Update on Lung Cancer Screening

Andrew R. Brownlee, MD; Jessica S. Donington, MD, MSCR

Disclosures

Semin Respir Crit Care Med. 2020;41(3):447-452. 

In This Article

Screening Trials

Early Trials

Two of the most influential early CT screening trials were nonrandomized. The first from Swensen et al. at the Mayo Clinic reported on a 5-year prospective study of annual CT screening in 1,520 individuals >50 years of age with a 20-plus-pack year smoking history.[6] Sixty-eight lung cancers were diagnosed in 66 participants, most of which were stage I, but they were unable to demonstrate a significant reduction in lung cancer mortality. The second and more controversial trial was from the Early Lung Cancer Action Project (ELCAP), led by Dr. Claudia Henscke. The initial ELCAP screened 1,000 high-risk smokers in New York with an annual CT.[7] The project then expanded internationally under the acronym I-ELCAP and enrolled >31,000 high-risk smokers worldwide. Screening resulted in diagnosis of lung cancer in 484 participants, 85% of which were stage I. Of the 302, who underwent surgical resection, the survival rate was 92%. The investigators concluded that annual CT screening could detect curable lung cancer.[8] The I-ELCAP trial lacked a control arm, and it was felt by many that the increased diagnosis of early tumors was simply a result of lead-time bias, length bias, and over diagnosis, and that screening did not impact lung cancer mortality.

National Lung Screening Trial

The publication of the NLST in 2011 profoundly changed the CT screening paradigm. It randomized 53,454 current or former smokers in 33 centers across the United States to three annual scans with either LDCT or chest radiograph.[9] Enrollment was limited to those 55 to 74 years of age with at least a 30-pack year smoking history, had quit within 15 years and were without symptoms of lung cancer. The trial launched in September 2002 and met its recruitment goal in April 2004. Positive CT findings were defined as a noncalcified nodule ≥4 mm on LDCT or any noncalcified nodule on radiograph. Twenty-four percent of the LDCT scans and 6.9% of the chest radiographs were abnormal. The cumulative false positive rate was 96.4 and 94.5% for LDCT and radiograph, respectively, indicating that most detected nodules were not cancers. There were 247 deaths from lung cancer per 100,000 person-years in the LDCT group and 309 deaths per 100,000 person years with radiograph, representing a 20% reduction in lung cancer mortality (95% confidence interval [CI]: 6.8–26.7). The number needed to screen (NNS) to prevent one death was 320. Of note, there was also a 6.7% relative-risk reduction in all-cause mortality in the LDCT group.[9]

The rate of lung cancer detection did not diminish significantly over the screening years, suggesting an advantage to serial screening. Extended follow-up through 11 years was reported in June 2019 with continued 20% reduction in lung-cancer mortality (hazard ratio [HR] = 0.89) and a decrease in the NNS to 303.[5]

European Trials

Several European CT screening trials started in parallel with the NLST. All of them were smaller and had less strict eligibility criteria than NLST. While some early reports did not demonstrate decreased mortality for screening,[10,11] three trials have reported findings in the past year, and each support the mortality reductions found in the NLST (Table 1).

The largest of these is the Dutch–Belgian Randomized Lung Cancer Screening (NELSON) Trial (NEderlands–Leuvens Longkanker Screenings ONderzoek) that reported results at the World Conference for Lung Cancer in October 2018.[12] It is a population-based randomized trial of LDCT for lung cancer screening designed to determine if LDCT at years 1, 2, and 4 could lead to a 25% reduction in lung cancer mortality in high-risk males. The study also assessed the effects of screening on quality of life, smoking cessation, and health care cost. A general health questionnaire including 11 questions related to smoking was sent to all men and women born between 1928 and 1953 in seven districts in the Netherlands and 14 municipalities around Leuven in Belgium. A follow-up questionnaire with trial information was sent to high-risk individuals who were eligible for participation and respondents were then randomized to LDCT or no intervention. Screened individuals were invited to one of four screening centers and underwent LDCT at 1, 2, and 4 years. Inclusion criteria were similar to, but less stringent than used in the NLST with regard to age and tobacco use. Patients were followed-up for a minimum of 10 years. Unlike NLST, scans were reported as positive, negative, or intermediate requiring short-term follow-up. Nine percent of participants had an intermediate scan, and only 2.1% patients were positive and referred for workup of a suspicious nodule. Sixty-nine percent of the screened lung cancers were detected at stage I. Surgical treatment of lung cancer was thrice more common in the screened arm compared with the control arm and the general population (67.7 vs. 24.5%). A total of 934 patients died from lung cancer in the control arm compared with 904 in the LDCT arm. This correlated to a 26% reduction in males at 10 years and a 61% reduction in females at 10 years of follow-up, respectively.[12]

Ten-year results from the Multicentric Italian Lung Detection (MILD) were reported in April 2019. The trial compared yearly or biennial LDCT screening to no screening in 4,099 current or former smokers with at least a 20-pack-year history who were 49 years or older. There was a 39% reduced lung cancer mortality in the LDCT arm compared with control at 10 years (HR = 0.61), and a 20% reduction of overall mortality (HR = 0.80). The benefit from LDCT improved past the fifth screening year, providing convincing evidence for the benefit of long-term screening.[13]

The German Lung Cancer Screening Intervention Study (LUSI) compared five annual LDCT scans to no intervention in 4,052 patients aged 50 to 69 years with ≥25-year smoking of 15 cigarettes a day or 30-year history of 10 cigarettes a day. At 8.8 years postrandomization, a 26% decrease in lung cancer mortality was detected. The mortality reduction was greater in women (HR = 0.31) than men (HR = 0.94),[14] which is similar to what was reported in the NELSON trial and may result from difference in tumor subtypes men and women.

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