Lung cancer screening in 2022: a narrative review

Introduction

Lung cancer is the most common cause of cancer death globally, estimated to have caused 18% (9.9 million) of cancer deaths in 2020 (1). It is also the most common cause of cancer death in the United Kingdom (UK), representing more than one-fifth (n=35,100) of all patients dying from cancer in 2018 (2). Half of these deaths occur under 75 years of age. The 5-year survival rate is 15%, putting it among the five cancer types with the poorest outcomes (3). A major reason for this is its insidious onset, leading to delayed symptoms and clinical presentation once disease has advanced. Indeed, 71% of lung cancers are diagnosed at stages III–IV. One-year survival with stage IV (metastatic) disease is 17%, compared to 83% with stage I (4). A key determinant of survival is stage at diagnosis, as resection of early-stage disease conveys the greatest survival advantage (5).

Encouragingly, the proportion of patients with lung cancer undergoing surgery in the UK, although low, is increasing. This correlates with the data reported by the Society for Cardiothoracic Surgery in Great Britain and Ireland who have tracked lung cancer surgery since the 1980s (6). The third national thoracic surgery activity and outcomes report from 2018 contains data on patients undergoing lung cancer surgery from 1980 to 2015 and highlights that prior to 2006, overall lung cancer surgery activity in the UK remained relatively static at approximately 4,000 cases per year. However, numbers have risen steadily over the last decade, with over 7,000 procedures performed across the UK in 2015 (6). Despite this increase in the number of resections for lung cancer, the UK was recently ranked 21^st out of 27 European countries based on lung cancer five-year survival rates (6).

Resection rates

The UK has historically had a particularly low resection rate for non-small cell lung cancer (NSCLC), with fewer than 20% of patients undergoing surgery with curative intent. The National Cancer Registration and Analysis Service reported that the approximate proportion of patients with NSCLC undergoing surgery was only 16% between 2013 and 2015. Nevertheless, this represents a marked increase from the 8.8% and 11% quoted for 1998 and 2008 respectively (7). However, contemporaneous studies from European countries such as Finland and Iceland report resection rates in excess of 25% (8,9).

Whilst this overall increase in the number of lung resections being performed is encouraging, the degree of variability between different regions of the country remains a concern and highlights the important role played by the infrastructure of regional cancer networks in facilitating radical treatment for patients with lung cancer. The resection rate is calculated by considering the number of people who underwent surgical resection for lung cancer against the number of people diagnosed with lung cancer in a given time period. Nationally collected data from 2017 reported regional resection rates ranging from 13–30% (10). Perhaps more salient is a further analysis of resection rates, undertaken as part of the same body of work and focussing solely on those patients most likely to be suitable to undergo radical surgical resection. Limited to patients with a performance status score of 0–2 and early stage (stage I/II) lung cancer, regional resection rates again varied from 51–93%. It has been calculated that if all thoracic surgical centres were able to increase their resection rates for these early-stage patients to 78% and over (as currently seen in the six centres in the country with the highest resection rates), more than 1,000 additional lung resections would be performed every year, which itself could further improve overall survival for patients with lung cancer throughout the whole of the UK (10).

Broadly, the two factors underpinning the selection process for lung resection are operability, where patients must be fit enough to undergo surgery, and resectability, where patients must have a pattern of disease for which the operating surgeon is confident of achieving a complete resection. Unfortunately, only a minority of patients have resectable disease. Moreover, an important proportion of patients with lung cancer are frail and comorbid, rendering them prohibitively high risk to undergo the rigours associated with major thoracic surgery. Whilst the high incidence of lung cancer in comparison to other malignancies undoubtedly plays a key role in making lung cancer the leading cause of death worldwide (11), the combination of a high incidence of metastatic disease and a low rate of radical treatment also accounts for its poor prognosis. Furthermore, lung cancer surgery has historically been performed by surgeons engaging in a mixed cardiothoracic practice. The role of the dedicated thoracic-only cardiothoracic surgeon is a relatively novel concept.

It is well recognised that the two of the most important approaches to improving overall lung cancer survival are increasing the proportion of patients undergoing surgery and reducing the rate of post-operative morbidity and mortality in this same patient cohort. In stark contrast to 1-year survival figures for lung cancer patients as a whole (which are around 40%) (7). One-year survival for lung cancer patients who have undergone surgery with curative intent is approximately 88% (10). This is because most patients undergoing surgery have early-stage disease. Hence, if more patients with early-stage lung cancer can be identified, offered and successfully treated with radical surgical resection without complications, it is likely to have a significant impact on overall lung cancer survival rates; if these patients survive the peri-operative period they are much more likely to survive to 5 years and beyond in comparison to patients with lung cancer who do not undergo surgery (12).

Objectives

Increasing availability of lung cancer screening is likely to have major impacts in thoracic oncology and allied disciplines. A wealth of evidence has accumulated in the past decade, with marked advancement in our understanding of lung cancer risk, diagnosis, and management. This review aims to outline the strengths and weaknesses of lung cancer screening as it relates to the thoracic surgical community, which is intrinsic to translating the diagnostic advances brought by screening into improved patient outcomes. We present the following article in accordance with the Narrative Review reporting checklist (available at https://vats.amegroups.com/article/view/10.21037/vats-22-10/rc).

Methods

Literature relating to lung cancer screening and the surgical management of early stage lung cancer was searched by the authors via PubMed up to May 2022. Reference lists were reviewed to identify further relevant sources. Topics included low dose CT lung cancer screening, harms of screening, targeted screening methods, service delivery, and surgical management of early stage lung cancer. Emphasis was placed on randomised controlled trials (RCTs) and clinical guidelines, particularly those relating to UK practice.

Lung cancer screening

Through the 1990s, low dose computed tomography (LDCT) emerged as an effective test for lung cancer (13-15). The first large-scale RCT performed to investigate the effect of LDCT as part of lung cancer screening was the National Lung Screening Trial (NLST) (16). This US-based study enrolled 53,454 individuals at elevated risk of lung cancer between 2002 and 2004, assigning half to the intervention arm for three annual LDCT scans and half to annual chest radiography. Lung cancer was detected through screening in 2.4% of the LDCT arm and in 1.0% of the chest X-ray (CXR) arm. Overall, 70% of LDCT-detected cancers were stage I–II, compared to 57% in the CXR arm. A total of 61% (n=642/1,060) of lung cancer cases in the LDCT group received surgical treatment. For the primary outcome of lung cancer-specific mortality, the LDCT arm had a 20% relative risk (RR) reduction (95% CI: 6.8–28%, P=0.004). For every 320 participants screened using LDCT, one lung cancer death was averted. There was also a 6.7% relative reduction of overall mortality (95% CI: 1.2–14%, P=0.02).

The other, more recent, large RCT was the Dutch-Belgian NEderlands-Leuvens Longkanker Screenings ONderzoek (NELSON) trial, which compared LDCT to usual care in a European setting (17). Here, 15,789 participants were allocated to either four rounds of LDCT screening over 5.5 years or no screening. Outcomes were monitored over a minimum of 10 years, up to the end of 2015. The primary outcome of lung cancer-specific mortality in men (who represented more than 85% of total study participants) found an RR reduction of 24% (RR 0.76, 95% CI: 0.61–0.94, P=0.01) in favour of screening.

In total, nine RCTs have investigated LDCT screening, as summarised in Table 1 (16-24). Smaller trials have provided mixed results. A meta-analysis was recently performed to examine the pooled effects of screening from all published RCTs, which together randomised 94,921 participants (24). This found LDCT screening to be associated with a 16% relative reduction in lung cancer mortality (RR 0.84, 0.76–0.92) and a 3% reduction in all-cause mortality (RR 0.97, 0.94–1.00). When compared to existing forms of mass screening, lung cancer screening is estimated to bring a maximum difference in all-cause mortality of 10 deaths per 1,000 participants at 15 years, compared to four deaths prevented by breast cancer screening by 25 years, and two deaths due to colorectal cancer screening after 10–20 years (25). The substantial improvement in lung cancer mortality demonstrated in randomised trials provides compelling evidence of the benefit of lung cancer screening.

Lung cancer screening has been widely offered in the USA since 2013, when the US Preventive Services Task Force (USPSTF) published its recommendation following the publication of the NLST, with the Canadian Task Force on Preventive Health Care following suit in 2016 (26,27). Many other countries are considering the feasibility of implementation in the context of their health services and populations (28-31). In the UK, NHS England has undertaken a pilot Targeted Lung Health Check (TLHC) programme in more than 20 areas with high lung cancer incidence, with the anticipation of reaching 600,000 eligible participants (32,33). This is built on a number of smaller locally arranged pilot programmes, including Manchester and Liverpool, as their promising results aligned well with the NHS Long Term Plan’s ambitious goal of increasing detection of all cancers at early stage from half to three quarters by 2028 (34-37). At the time of writing, the UK National Screening Committee has made a provisional recommendation for targeted lung cancer screening in the UK. Subject to public consultation, this will likely lead to a national screening programme (38).

It was demonstrated that lung cancer screening programmes would yield a significantly higher proportion of early-stage lung cancers suitable for treatment with radical surgery. Indeed, several UK trials, including the UK Lung Cancer Screening (UKLS) trial and a further pilot study in Greater Manchester found that lung cancer was detected in 2–3% of patients, of which, importantly, more than 80% were early stage (stage I/II) lung cancers (35,39). Whilst patients must still be physiologically suitable to undergo surgery, these findings suggest that a much greater proportion of patients with screen-detected lung cancer are likely to undergo surgery, in comparison to the overall population of patients with newly diagnosed lung cancer. This conclusion is supported by the results of the clinical trials, where 61–84% of patients with screen-detected lung cancer underwent surgical resection with curative intent (Table 1). Real-world implementation may bring different resection rates to those of formal trials, but so far appear to be comparable. Following a baseline screening round in five UK pilot programmes (n=11,148 screened), the surgical resection rate was 66% (n=165/250 lung cancers) (40). Outcome rates can also change over time. In a 5-year Canadian cohort study, 80% (n=137/175) of cancers were detected at the baseline screening round, with 5–10% of the cancers diagnosed in subsequent rounds (41). The resection rate in NLST at baseline ‘prevalence’ round was 69% (n=202/292), but this dropped to 42% (n=440/1,059) across the subsequent two annual ‘incident’ rounds (16,42). In the implementation pilot in Manchester, resection rate changed from 65% (n=30/46 lung cancers) at baseline to 42% (n=9/19) after a 1-year interval (35,36). Widespread adoption of screening is therefore highly likely to lead to further increases in surgical activity, particularly around the time of an initial screening round. Although an exciting prospect, such numbers also represent a challenge in ensuring that existing services are reconfigured in order to cope with such a significant increase in numbers over a relatively short space of time.

Balancing the benefits and harms of screening

As with any medical intervention, screening may cause harm to a proportion of those taking part. Screening harms take a number of forms, not least the direct complications arising from procedures performed to investigate and treat abnormalities identified through imaging. Screening also requires significant healthcare resource utilisation, which needs to deliver value to the population it serves.

False positives and nodule management protocols

As for all clinical tests, the diagnostic performance of LDCT scanning is imperfect. All positive results are relayed to participants, and a proportion of these are anticipated to not represent malignancy, i.e., false positives. There is also significant distress, medicolegal implications, and loss of public trust in screening if cancers are missed (false negatives), resulting in delayed diagnosis with more advanced lung cancer (43).

The NLST considered any non-calcified pulmonary nodule to be a positive result, leading to further investigation at the discretion of treating clinicians. This led to 23% of all scans (n=17,479/75,126) being falsely positive (16). Since then, nodule management protocols have evolved such that most nodules that NLST considered positive would now be considered ‘indeterminate’, able to be handled with surveillance imaging alone. The American College of Radiologists has developed the Lung Imaging Reporting and Data System (Lung-RADS) protocol, which stratifies the risk of malignancy associated with a nodule and recommends either a screening interval or further investigation accordingly (44). Had the Lung-RADS nodule management protocol been applied in NLST, only 1.8% of individuals would have had a false positive scan (45). Notably, most screen-detected nodules are not malignant. NELSON data showed that nodules ≥10 mm diameter have a lung cancer probability of 15% (46). Further evaluation of suspicious nodules is undertaken prior to committing to surgery. This can include interval imaging for indeterminate lesions to determine volume doubling time (VDT), and/or positron emission tomography (PET) to identify aggressive lesions.

The merits of nodule management protocols in practice are continually being evaluated, particularly as guidelines are updated in light of evolving evidence. The Lung-RADS and PanCan protocols are currently being directly compared in the International Lung Screening Trial (ILST), which will provide insights into their comparative clinical impact (47,48). A summary of findings from the baseline screening rounds of trial and pilot screening programmes in the UK [all but one of which used the British Thoracic Society (BTS) guideline (49)] reported 4.2% (n=469/11,148) positives and 2.0% (n=219/11,148) false positives, giving a positive predictive value of 47%. Of those without lung cancer, 0.6% (n=61/10,898) had invasive investigations and benign resections were performed in less than 0.1% (n=8/10,898) (40).

Overdiagnosis

Screen-detected lung nodules, by definition, have not caused symptomatic disease at the time of LDCT. In the absence of screening, some would develop into fatal malignancies, but a proportion would remain indolent for the individual’s lifetime. By drawing indolent disease into the screen-detected cancer group, a screening programme can look more effective when these individuals go on to survive the follow-up period, a bias known as the ‘length time effect’. Conversely, more aggressive cancers are less likely to be detected by screening as they have a shorter preclinical phase. Identifying clinically insignificant lesions through screening, and subjecting participants to invasive tests and treatment, leads to a degree of harm with no benefit. This is referred to as ‘overdiagnosis’ which may be followed by ‘overtreatment’. Overdiagnosis is a notable issue in breast cancer screening, where it is estimated to account for 19% of breast cancers diagnosed, or three overdiagnoses per breast cancer death prevented, and it is why prostate specific antigen screening is not recommended (50-52).

Overdiagnosis is a typical feature of screening, as the aim is to diagnose asymptomatic disease in order to consider intervention. While radiological features (ground glass, spiculation, VDT) and risk prediction tools (e.g. Brock, Herder, PanCan) to predict malignancy risk are helpful, the true pathological potential of a given nodule is often unclear (47,49,53,54). Consequently, long-term data from patients included in lung cancer screening trials are awaited by surgeons with great interest, as such outcomes will undoubtedly shape future surgical practice.

Estimating the degree of overdiagnosis in a trial requires a substantial follow-up period. More cases of lung cancer are detected during initial rounds of screening, but screening does not prevent lung cancer—the same number of cases should be detected eventually in both arms of a large trial. The elevated lung cancer detection in the initial years of a trial reflects the ‘lead time effect’, whereby disease is detected earlier than it would have been if detected following symptomatic presentation. Of note, introducing a lead time effect is an explicit goal of early diagnosis, not an undesirable systematic error, although it should be taken into consideration when comparing screened groups to control groups.

In order to see beyond lead time and length time effects, enough time must elapse after a screening programme commences to detect a difference in outcomes between the groups. Survival time refers to the interval between diagnosis and death, which is susceptible to the lead time effect, so the preferred outcome in trials is mortality rate from the time of randomisation. In NLST, the initial reported lung cancer incidence was higher in the LDCT group after median 6.5 years since randomisation (RR 1.13, 95% CI: 1.03–1.23) and indeed this gap closed after extended follow-up (after median 11.3 years, RR 1.01, 95% CI: 0.95–1.09) (55). This change corresponded to an estimated overdiagnosis rate of 18.5% decreasing to 3% after longer observation. Similarly, NELSON’s epidemiological overdiagnosis rate dropped from 20% at 10 years after randomisation to 8.9% at 11 years (17). There is ongoing uncertainty about the extent of overdiagnosis in lung cancer screening, and its impact on cost-effectiveness, although now that longer follow-up data are available it appears to be less pronounced than initially feared. When reliable nodule risk stratification tools are used, lower false positive rates bring less overdiagnosis and less overtreatment.

Targeted screening

In order to focus screening efforts on individuals at highest risk, eligibility criteria for screening must be applied. There is currently no evidence to support screening in never smokers (56). In the US, eligibility is determined through categorical criteria (USPSTF 2021 criteria: age 50–80 years, smoking history of 20 pack-years or more, and are either a current smoker or have quit within the last 15 years; the previous USPSTF 2013 criteria more closely matched NLST: age 55–74 years, smoking history of 20 pack-years within the past 20 years) (26,57,58). Alternatively, risk prediction models can be used to estimate the risk of lung cancer for an individual within a given time period, and screening eligibility can be based on a threshold percentage risk. In the UK, the TLHC programme uses the Prostate, Lung, Colorectal and Ovarian model 2012 (PLCO_m2012) and Liverpool Lung Project (LLP) model (59,60). Others with promising validity include the Lung Cancer Risk Assessment Tool (LCRAT), Lung Cancer Death Risk Assessment Tool (LCDRAT), and Bach models, which were shown to have good discrimination [area under the curve (AUC) range, 0.75 to 0.79] and calibration (observed to expected ratio range, 0.92 to 1.12) through retrospective external validation in large US cohorts (61). An alternative approach to determining eligibility incorporates the risk of cancer against the risks of competing causes of death, in order to select those who have most life-years to gain from screening [Life-Years gained From Screening-CT (LYFS-CT) model] (62). Whilst their relative complexity of risk prediction models has precluded their recommendation by the USPSTF, analyses of large trial and national registry datasets have found them to have the potential to avert more lung cancer deaths, gain life-years, and be more cost-effective, than categorical approaches (63-67). Clinical trials are underway to prospectively test the performance of risk models in UK (Yorkshire Lung Screening Trial) and other European populations (4-In-The-Lung-Run) (29,68).

Radiation

The application of ionizing radiation to large populations for screening purposes warrants consideration as a potential harm, particularly as the target population has already received a prolonged carcinogenic insult from smoking. Radiation doses in screening LDCTs are lower than ‘standard’ dose diagnostic CTs of the chest (<2 vs. ~8 mSv), and, as technology advances, doses have reduced further (‘ultra-low dose’ <1 mSv). The exact risks of radiation exposures <50 mSv, if any, are a matter of ongoing debate, as estimates are extrapolated from Japanese nuclear bomb survivors and paediatric populations (69-73). It has been estimated that over 10 years of annual screening with 1 mSv LDCTs, the risk of developing cancer is 0.05% (74). This equates to 1 radiation-induced cancer for every 108 screen-detected lung cancers. The low theoretical risk is therefore vastly outweighed by the benefit of screening.

Psychological impact

Participation in screening has a range of psychological impacts, both positive and negative (75). Inducing distress amongst an asymptomatic population is a screening harm, especially when it results from inconsequential findings such as false positives and overdiagnosis. Longitudinal study of trial participants found transient adverse responses among those with concerning LDCT findings, but these did not reach clinical significance or persist long-term (76-80). Whilst the magnitude of this harm appears limited, it is important to minimise any anxiety that may deter high-risk, often socioeconomically disadvantaged and hard-to-reach, individuals from engaging (81). Positive responses to screening have been identified, including empowering otherwise fatalistic smokers to exert control over their health, which could be leveraged to augment the benefit of screening (82).

Incidental findings

The identification of incidental findings on LDCTs presents both challenges and opportunities. Extrapulmonary abnormalities can represent significant disease that would benefit from treatment, such as other malignancies. However, many incidental findings do not represent clinically significant disease, and further investigation of these leads to unnecessary cost and patient harm. Reported rates of incidental findings range from 7% to 46%, partly depending on definitions used (16,83-89). While the optimal strategy for handling incidental findings has been debated (85,90). Pragmatic protocols have been produced to streamline management (91-93). The net impacts of incidental findings on screened populations’ health and on the cost-effectiveness of screening programmes are beginning to be evaluated and may be modest (87,89), but these impacts will vary according to scan reporting practices and thresholds for further investigation, so further study is required.

Healthcare resource utilisation

With so many moving parts at all stages of the lung cancer screening pathway, including cancer risk prediction, variation between screening protocols, advancing treatments, and changing costs over time, estimating cost-effectiveness based on available (and ever-ageing) evidence is highly complex and imprecise. Existing estimates of certain protocols show that lung cancer screening is likely to meet cost-effectiveness thresholds in affluent healthcare systems. While the NLST had an incremental cost-effectiveness ratio (ICER) of $81,000 per quality adjusted life year (QALY) gained (94) and the USPSTF 2021 programme estimates $72,564/QALY (95). UK initiatives appear to have more controlled costs, at £8,466/QALY in the UKLS trial and £10,069/QALY in the Manchester pilot (96-98). These estimates are well below the US cost-effectiveness threshold of $100,000/QALY (95) and the UK willingness-to-pay threshold of £20,000–30,000/QALY (99). Furthermore, a preliminary cost-effectiveness evaluation commissioned by the UK National Screening Committee estimates an ICER as low as £1,529 (38).

Additionally, the healthcare infrastructure required for lung cancer screening brings a number of indirect benefits to the system. Investment in scanning capacity, thoracic radiology expertise, and lung cancer care pathways may benefit many patients who do not participate in screening. Longitudinal imaging over time in a large number of individuals presents an opportunity for research to better understand the natural history of pulmonary nodules, as well as data on which to train machine learning technologies as the field of radiomics and computer-aided reporting develops at pace (100).

Screening programmes can be organised in a variety of ways. Decentralised approaches are based on referral to screening from primary care to diagnostic providers. While this can promote local engagement, standardisation of practice is challenging. Centralised models are led by diagnostic services, encouraging referrals from primary care. Referral rates can be lower, but specialist expertise and quality assurance can be more easily maintained. Hybrid models integrate community services and screening providers, being overseen by a multidisciplinary stakeholder committee. Centralised and hybrid models have been most common in clinical trials and are likely to be favoured for large-scale implementation (101,102).

Surgical considerations

Benign resection

Screen-detected suspected lung cancer brings a multitude of challenges in terms of diagnosis and management. The bête noire of screening programmes is the patient who undergoes unnecessary resection for subsequently proven benign disease. All management principles should be underpinned by the need to avoid such a scenario. Although CT-guided biopsy is now routinely performed, such a procedure can be precluded by size and location of the suspected pathology. Emerging options such as navigation bronchoscopy and robotic bronchoscopy seek to further improve rates of tissue diagnosis (103). Nonetheless, it is foreseeable that screening programmes will lead to an increase in the number of patients referred for resection of lung nodules and lesions without pre-operative histological confirmation of malignancy. Thorough discussion at multidisciplinary team meetings is essential, as is robust discussion with patients where the risk of resecting healthy parenchyma without evidence of cancer is emphasised. Emerging bronchoscopic interventions such as radiofrequency and microwave ablation to treat peripheral lung lesions, or brachytherapy or photodynamic therapy for endobronchial lesions, may eventually obviate the need for surgery in a proportion of cases (103).

Considering surgical options, one approach is to undertake a greater number of intra-operative frozen sections. However, this brings with it longer operative times, reduced operating list capacity and greater pressures on histopathology services. Furthermore, particularly for very small lesions and those in difficult to reach areas of the chest, identification of the pathology can be challenging. This is especially true when surgery is undertaken via a minimally invasive approach, and the surgeon relies on either visualising the lesion on the screen or palpating it with a finger through one of the small surgical incisions. Alternative technical solutions to this issue include the use of indocyanine green (ICG). ICG is a dye which emits light when exposed to near-infrared light and has been used in medicine for many years. Within thoracic surgery, its uses include identification of chyle leaks, identification of bullous lesions, delineation of anatomical intersegmental planes and identification of pulmonary nodules (104). Again, whilst it has been proven to be beneficial in terms of aiding identification of small lung nodules, there are cost, technology and training implications which must be addressed if centres intend to adopt its use as part of their routine practice.

Minimally invasive surgery

The proportion of patients undergoing minimally invasive surgery [both video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS)] has increased exponentially in recent years (10). Indeed, UK guidelines now advocate that all patients with early-stage lung cancer should undergo minimally invasive resection as the gold standard of care, where anatomically possible (105). Consequently, additional financial investment to augment the capacity of operating centres to support increased numbers of minimally invasive resections will be required. Specialised instruments, cameras and video systems are all essential prerequisites for thoracoscopic surgery in current practice. Taken together with the needs of the broader lung cancer team, new hybrid theatre environments are likely required to support the diagnostic and treatment impact of lung cancer screening.

Parenchymal sparing resections

In recent years, surgeons have started to consider whether sublobar resection, with its associated parenchymal-sparing benefits, can provide similar oncological outcomes when compared to anatomical lobectomy, traditionally recognised as the gold standard operation for primary lung cancer and supported both by NICE and BTS guidelines as the first line for all suitable patients (49,106,107). The underlying evidence base is mainly derived from the Lung Cancer Surgery Group (LCSG) randomised trial from Ginsberg et al. published in 1995. This study demonstrated a superiority for lobectomy over sublobar resections (a subgroup which included both anatomical segmentectomy and non-anatomical wedge resection), for NSCLC ≤3 cm in terms of recurrence rate, with no significant difference in 5-year overall survival (P=0.088) (108). It has been postulated that the lower recurrence rate associated with lobectomy may be attributed to the higher number of intrapulmonary lymph nodes intrinsically provided in the specimen (whilst sublobar resections may simultaneously lead to under-staging of patients with occult nodal disease) and to the more extensive mediastinal lymph node dissection reported with lobectomy in comparison to the sublobar approach (109). Conversely, greater peri-operative morbidity and mortality, in addition to a potentially heavier impact on cardiopulmonary function may be expected with lobectomy, given the more extensive parenchymal resection performed.

Following the LCSG trial, multiple other non-randomised studies have been undertaken, which have, overall, demonstrated a trend towards oncological superiority for segmentectomy over wedge resection (49,110,111) and non-inferiority for segmentectomy compared to lobectomy (111-120). A welcome recent addition to the literature is a study outlining the preliminary results of the JCOG 0802 trial (121). This study randomised 1,106 patients with NSCLC <2 cm to either lobectomy or segmentectomy. Although segmentectomy was associated with a significantly greater proportion of locoregional recurrence, there was no significant difference in overall survival and relapse-free survival between the two groups. There was also a significantly lower reduction in post-operative respiratory function in the segmentectomy group, leading to the study authors suggesting that anatomical segmentectomy should become the standard operation for very small early-stage lung cancers. Of note, more than 90% of tumours included in this study were adenocarcinomas, meaning that application of these findings to other histological subtypes, such as squamous cell carcinoma, should be undertaken with caution. The study is of particular relevance in the context of lung cancer screening where small tumours represent a much greater proportion of the overall caseload. Although not yet formally supported by international guidelines, there is increasingly compelling evidence emerging to support the introduction of anatomical sublobar resections for small tumours to preserve pulmonary function without sacrificing long-term oncological outcomes (122-124).

Lung Health Check (LHC) model

Smokers carry a high burden of comorbidity and early mortality in addition to their cancer risk. Overlapping risk factors such as socioeconomic deprivation mean that they are less likely to access preventive care, further compounding the harms of smoking. As lung cancer screening seeks to engage such a population, it presents an opportunity to offer targeted assessment during an initial ‘LHC’ consultation and provide high-value interventions to wed prevention to early detection, a model that has been developed and adopted in the UK.

Tobacco dependency

Smoking cessation reduces the risk of developing lung cancer (125). For those who are diagnosed with lung cancer, it is associated with substantially improved overall survival (summary RR 0.71, 95% CI: 0.64–0.80) (126). Interventions to aid cessation are highly cost-effective, particularly varenicline and nicotine replacement therapy, which cost approximately £700 per QALY gained (127-130).

Airways disease

The global prevalence of COPD is estimated to be 11.7% and it is the third biggest cause of death, yet it is grossly underdiagnosed even in affluent countries: a French cohort found an underdiagnosis rate of 70% (131-134). Whilst screening for asymptomatic COPD is not recommended generally, it is an independent predictor of lung cancer risk (OR 2.5) (135,136). Spirometry can be performed alongside lung cancer screening and may help, ultimately, to refine the current risk algorithms. Lung cancer screening studies have identified airways obstruction in 37–45% of participants, 42–50% of whom had no previous diagnosis of COPD (137,138). In the Manchester LHC pilot, 9.9% of the screened cohort had undiagnosed symptomatic airways obstruction (138), a cohort at-risk of exacerbation, hospitalisation and death (139). Identifying symptomatic cases is important to enable sufferers to access the pharmacological and non-pharmacological interventions available to them.

Cardiovascular disease

Many of those at high risk of lung cancer are also at high risk of cardiovascular disease, given their overlapping risk factors. Indeed, more NLST participants died from cardiovascular disease than from lung cancer (25% vs. 24%) (140). Cardiovascular risk profiling can be performed using prediction scores (e.g., QRISK2) and coronary artery calcification seen on LDCT. Therefore, it has been proposed that this be assessed on LDCTs performed in lung cancer screening (141). In two UK programmes, approximately half (47–57%) of those with QRISK2 scores ≥10% had not been on statin therapy, despite this being recommended in clinical guidelines (142-144).

Opportunistic assessment for high-prevalence comorbidity during an LHC is an appealing approach which can add to the cost-effectiveness of lung cancer screening programmes (98) and make a substantial contribution to tackling the leading causes of health inequality and the mortality gap between the most and least deprived in society (145).

Conclusions

Lung cancer screening has the potential to greatly increase the number of early-stage lung cancers identified in the UK, which is likely to lead to a significant increase in both the number and proportion of patients with lung cancer undergoing radical surgery with curative intent. Further trials are underway to evaluate and refine screening methods (48,68,92,146), Novel approaches to improve risk prediction are being explored, including blood-borne markers (147-149) and machine learning-assisted image analysis (100). Emerging national projects will provide lessons in service provision in diverse settings. Lung cancer screening prevents deaths, and a major current priority is to improve the identification of those who will benefit the most so that healthcare resources can be focused on them. In parallel with ongoing improvements in prevention (150-153), diagnostics, and treatment, there is cause for optimism that real progress to reduce the burden of lung cancer is feasible. However, the management of screen-detected lung pathology brings additional challenges in terms of diagnosis and management, particularly for small lesions with no pre-operative histological diagnosis of cancer. Contemporary technology, effective patient prehabilitation, a minimally invasive surgical approach, and minimising the amount of lung parenchyma resected are emerging as key concepts in this area of lung cancer surgery. Long-term follow-up of patients already participating in screening trials is expected to inform robust guidelines to support the management of these patients.

Acknowledgments

Funding: PB receives a PhD studentship from the North West Lung Centre Charity.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Michael Shackcloth and Amer Harky) for the series “Lung Cancer Surgery” published in Video-Assisted Thoracic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://vats.amegroups.com/article/view/10.21037/vats-22-10/rc

Peer Review File: Available at https://vats.amegroups.com/article/view/10.21037/vats-22-10/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://vats.amegroups.com/article/view/10.21037/vats-22-10/coif). The series “Lung Cancer Surgery” was commissioned by the editorial office without any funding or sponsorship. RB reports that he received Honoraria for educational symposia by Siemens, Medtronic and Olympus. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Cancer Research UK. Lung cancer statistics. In: CRUK. Available online: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer
3. Office for National Statistics. Cancer survival in England: adult, stage at diagnosis and childhood - patients followed up to 2018. Dandy Booksellers Limited, 2019.
4. Royal College of Physicians - Care Quality Improvement Department. National Lung Cancer Audit annual report (for the audit period 2018): Royal College of Physicians; 2021. Report No.: 9781860167997.
5. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016;11:39-51. [Crossref] [PubMed]
6. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018;391:1023-75. [Crossref] [PubMed]
7. NCRAS. National Cancer Registration & Analysis Service and Cancer Research UK: “Chemotherapy, Radiotherapy and Tumour Resections in England: 2013-2014”: Cancer Research UK - Public Health England Partnership; 2017.
8. Helminen O, Valo J, Andersen H, et al. Real-world guideline-based treatment of lung cancer improves short- and long-term outcomes and resection rate: A population-based study. Lung Cancer 2020;140:1-7. [Crossref] [PubMed]
9. Thorsteinsson H, Alexandersson A, Oskarsdottir GN, et al. Resection rate and outcome of pulmonary resections for non-small-cell lung cancer: a nationwide study from Iceland. J Thorac Oncol 2012;7:1164-9. [Crossref] [PubMed]
10. Royal College of Physicians. Lung cancer clinical outcomes publication 2019 (for the 2017 audit period). London; 2020. Report No.: 9781860167713.
11. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 2011;32:605-44. [Crossref] [PubMed]
12. Strand TE, Rostad H, Møller B, et al. Survival after resection for primary lung cancer: a population based study of 3211 resected patients. Thorax 2006;61:710-5. [Crossref] [PubMed]
13. Naidich DP, Marshall CH, Gribbin C, et al. Low-dose CT of the lungs: preliminary observations. Radiology 1990;175:729-31. [Crossref] [PubMed]
14. Costello P, Anderson W, Blume D. Pulmonary nodule: evaluation with spiral volumetric CT. Radiology 1991;179:875-6. [Crossref] [PubMed]
15. Remy-Jardin M, Remy J, Giraud F, et al. Pulmonary nodules: detection with thick-section spiral CT versus conventional CT. Radiology 1993;187:513-20. [Crossref] [PubMed]
16. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. [Crossref] [PubMed]
17. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 2020;382:503-13. [Crossref] [PubMed]
18. Blanchon T, Bréchot JM, Grenier PA, et al. Baseline results of the Depiscan study: a French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR). Lung Cancer 2007;58:50-8. [Crossref] [PubMed]
19. 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. [Crossref] [PubMed]
20. 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. [Crossref] [PubMed]
21. 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. [Crossref] [PubMed]
22. Pastorino U, Silva M, Sestini S, et al. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol 2019;30:1162-9. [Crossref] [PubMed]
23. Becker N, Motsch E, Trotter A, et al. Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial. Int J Cancer 2020;146:1503-13. [Crossref] [PubMed]
24. Field JK, Vulkan D, Davies MPA, et al. Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis. Lancet Reg Health Eur 2021;10:100179. [Crossref] [PubMed]
25. Heijnsdijk EAM, Csanádi M, Gini A, et al. All-cause mortality versus cancer-specific mortality as outcome in cancer screening trials: A review and modeling study. Cancer Med 2019;8:6127-38. [Crossref] [PubMed]
26. US Preventive Services Task Force. Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325:962-70. [Crossref] [PubMed]
27. Canadian Task Force on Preventive Health Care. Recommendations on screening for lung cancer. CMAJ 2016;188:425-32. [Crossref] [PubMed]
28. Lee J, Kim Y, Kim HY, et al. Feasibility of implementing a national lung cancer screening program: Interim results from the Korean Lung Cancer Screening Project (K-LUCAS). Transl Lung Cancer Res 2021;10:723-36. [Crossref] [PubMed]
29. van Meerbeeck JP, Franck C. Lung cancer screening in Europe: where are we in 2021? Transl Lung Cancer Res 2021;10:2407-17. [Crossref] [PubMed]
30. Pinsky PF. Lung cancer screening with low-dose CT: a world-wide view. Transl Lung Cancer Res 2018;7:234-42. [Crossref] [PubMed]
31. Cancer Australia. Lung cancer screening update. In: Cancer Australia. 2021. Available online: https://www.canceraustralia.gov.au/about-us/lung-cancer-screening#:~:text=The%20Australian%20Government%20has%20announced,and%20improve%20lung%20cancer%20outcomes
32. NHS England. Evaluation of the Targeted Lung Health Check programme. Available online: https://www.england.nhs.uk/contact-us/privacy-notice/how-we-use-your-information/our-services/evaluation-of-the-targeted-lung-health-check-programme/
33. NHS England - National Cancer Programme. Targeted Screening for Lung Cancer with Low Radiation Dose Computed Tomography: Standard Protocol prepared for the Targeted Lung Health Checks Programme; 2019.
34. National Health Service. The NHS Long Term Plan; 2019. Available online: https://www.longtermplan.nhs.uk/publication/nhs-long-term-plan/
35. Crosbie PA, Balata H, Evison M, et al. Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester. Thorax 2019;74:405-9. [Crossref] [PubMed]
36. Crosbie PA, Balata H, Evison M, et al. Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot. Thorax 2019;74:700-4. [Crossref] [PubMed]
37. Ghimire B, Maroni R, Vulkan D, et al. Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme. Lung Cancer 2019;134:66-71. [Crossref] [PubMed]
38. UK National Screening Committee. Adult screening programme: Lung Cancer. 2022. Available online: https://view-health-screening-recommendations.service.gov.uk/lung-cancer/. Accessed May 2022.
39. 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. [Crossref] [PubMed]
40. Balata H, Ruparel M, O'Dowd E, et al. Analysis of the baseline performance of five UK lung cancer screening programmes. Lung Cancer 2021;161:136-40. [Crossref] [PubMed]
41. 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. [Crossref] [PubMed]
42. National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013;368:1980-91. [Crossref] [PubMed]
43. Bartlett EC, Silva M, Callister ME, et al. False-Negative Results in Lung Cancer Screening-Evidence and Controversies. J Thorac Oncol 2021;16:912-21. [Crossref] [PubMed]
44. American College of Radiology Committee on Lung-RADS®. Lung‐RADS® Version 1.1 Assessment Categories; 2019.
45. Robbins HA, Callister M, Sasieni P, et al. Benefits and harms in the National Lung Screening Trial: expected outcomes with a modern management protocol. Lancet Respir Med 2019;7:655-6. [Crossref] [PubMed]
46. 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. [Crossref] [PubMed]
47. González Maldonado S, Delorme S, Hüsing A, et al. Evaluation of Prediction Models for Identifying Malignancy in Pulmonary Nodules Detected via Low-Dose Computed Tomography. JAMA Netw Open 2020;3:e1921221. [Crossref] [PubMed]
48. Lim KP, Marshall H, Tammemägi M, et al. Protocol and Rationale for the International Lung Screening Trial. Ann Am Thorac Soc 2020;17:503-12. [Crossref] [PubMed]
49. Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70:ii1-ii54. [Crossref] [PubMed]
50. Frankel S, Smith GD, Donovan J, et al. Screening for prostate cancer. Lancet 2003;361:1122-8. [Crossref] [PubMed]
51. UK National Screening Committee. Adult Screening Programme: Prostate Cancer. In: UK National Screening Committee. 2020. Available online: https://view-health-screening-recommendations.service.gov.uk/prostate-cancer/
52. Marmot MG, Altman DG, Cameron DA, et al. The benefits and harms of breast cancer screening: an independent review. Br J Cancer 2013;108:2205-40. [Crossref] [PubMed]
53. Yip R, Yankelevitz DF, Hu M, et al. Lung Cancer Deaths in the National Lung Screening Trial Attributed to Nonsolid Nodules. Radiology 2016;281:589-96. [Crossref] [PubMed]
54. Devaraj A, van Ginneken B, Nair A, et al. Use of Volumetry for Lung Nodule Management: Theory and Practice. Radiology 2017;284:630-44. [Crossref] [PubMed]
55. National Lung Screening Trial Research Team. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac Oncol 2019;14:1732-42. [Crossref] [PubMed]
56. Tammemägi MC, Church TR, Hocking WG, et al. Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 2014;11:e1001764. [Crossref] [PubMed]
57. US Preventive Services Task Force. Recommendation: Lung Cancer Screening. 2021. Available online: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/lung-cancer-screening#fullrecommendationstart. Accessed 01/02/2022.
58. Moyer VAU.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330-8. [Crossref] [PubMed]
59. Tammemägi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368:728-36. [Crossref] [PubMed]
60. Field JK, Vulkan D, Davies MPA, et al. Liverpool Lung Project lung cancer risk stratification model: calibration and prospective validation. Thorax 2021;76:161-8. [Crossref] [PubMed]
61. Katki HA, Kovalchik SA, Petito LC, et al. Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med 2018;169:10-9. [Crossref] [PubMed]
62. Cheung LC, Berg CD, Castle PE, et al. Life-Gained-Based Versus Risk-Based Selection of Smokers for Lung Cancer Screening. Ann Intern Med 2019;171:623-32. [Crossref] [PubMed]
63. Katki HA, Kovalchik SA, Berg CD, et al. Development and Validation of Risk Models to Select Ever-Smokers for CT Lung Cancer Screening. JAMA 2016;315:2300-11. [Crossref] [PubMed]
64. 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. [Crossref] [PubMed]
65. Ten Haaf K, Bastani M, Cao P, et al. A Comparative Modeling Analysis of Risk-Based Lung Cancer Screening Strategies. J Natl Cancer Inst 2020;112:466-79. [Crossref] [PubMed]
66. Tammemägi MC, Ruparel M, Tremblay A, et al. USPSTF2013 versus PLCOm2012 lung cancer screening eligibility criteria (International Lung Screening Trial): interim analysis of a prospective cohort study. Lancet Oncol 2022;23:138-48. [Crossref] [PubMed]
67. Mazzone PJ, Silvestri GA, Souter LH, et al. Screening for Lung Cancer: CHEST Guideline and Expert Panel Report. Chest 2021;160:e427-94. [Crossref] [PubMed]
68. Crosbie PA, Gabe R, Simmonds I, et al. Yorkshire Lung Screening Trial (YLST): protocol for a randomised controlled trial to evaluate invitation to community-based low-dose CT screening for lung cancer versus usual care in a targeted population at risk. BMJ Open 2020;10:e037075. [Crossref] [PubMed]
69. Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology 2004;231:440-5. [Crossref] [PubMed]
70. Hendee WR, O'Connor MK. Radiation risks of medical imaging: separating fact from fantasy. Radiology 2012;264:312-21. [Crossref] [PubMed]
71. Brenner DJ, Hall EJ. Cancer risks from CT scans: now we have data, what next? Radiology 2012;265:330-1. [Crossref] [PubMed]
72. Calabrese EJ, O'Connor MK. Estimating risk of low radiation doses - a critical review of the BEIR VII report and its use of the linear no-threshold (LNT) hypothesis. Radiat Res 2014;182:463-74. [Crossref] [PubMed]
73. McCunney RJ, Li J. Radiation Risks in Lung Cancer Screening Programs. Chest 2014;145:618-24. [Crossref]
74. 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. [Crossref] [PubMed]
75. Kummer S, Waller J, Ruparel M, et al. Mapping the spectrum of psychological and behavioural responses to low-dose CT lung cancer screening offered within a Lung Health Check. Health Expect 2020;23:433-41. [Crossref] [PubMed]
76. Brain K, Lifford KJ, Carter B, et al. Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial. Thorax 2016;71:996-1005. [Crossref] [PubMed]
77. 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. [Crossref] [PubMed]
78. van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J 2011;38:154-61. [Crossref] [PubMed]
79. Gareen IF, Duan F, Greco EM, et al. Impact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial. Cancer 2014;120:3401-9. [Crossref] [PubMed]
80. Wu GX, Raz DJ, Brown L, et al. Psychological Burden Associated With Lung Cancer Screening: A Systematic Review. Clin Lung Cancer 2016;17:315-24. [Crossref] [PubMed]
81. Quaife SL, Marlow LAV, McEwen A, et al. Attitudes towards lung cancer screening in socioeconomically deprived and heavy smoking communities: informing screening communication. Health Expect 2017;20:563-73. [Crossref] [PubMed]
82. Quaife SL, Janes SM. Lung cancer screening: improving understanding of the psychological impact. Thorax 2016;71:971-2. [Crossref] [PubMed]
83. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003;226:756-61. [Crossref] [PubMed]
84. MacRedmond R, Logan PM, Lee M, et al. Screening for lung cancer using low dose CT scanning. Thorax 2004;59:237-41. [Crossref] [PubMed]
85. van de Wiel JC, Wang Y, Xu DM, et al. Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT. Eur Radiol 2007;17:1474-82. [Crossref] [PubMed]
86. Kucharczyk MJ, Menezes RJ, McGregor A, et al. Assessing the impact of incidental findings in a lung cancer screening study by using low-dose computed tomography. Can Assoc Radiol J 2011;62:141-5. [Crossref] [PubMed]
87. Priola AM, Priola SM, Giaj-Levra M, et al. Clinical implications and added costs of incidental findings in an early detection study of lung cancer by using low-dose spiral computed tomography. Clin Lung Cancer 2013;14:139-48. [Crossref] [PubMed]
88. Morgan L, Choi H, Reid M, et al. Frequency of Incidental Findings and Subsequent Evaluation in Low-Dose Computed Tomographic Scans for Lung Cancer Screening. Ann Am Thorac Soc 2017;14:1450-6. [Crossref] [PubMed]
89. Bartlett EC, Belsey J, Derbyshire J, et al. Implications of incidental findings from lung screening for primary care: data from a UK pilot. NPJ Prim Care Respir Med 2021;31:36. [Crossref] [PubMed]
90. Veronesi G, Bellomi M, Spaggiari L. The rate of incidental findings in lung cancer screening trials is not negligible. Eur Radiol 2008;18:529. [Crossref] [PubMed]
91. NHS England - National Cancer Programme. Targeted Screening for Lung Cancer with Low Radiation Dose Computed Tomography: Quality Assurance Standards prepared for the Targeted Lung Health Checks Programme: NHS England; 2019.
92. Horst C, Dickson JL, Tisi S, et al. Delivering low-dose CT screening for lung cancer: a pragmatic approach. Thorax 2020;75:831-2. [Crossref] [PubMed]
93. IELCAP Team. International Early Lung Cancer Action Program: Screening Protocol; 2021.
94. Black WC, Gareen IF, Soneji SS, et al. Cost-effectiveness of CT screening in the National Lung Screening Trial. N Engl J Med 2014;371:1793-802. [Crossref] [PubMed]
95. Toumazis I, de Nijs K, Cao P, et al. Cost-effectiveness Evaluation of the 2021 US Preventive Services Task Force Recommendation for Lung Cancer Screening. JAMA Oncol 2021;7:1833-42. [Crossref] [PubMed]
96. Snowsill T, Yang H, Griffin E, et al. Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation. Health Technol Assess 2018;22:1-276. [Crossref] [PubMed]
97. Griffin E, Hyde C, Long L, et al. Lung cancer screening by low-dose computed tomography: a cost-effectiveness analysis of alternative programmes in the UK using a newly developed natural history-based economic model. Diagn Progn Res 2020;4:20. [Crossref] [PubMed]
98. Hinde S, Crilly T, Balata H, et al. The cost-effectiveness of the Manchester 'lung health checks', a community-based lung cancer low-dose CT screening pilot. Lung Cancer 2018;126:119-24. [Crossref] [PubMed]
99. McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics 2008;26:733-44. [Crossref] [PubMed]
100. Ather S, Kadir T, Gleeson F. Artificial intelligence and radiomics in pulmonary nodule management: current status and future applications. Clin Radiol 2020;75:13-9. [Crossref] [PubMed]
101. American Thoracic Society and American Lung Association. Implementation Guide for Lung Cancer Screening. 2018. Available online: https://www.lungcancerscreeningguide.org/. Accessed 01/02/2022.
102. Balata H, Evison M, Sharman A, et al. CT screening for lung cancer: Are we ready to implement in Europe? Lung Cancer 2019;134:25-33. [Crossref] [PubMed]
103. Kalsi HS, Thakrar R, Gosling AF, et al. Interventional Pulmonology. Thoracic Surgery Clinics: Elsevier Inc.; 2020:321-38.
104. Taylor M, Joshi V. The use of near infra-red fluorescence mapping with indocyanine green in thoracic surgery: an exciting real-world clinical application of an established scientific principle. Video-assist Thorac Surg 2019;4:22. [Crossref]
105. Richens D. GIRFT Programme National Specialty Report for Cardiothoracic Surgery; 2018.
106. Lim E, Baldwin D, Beckles M, et al. Guidelines on the radical management of patients with lung cancer. Thorax 2010;65:iii1-27. [Crossref] [PubMed]
107. NICE Guideline [CG122]: Lung cancer: diagnosis and management 2019. London: National Institute for Health and Care Excellence (NICE); 2019 Mar 28.
108. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22; discussion 622-3. [Crossref] [PubMed]
109. Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data. Chest 2011;139:491-6. [Crossref] [PubMed]
110. Sienel W, Dango S, Kirschbaum A, et al. Sublobar resections in stage IA non-small cell lung cancer: segmentectomies result in significantly better cancer-related survival than wedge resections. Eur J Cardiothorac Surg 2008;33:728-34. [Crossref] [PubMed]
111. Rami-Porta R, Tsuboi M. Sublobar resection for lung cancer. Eur Respir J 2009;33:426-35. [Crossref] [PubMed]
112. Winckelmans T, Decaluwé H, De Leyn P, et al. Segmentectomy or lobectomy for early-stage non-small-cell lung cancer: a systematic review and meta-analysis. Eur J Cardiothorac Surg 2020;57:1051-60. [Crossref] [PubMed]
113. Rao S, Ye L, Min L, et al. Meta-analysis of segmentectomy versus lobectomy for radiologically pure solid or solid-dominant stage IA non-small cell lung cancer. J Cardiothorac Surg 2019;14:197. [Crossref] [PubMed]
114. Lex JR, Naidu B. In patients with resectable non-small-cell lung cancer, is video-assisted thoracoscopic segmentectomy an appropriate alternative to video-assisted thoracoscopic lobectomy? Interact Cardiovasc Thorac Surg 2016;23:826-31. [Crossref] [PubMed]
115. Bao F, Ye P, Yang Y, et al. Segmentectomy or lobectomy for early stage lung cancer: a meta-analysis. Eur J Cardiothorac Surg 2014;46:1-7. [Crossref] [PubMed]
116. Zeng W, Zhang W, Zhang J, et al. Systematic review and meta-analysis of video-assisted thoracoscopic surgery segmentectomy versus lobectomy for stage I non-small cell lung cancer. World J Surg Oncol 2020;18:44. [Crossref] [PubMed]
117. Feng J, Wang LF, Han TY, et al. Survival Outcomes of Lobectomy Versus Segmentectomy in Clinical Stage I Non-Small Cell Lung Cancer: A Meta-Analysis. Adv Ther 2021;38:4130-7. [Crossref] [PubMed]
118. Liu Q, Wang H, Zhou D, et al. Comparison of clinical outcomes after thoracoscopic sublobectomy versus lobectomy for Stage I nonsmall cell lung cancer: A meta-analysis. J Cancer Res Ther 2016;12:926-31. [Crossref] [PubMed]
119. Fan J, Wang L, Jiang GN, et al. Sublobectomy versus lobectomy for stage I non-small-cell lung cancer, a meta-analysis of published studies. Ann Surg Oncol 2012;19:661-8. [Crossref] [PubMed]
120. Cao C, Chandrakumar D, Gupta S, et al. Could less be more?-A systematic review and meta-analysis of sublobar resections versus lobectomy for non-small cell lung cancer according to patient selection. Lung Cancer 2015;89:121-32. [Crossref] [PubMed]
121. Suzuki K, Saji H, Aokage K, et al. Comparison of pulmonary segmentectomy and lobectomy: Safety results of a randomized trial. J Thorac Cardiovasc Surg 2019;158:895-907. [Crossref] [PubMed]
122. Wang X, Guo H, Hu Q, et al. Pulmonary function after segmentectomy versus lobectomy in patients with early-stage non-small-cell lung cancer: a meta-analysis. J Int Med Res 2021;49:3000605211044204. [PubMed]
123. Stamatis G, Leschber G, Schwarz B, et al. Perioperative course and quality of life in a prospective randomized multicenter phase III trial, comparing standard lobectomy versus anatomical segmentectomy in patients with non-small cell lung cancer up to 2 cm, stage IA (7th edition of TNM staging system). Lung Cancer 2019;138:19-26.
124. Tsou KC, Hsu HH, Tsai TM, et al. Clinical outcome of subcentimeter non-small cell lung cancer after VATS resection: Single institute experience with 424 patients. J Formos Med Assoc 2020;119:399-405. [Crossref] [PubMed]
125. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ 2000;321:323-9. [Crossref] [PubMed]
126. Caini S, Del Riccio M, Vettori V, et al. Quitting Smoking At or Around Diagnosis Improves the Overall Survival of Lung Cancer Patients: A Systematic Review and Meta-Analysis. J Thorac Oncol 2022;17:623-36. [Crossref] [PubMed]
127. Villanti AC, Jiang Y, Abrams DB, et al. A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLoS One 2013;8:e71379. [Crossref] [PubMed]
128. Thomas KH, Dalili MN, López-López JA, et al. Comparative clinical effectiveness and safety of tobacco cessation pharmacotherapies and electronic cigarettes: a systematic review and network meta-analysis of randomized controlled trials. Addiction 2022;117:861-76. [Crossref] [PubMed]
129. Keeney E, Welton NJ, Stevenson M, et al. Cost-Effectiveness Analysis of Smoking Cessation Interventions in the United Kingdom Accounting for Major Neuropsychiatric Adverse Events. Value Health 2021;24:780-8. [Crossref] [PubMed]
130. NICE Guideline [NG209]: Evidence review for cessation and harm-reduction treatments2021. Report No.: 9781473143470.
131. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health 2015;5:020415. [Crossref] [PubMed]
132. Quach A, Giovannelli J, Chérot-Kornobis N, et al. Prevalence and underdiagnosis of airway obstruction among middle-aged adults in northern France: The ELISABET study 2011-2013. Respir Med 2015;109:1553-61. [Crossref] [PubMed]
133. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management and Prevention of COPD (2022 Report); 2022.
134. World Health Organization. Global Health Estimates: Life expectancy and leading causes of death and disability. In: The Global Health Observatory. 2019. Available online: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death
135. US Preventive Services Task Force (USPSTF). Screening for Chronic Obstructive Pulmonary Disease: US Preventive Services Task Force Recommendation Statement. JAMA 2016;315:1372-7. [Crossref] [PubMed]
136. Sekine Y, Katsura H, Koh E, et al. Early detection of COPD is important for lung cancer surveillance. Eur Respir J 2012;39:1230-40. [Crossref] [PubMed]
137. Goffin JR, Pond GR, Puksa S, et al. Chronic obstructive pulmonary disease prevalence and prediction in a high-risk lung cancer screening population. BMC Pulm Med 2020;20:300. [Crossref] [PubMed]
138. Balata H, Harvey J, Barber PV, et al. Spirometry performed as part of the Manchester community-based lung cancer screening programme detects a high prevalence of airflow obstruction in individuals without a prior diagnosis of COPD. Thorax 2020;75:655-60. [Crossref] [PubMed]
139. Çolak Y, Afzal S, Nordestgaard BG, et al. Prognosis of asymptomatic and symptomatic, undiagnosed COPD in the general population in Denmark: a prospective cohort study. Lancet Respir Med 2017;5:426-34. [Crossref] [PubMed]
140. Chiles C, Paul NS. Beyond lung cancer: a strategic approach to interpreting screening computed tomography scans on the basis of mortality data from the National Lung Screening Trial. J Thorac Imaging 2013;28:347-54. [Crossref] [PubMed]
141. Shemesh J. Coronary artery calcification in clinical practice: what we have learned and why should it routinely be reported on chest CT? Ann Transl Med 2016;4:159. [Crossref] [PubMed]
142. NICE Guideline [NG181]: Cardiovascular disease: risk assessment and reduction, including lipid modification 2014. London: National Institute for Health and Care Excellence (NICE); 2018 Jan 25.
143. Ruparel M, Quaife SL, Dickson JL, et al. Evaluation of cardiovascular risk in a lung cancer screening cohort. Thorax 2019;74:1140-6. [Crossref] [PubMed]
144. Balata H, Blandin Knight S, Barber P, et al. Targeted lung cancer screening selects individuals at high risk of cardiovascular disease. Lung Cancer 2018;124:148-53. [Crossref] [PubMed]
145. Marmot M. Health equity in England: the Marmot review 10 years on. BMJ 2020;368:m693. [Crossref] [PubMed]
146. van der Aalst CM, Ten Haaf K, de Koning HJ. Implementation of lung cancer screening: what are the main issues? Transl Lung Cancer Res 2021;10:1050-63. [Crossref] [PubMed]
147. Lebrett MB, Crosbie EJ, Smith MJ, et al. Targeting lung cancer screening to individuals at greatest risk: the role of genetic factors. J Med Genet 2021;58:217-26. [Crossref] [PubMed]
148. Biomarkers in Lung Cancer Screening: Achievements, Promises, and Challenges; 2019.
149. Mathios D, Johansen JS, Cristiano S, et al. Detection and characterization of lung cancer using cell-free DNA fragmentomes. Nat Commun 2021;12:5060. [Crossref] [PubMed]
150. Tobacco Advisory Group. Smoking and health 2021: A coming of age for tobacco control?2021. Report No.: 9781860168475.
151. Department of Health. Towards a Smokefree Generation: A Tobacco Control Plan for England; 2017 Jul.
152. Gredner T, Mons U, Niedermaier T, et al. Impact of tobacco control policies implementation on future lung cancer incidence in Europe: An international, population-based modeling study. Lancet Reg Health Eur 2021;4:100074. [Crossref] [PubMed]
153. Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med 2014;370:60-8. [Crossref] [PubMed]