Risk of Complications

Lung cancer screening results in a signi cant proportion of invasive procedures including surgery. These are done for both diagnosis and for treatment. In the IELCAP study, the rate of perioperative mortality was 0.5% [14]. However, the surgical mortality rate for major lung surgery across the US is 5% [19]. Major complications after a diagnostic procedure in the NLST occurred in 0.06% of patients with a positive LDCT that did not result in cancer, and 11.2% of those that did result in the diagnosis of cancer [15].

There is consensus among the different guidelines that lung cancer screening should be performed in centers with multidisciplinary lung cancer groups with expertise in minimally invasive diagnostic techniques (endobronchial ultrasound and navigational bronchoscopy), and in treatments with less morbidity, such as VATS, robotic surgery, or SBRT.

Lung Cancer Screening: Eligibility

Criteria

In December of 2013, the United States Preventive Services Task Force (USPSTF) published its rst recommendation in favor of annual lung cancer screening in the US for adults aged 55–80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years [27]. These selection criteria based on age and smoking history are similar to the entry criteria to the NLST, except that in the latter, the age range was between 55 and 74 years [15]. In an updated version in 2021, the USPSTF changed the age range and pack-year eligibility, recommending screening with LDCT in adults aged 50–80 years who have a 20 pack-year history of smoking and currently smoke or have quit within 15 years [28].

Retrospective studies have shown that applying the NLST entry criteria to other lung cancer screening cohorts would have rendered up to 40% of patients who were diagnosed with lung cancer ineligible for screening [29]. Retrospective analyses of lung cancer screening cohorts suggest that

other risk factors for lung cancer may play a role in selecting the right candidates for screening. For example, the presence of emphysema on the baseline LDCT in a screening program is associated with a two to threefold increased risk of a lung cancer diagnosis [29, 30]. Some suggest that entry criteria should be different for the initial screenings than for subsequent annual screenings. More fexible entry criteria in the rst screening may allow for better risk prediction for subsequent annual screening using data obtained on the baseline LDCT (e.g., radiologic emphysema) [29]. The USPSTF acknowledges that other risk factors for lung cancer may play an important role in identifying high risk individuals who can bene t from lung cancer screening but recommends determining risk by age and smoking history because of lack of evidence that risk prediction models would improve outcomes [28].

Lung Cancer Screening Around the World

Almost 10 years after the publication of the initial favorable recommendations, less than 10% of eligible individuals each year in the US undergo lung cancer screening. In Europe, no of cial recommendation for screening had been made up until 2022 when the EU published an of cial report in which it recommends, “extending population-­based screening programs to lung and prostate cancer and ensure preparedness for the introduction of new methods” [31]. Croatia is the only European country that has implemented a nation-wide lung cancer screening program [32]. Other countries in the EU are currently analyzing bene ts and risks associated with the implementation of nationwide programs or are designing pilot studies to determine the feasibility of nationwide population-based lung cancer screening programs [33].

Japan was one of the rst countries in the world to conduct research on the use of LDCT for lung cancer screening. In 1993, the Anti-lung Cancer Association, a for pro t organization supported by a government grant, conducted the rst trial exploring LDCT as an alternative to chest-­

X-­ray (CXR) for lung cancer screening [34]. Results showed that screening with LDCT is superior to CXR and can detect stage I lung cancer in more than 90% of high-risk individuals diagnosed with the disease [34]. Since, there have been numerous studies con rming the ben- e ts of lung cancer screening using LDCT [5]. By 2009, more than 125,000 individuals had been screened in Japan, with cancer detection rates between 0.15% and 0.33% and stage I diagnoses between 70% and 79% [5]. By 2015, there were 1347 physicians, and 854 centers, certi ed by the Japanese Accreditation Council for Lung Cancer CT Screening to do screening using LDCT [5]. Despite Japan’s pioneering efforts in conducting research and in implementing lung cancer screening, few studies from this country, if any, are included in the discussions about implementation of lung cancer screening programs in Western countries.

Screening with LDCT also started in China many years before the rest of the world. Initial efforts in the early 90s were followed by international collaborations with the groups from I-ELCAP and NELSON [5]. There are currently large ongoing trials exploring LDCT for screening not only lung cancer, but also COPD and cardiovascular diseases [27]. One of these studies, the China National Cancer Early Screening Trial (CHANCES), will randomize 78,500 individuals to explore different aspects of lung and colorectal cancer screening: biomarkers, screening intervals, and mortality rates [5].

South Korea has ongoing pilot programs to assess the feasibility to implement population-­ based lung cancer screening with LDCT [5]. Australia’s government is engaging and consulting key stakeholders to seek input on key design elements of a potential population based, nationwide, lung cancer screening program [35].

Incidental Lung Nodules

Since the publication of the rst studies on lung cancer screening using LDCT, the number of lung nodules on CT reports has increased notably. One study suggests that most of the increase

is due to more awareness of radiologists, and perhaps also due to improvements in technology [36]. Using natural language processing algorithms to scan free text on radiology reports, researchers analyzed trends in lung nodule detection over a period of 7 years. The study was conducted in a large integrated healthcare system prior to the implementation of lung cancer screening programs, but more than a decade after positive results of several lung cancer screening studies were published. Extrapolating data to the census of the United States, 1.57 million new lung nodules were reported in 2010 [36], more than ten times prior estimates of the prevalence of incidental lung nodules, previously referred to as solitary pulmonary nodules [37]. Furthermore, the incidence of lung nodules detected increased steadily throughout the study duration, from 2006 to 2012 [12]. Approximately 5% of individuals with a new lung nodule were diagnosed with lung cancer [36]. Despite the increase in the number of nodules detected, the incidence of lung cancer diagnosis did not increase in this group of individuals, suggesting the main reasons for the increases in lung nodule incidence are greater awareness of the radiologists and improvements in CT technology. This translates into a higher risk of unnecessary invasive diagnostic and therapeutic procedures. Another concern raised by several studies is an exceedingly high proportion (up to 60%) of patients with lung nodules detected outside of lung cancer screening programs that are lost to follow-up [38]. For this reason, some centers are developing programs aimed at tracking incidental lung nodules and other ndings. In a large healthcare system in southern United States, researchers analyzed the diagnosis of lung cancer through three different pathways: a lung cancer screening program (5659 participants between 2015 and 2021), an incidental lung nodule program (15,461 patients between 2015 and 2021), and a multidisciplinary thoracic oncology program (1766 patients not belonging to any of the other two groups, between 2015 and 2020) [39]. The number of lung cancers diagnosed in each pathway was 156 (3%), 772 (5%), and 1139 (65%), respectively. Moreover, the proportion of patients diagnosed in stage I or II was

61%, 61%, and 44%, respectively. In comparison to the lung cancer screening pathway, there were more underserved patients belonging to minorities or uninsured in the lung nodule program. Several reports suggest that lung cancer screening using LDCT is being implemented more widely among more affuent and predominantly white individuals. Thus, a program that detects nodules incidentally may be an opportunity, not only to identify more individuals with lung cancer in early stages, but also to overcome the racial and economic inequalities seen with screening.

Management of Lung Nodules

Guidelines for the management of nodules published by several professional societies based on expert consensus have been evolving over the last decade and are being updated frequently. Some have been developed speci cally for nodules detected in the course lung cancer screening (Lung-RADS→, NCCN), others for nodules detected incidentally (Fleischner Society), and some independent of the detection pathway (American College of Chest Physicians and British Thoracic Society) [18, 40–43]. In general, most recommendations are based on expert reviews and are evolving so quickly that a comprehensive analysis is beyond the scope of this text. The main objectives of guidelines must be to reduce unnecessary invasive procedures and to minimize risks for patients while optimizing the chances of diagnosing the disease in early stages when cure is still feasible with surgery. As mentioned previously, in the IELCAP trial, 11% of surgical procedures were performed on nodules that had benign histology. In NLST, 25% of surgical procedures were performed on benign nodules [44].

Recommendations of all guidelines are based on the pretest probability a nodule has of being cancer, with minor differences in thresholds of risk chosen for immediate diagnostic procedures or observation. In an analysis of two Canadian cohorts of individuals with lung nodules, one from a lung cancer screening study (PanCan), and the other from a chemoprevention study (British Columbia Cancer Agency or BCCA),

researchers tested and validated parameters potentially associated with lung cancer [44]. Over 1800 individuals from the PanCan study, and 1090 from the BCCA study were included with prevalence rates of lung cancer of 5.5% and 3.7%, respectively. In a univariate analysis, size, type (non-solid, part-solid, or solid), location, and the number of nodules were signi cant predictors of lung cancer. In a parsimonious model, the diagnosis of cancer was associated with female sex, increasing size of the nodule, location of the nodule in the upper lobes, and spiculation of the borders. Additional parameters associated with lung cancer in a full model were older age, family history of cancer, emphysema, lower nodule count, and part solid as compared with solid nodules. Non-solid nodules (ground glass opacities) had a reduced risk when compared to solid nodules [44].

Lung Cancer Screening

and Incidental Findings

A high proportion of LDCTs done in the lung cancer screening setting detect incidental ndings [45]. The most common are cardiovascular (coronary calci cations and aortic disorders) and respiratory (emphysema and reticular opacities) [45, 46]. Other less common ndings that may have an impact on patients undergoing lung cancer screening include lymphadenopathy, thyroid nodules, and extrapulmonary malignancies [45, 47]. Some incidental ndings have been found to have a major impact on lung cancer screening itself, especially emphysema, and lymphadenopathy [45, 47, 48]. Although the prevalence of mediastinal lymphadenopathy is low (<2%), in a retrospective analysis of NLST, individuals with enlarged lymph nodes had a signi cantly higher incidence of lung cancer as compared to those without enlarged nodes (17.1% vs. 3.9%). Furthermore, the presence of enlarged lymph nodes was associated with a later stage at diagnosis, increased number of deaths, and reduced survival times [45].

The prevalence of emphysema observed on LDCT in the context of lung cancer screening has been reported to range between 28% and 44%

[47–49]. For decades it has been known that patients with chronic obstructive pulmonary disease (COPD) have a higher risk of lung cancer [50, 51]. In 2006, an analysis of a lung cancer screening cohort was rst to show that emphysema detected qualitatively on the LDCT was signi cantly associated with a 2.5-fold greater risk of lung cancer [48]. When both emphysemas, detected on LDCT, and COPD, diagnosed by spirometry, were included in a multivariate analysis adjusted for age, sex, and smoking history, only emphysema remained as an independent predictor of risk of lung cancer. Thesendings have been con rmed by other studies [30, 52–55]. Most retrospective analyses of lung cancer screening cohorts have found a signi cant association between emphysema and the risk of diagnosis of lung cancer, with one study also reporting an increased risk of death from lung cancer [52].

How incidental ndings may impact outcomes in lung cancer screening is yet to be determined. There is the risk of harm caused by detecting abnormalities that may lead to unnecessary invasive diagnostic procedures or treatments, but there are potential bene ts beyond early treatment of potentially severe diseases. For example, as mentioned previously, one study has suggested that the presence of emphysema on a baseline lung cancer screening LDCT may have a bene cial impact on the selection of high-risk individuals who should undergo subsequent annual screening [29]. Other possible bene ts include early diagnosis of diseases other than lung cancer, such as coronary artery diseases or other malignancies.

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