selecting the high-risk population. This is especially important for China, where the trade-off between effectiveness and costs should be considered for most resource-limited areas. On the other hand, when we consider feasibility of screening in an extended population living with favorable conditions, there is currently no evidence that younger non-smoking patients with lung cancer could not benefit. For example, long-term screening experience in Hitachi district in Japan showed that prognoses of non/light smokers with lung cancer detected in screening were favorable, which provided the rationale for a trial investigating screening among non/light smokers in Japan [12]. Similarly, the results from the Cancer Hospital Chinese Academy of Medical Sciences also indicated the necessity for screening among women who were passive smokers with a minimum age of 40 years [13]. Therefore, more work, including statistical modeling, needs to be done to refine region-specific screening eligibility criteria and to balance effectiveness and cost.

2. Reducing false-positive findings on LDCT images

According to Wang et al.’s work [4], effectiveness of lung cancer screening should be further improved by solving some bottleneck technical problems with the aim to optimize population outcomes, the difficulty in differentiating early stage cancers from benign nodules being the most influential problem. The high false-positive rate of LDCT images resulted in a considerable percentage (24.2%) of screened participants requiring further examination, 96.4% of whom were not finally diagnosed with lung cancer in the NLST [12]. As revealed in Wang et al.’s study [4], false-positive findings may lead to diminished or negative gains in quality of life due to anxiety experienced before final diagnosis and are also associated with a 3.5-fold risk of death due to unnecessary diagnosis and treatment. Although the volume doubling time showed strong potential for determining malignancy in NELSON [14], volumetric analysis is not applicable to non-solid nodules and is heavily reliant on subsequent screening. Therefore, for a better and timely judgment about benign and malignant nodules, more quantitative analysis approaches and empirical validation studies are needed.

3. Determining screening frequency and optimization of intervals

The NELSON trial used three intervals between screens (1, 2, and 2.5 years) to determine the best screening frequency. A recent report from that study observed a significantly increased rate of “missed” cancers and a decreased proportion of early-stage cancers with the longest screening interval [15], which highlights the debate between annual and biennial screening, as discussed in other studies [16]. Compared with fixed intervals, a better choice may be adjusting screening intervals according to individual risk of lung cancer. However, no evidence is available regarding this option, and a more elaborate protocol for determining and changing individual screening frequencies is needed. In contrast to developing models for the selection of screening candidates, models to calculate individual risk for the purpose of optimizing screening intervals can be based on both patient characteristics and lesion signs detected in previous LDCT images [17]. Such comprehensive modeling with multivariate and heterogeneous data would certainly contribute to this but presents more challenges.

4. Understanding cancer heterogeneity and its impact on screening

The high heterogeneity of cancer is another issue that has important implications for lung cancer screening. According to our recent meta-analysis [18], indolent cancers contributed to over-diagnosis, as they comprised a large proportion of cancers additionally detected with LDCT. In addition, no evidence of superiority with LDCT for the early detection of small cell lung cancers was observed, unlike non-small cell lung cancers. Therefore, more pathologic type-specific analyses with a sufficient number of cases are needed to quantify the degree to which “early detection” translates into real “increased lives.” With the recent surge in precision medicine studies on molecular reconstruction of cancer classification systems [19], bridging such studies with lung cancer screening may present new opportunities and provide more enlightening insights.

5. Combination of LDCT with novel biomarkers

Although evidence from population-level studies is scarce, biomarkers are considered the best way to assist in lung cancer screening [20]. They can be used in various stages of screening, including selecting high risk populations, serial screening tests, and establishing molecular diagnoses for further individualized clinical management. However, challenges remain regarding the discovery, optimal selection and validation of markers. Research frameworks and standards (including statistical requirements) to routinize the whole process are lacking; subject numbers are usually small because of a disconnection between basic research and clinical resources; and failures are common in replicating the claimed diagnostic value when applied to patients in different cancer stages or with greater tumor heterogeneity [21]. As discussed earlier, integrating molecular studies into LDCT screening programs provides a unique opportunity to resolve some of these problems. This modality has already been adopted in some recent large programs [22–24]. For example, a biomarker panel composed of plasma DNA and genomic analyses in the ITALUNG biomarker study was as sensitive as LDCT (90%) and increased screening specificity from 71% (LDCT alone) to 89% via a multimodal approach [22]. Another diagnostic test consisting of seven autoantibodies is currently under a randomized controlled trial among 12,000 Scotsmen, aiming to examine whether pre-screening with this test would be helpful to identify high-risk candidates, thereby increasing the overall effectiveness of LDCT screening [23].

6. Dynamic monitoring of cancer natural history

An inherent but usually neglected advantage of lung cancer screening studies is the ability to gain a better understanding of the natural history of the disease. A recent report from the NELSON trial revealed that the volume growth pattern of screen-detected lung cancers can be fitted to an exponential function [25]. In a prospective cohort study, Jamal-Hanjani et al. [26] tracked the evolution of non-small cell lung cancer and observed detailed data about clonal and sub-clonal events using multiregion whole-exome sequencing. These reports indicated the start of an era of dynamic lung cancer studies from both morphological and molecular perspectives. More refined protocols for lung cancer screening may be obtained when we have a clearer picture of the macroscopic and microscopic evolutional processes.

7. Integration of databases and assurance of accurate cases

As incidences and mortality of cancers are relatively low, a longitudinal cancer study calls for a large number of subjects and is heavily reliant on the accuracy of collecting and confirming incident or mortal cases. This task is challenging for lung cancer screening studies, particularly when participants were not diagnosed at the hospital that conducted the screening. A project was recently initiated in Shandong Province, China, that aimed to create a database linking the cancer registry with health insurance claims [27], which suggests a way to facilitate such large-scale population-based studies. However, as noted by the NELSON study team [28], registry data are not 100% sensitive and accurate. Therefore, more mechanisms need to be developed to guarantee accuracy of these primary outcomes.

8. Influences of tobacco control policy and environment protection

Smoking and other environmental factors are well-known risk factors that are targeted in primordial or primary prevention of lung cancer. As screening is a secondary prevention approach, secular variation in these risk factors may have non-linear effects on lung cancer incidence [29] and, thus, may complicate the predicted effectiveness of screening. In addition, cancer screening motivated smokers to quit, as ex-smokers concerned with their health status were more willing to participate in the United Kingdom Lung Cancer Screening Trial [30]. Therefore, socio-behaviors should be carefully monitored and considered to take advantage of combining programs such as tobacco control and lung cancer screening. A third important factor is that the spectrum of cancer pathological type may change along with changes in environmental risk factors, which further complicates the issue. Therefore, future research should also be placed in a broader context and investigate the impact of policies on tobacco control and environment protection, which are currently undergoing significant changes in China.

In summary, research on lung cancer screening is about to reach a turning point that will shift the focus from evaluating whether the refinement of such screening protocols for increased cost efficiency is effective in reducing deaths. Several challenges and major research opportunities remain to be considered in future studies, especially studies conducted in China where more than 0.5 million people may benefit from such scientific progress.