Introduction

With more than 10 million deaths in 2019, cancer was the second cause of mortality worldwide, preceded by cardiovascular diseases, which caused 18.56 million deaths [1]. Tracheal, bronchus, and lung cancer led all cancers in mortality with a rate of 25 deaths per 100.000 individuals, more than the next two categories (i.e., colon and stomach) combined [1]. In some parts of the world, lung cancer incidence is decreasing, but in others, it is still increasing, especially in women [2]. In the United States, between the years 2000 and 2018, the incidence of lung cancer per 100.000 in men has decreased by 36%, from 87.6 (95% con - dence interval [CI], 86.7–88.5) to 56.3 (95% CI, 46.2–47.2) [3]. In women, the incidence over the same period has only dropped by 13%, from 53.7 (95% CI, 53.1–54.3) to 46.7 (95% CI, 46.2–47.2). In some countries in central and eastern Europe, and in South America (i.e., Brazil), the incidence in women continues to increase [4]. Regional differences in lung cancer incidence by sex refect geographic trends in tobacco consumption, except

J. J. Zulueta (*)

Pulmonary, Critical Care, and Sleep Medicine, Icahn

School of Medicine, Mount Sinai Morningside

Hospital, New York, NY, USA

e-mail: Javier.zulueta@mountsinai.org

M. Marín

Pulmonary Medicine Service, Hospital

Clinico-Universitario Lozano Blesa, Zaragoza, Spain

for women in some Asian countries where the incidence of lung cancer in never smokers is higher [4, 5]. In China and Brunei, the prevalence of smoking among women is as low as 2%, signi cantly lower than in most western countries, but the incidence rates of lung cancer are similar, between 22 and 27 per 100,000 [5].

Lung cancer remains the deadliest cancer mainly because it is predominantly diagnosed in advanced stages, even after numerous studies have shown that screening individuals at high risk for the disease results in early detection and in signi cant reductions in mortality. In the United States, between the years 2011 and 2017, the 5-year relative survival rate of patients diagnosed with lung cancer was 21.7% [6]. This is an improvement when compared to just a few years earlier but is still much lower than the survival rates of other common cancers. The small improvement may be attributed to multiple factors, including the emergence of new targeted therapies and immunotherapies that achieve better survival rates in a large proportion of patients. A recent analysis of the surveillance, epidemiology, and end results (SEER) database suggests that the awareness of lung cancer screening using low-dose computed tomography (LDCT) has resulted in slightly increased rates of early detection although, according to the national cancer institute (NCI), only 5.9% of adults who were eligible in 2015 underwent lung cancer screening [7].

Lung Cancer Screening: Historical

Review

Randomized controlled trials of lung cancer screening of individuals at high risk for lung cancer with chest-X-rays (CXRs) and/or sputum cytology conducted in the 1970s failed to show any bene t in lung cancer mortality [8–11]. Subsequently, studies conducted in Japan showed promising results, but it wasn’t until 1999, with the publication of a study conducted by the Early Lung Cancer Action Program (ELCAP), that a new era in lung cancer screening using low-­ radiation dose computed tomography (LDCT) commenced [12]. The authors of this study performed a LDCT of the thorax on 1000 asymptomatic individuals at high risk for lung cancer due to their smoking history. The LDCT was done at the time of recruitment (baseline) and repeated 1 year later (annual). The study used a novel lung cancer screening protocol based on detection of non-calci ed nodules and tracking of their potential growth using periodic follow-up LDCTs at predetermined intervals. The results of the initial baseline screening showed that 23% of the participants had between one and six non-­ calci ed nodules of at least 5 mm in diameter on LDCT, of which only a fraction was detected on a simultaneous chest radiograph (CXR). Of these nodules, 27 were diagnosed as lung cancer for a prevalence of 2.7%, and 85% of them were diagnosed in stage I according to the seventh Edition of the TNM staging system for lung cancer [13]. Only 7 of the 27 cancers were visualized on CXR. This publication generated great interest in lung cancer screening. The same authors expanded the research group creating an international consortium of investigators named international ELCAP, or I-ELCAP. This group included over 60 centers around the world in which lung cancer screening using LDCT was conducted using a similar protocol and a central database [14]. The most important results of this study were published in a landmark publication in 2006 (Fig. 17.1). After 59,023 screenings (31,567 baseline screenings and 27,456 annual screenings) with LDCT, 484 lung cancers were diagnosed, 85% of which were in stage I at the time

of diagnosis. The overall 10-year survival of these patients with cancer was 80% (95% CI: 74%–85%). Of those patients diagnosed in stage I, and in whom surgery was performed within 1 month since the moment of diagnosis, the 10-year survival reached 92% (95% CI: 88%– 95%) (Fig. 17.1).

In 2011, results of the National Lung Screening Trial (NLST), the rst randomized, controlled trial of lung cancer screening using LDCT, were published. In a trial sponsored by the NCI Division of Cancer Treatment and Diagnosis, Cancer Imaging Program, 53,454 individuals were recruited and randomized to undergo lung cancer screening with LDCT or CXR in 33 participating medical institutions. Participants were men and women between 55 and 74 years of age, with a history of smoking of at least 30 pack-­ years, and who currently smoked or had quit within the last 15 years prior to enrollment [15]. Exclusion criteria included a previous diagnosis of cancer, a chest CT done within 18 months before enrollment, hemoptysis, or an unexplained weight loss of more than 6.8 kg in the preceding year. Screenings occurred at 3 time-points: time of recruitment (initial screening), and after 12 and 24 months (annual screenings) [15]. Based on concepts established previously by IELCAP investigators but with slight differences, a screening in NLST was considered positive if a LDCT had a non-calci ed nodule of 4 mm in diameter or more in any diameter. Positive LDCTs were noti ed to the participants or their health care providers, but no speci c evaluation approach was recommended. The main outcome of the study, a 20% reduction in lung cancer-speci c mortality in the arm in which screening was done with LDCT, was reached ahead of the expected end of the follow-up period and the study had to be stopped prematurely (Fig. 17.2). One-third of the cancers diagnosed in this trial were detected during the follow-up period following the rst three cycles of screening that occurred in years 0, 1, and 2 (Fig. 17.2). When compared to the distribution of lung cancers diagnosed in one of the screening cycles, the proportion of lung cancers diagnosed in early stages was smaller during the subsequent follow-up years. Although impossi-

a

31,567 Asymptomatic participants underwent baseline screening

27,456 Annual screenings

Workup within 12 mo after Annual management algorithm previous CT prompted

by symptoms

b

Survival (%)

0

Fig. 17.1  Panel a: diagnosis of Lung Cancer in the IECALP study resulting from baseline screening and annual screening with LDCT. Panel b: Kaplan-Meier sur-

vival curves for 484 participants with lung cancer and 302 participants with stage I cancer resected within a month after diagnosis. (N Engl J Med. 2006; 355 (17): 1763–71)

Low-dose CT

Chest radiography

3 4 5 6 7 8 Years since Randomization

Chest radiography

Low-dose CT

3 4 5 6 7 8 Years since Randomization

ble to know retrospectively, if lung cancer screening would have been performed yearly over the entire trial period, it is possible that the differences in mortality between the groups might have been greater.

Two additional studies from Europe have con rmed the effectiveness of lung cancer screening using LDCT in reducing lung cancerspeci c mortality, the NELSON trial, and the MILD trial [16, 17]. The Dutch-Belgian lung cancer screening trial, known as the NELSON, was a population-­based, randomized, controlled

trial that recruited 15,792 current or former smokers between 50 and 74 years of age (84% men), who had smoked more than15 cigarettes a day for more than 25 years, or more than 10 cigarettes a day for more than 30 years. Former smokers had to have quit within 10 years of recruitment. One of the novelties of this trial with respect to previous studies was the use of volumetric analysis of nodules to determine growth. Individuals were randomized to undergo four rounds of screening with LDCT with intervals of 1, 2, and 2.5 years (screening group), or