Overdiagnosis in lung cancer screening: Estimates from the German Lung Cancer Screening Intervention Trial.

Overdiagnosis is a major potential harm of lung cancer screening; knowing its potential magnitude helps to optimize screening eligibility criteria. The German Lung Screening Intervention Trial ("LUSI") is a randomized trial among 4052 long-term smokers (2622 men), 50.3 to 71.9 years of age from the general population around Heidelberg, Germany, comparing five annual rounds of low-dose computed tomography (n = 2029) with a control arm without intervention (n = 2023). After a median follow-up of 9.77 years postrandomization and 5.73 years since last screening, 74 participants were diagnosed with lung cancer in the control arm and 90 in the screening arm: 69 during the active screening period; of which 63 screen-detected and 6 interval cancers. The excess cumulative incidence in the screening arm (N = 16) represented 25.4% (95% confidence interval: -11.3, 64.3] of screen-detected cancer cases (N = 63). Analyzed by histologic subtype, excess incidence in the screening arm appeared largely driven by adenocarcinomas. Statistical modeling yielded an estimated mean preclinical sojourn time (MPST) of 5.38 (4.76, 5.88) years and a screen-test sensitivity of 81.6 (74.4%, 88.8%) for lung cancer overall, all histologic subtypes combined. Based on modeling, we further estimated that about 48% (47.5% [43.2%, 50.7%]) of screen-detected tumors have a lead time ≥4 years, whereas about 33% (32.8% [28.4%, 36.1%]) have a lead time ≥6 years, 23% (22.6% [18.6%, 25.7%]) ≥8 years, 16% (15.6% [12.2%, 18.3%]) ≥10 years and 11% (10.7% [8.0%, 13.0%]) ≥12 years. The high proportions of tumors with relatively long lead times suggest a major risk of overdiagnosis for individuals with comparatively short remaining life expectancies.

Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial.

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.

Longitudinal airway remodeling in active and past smokers in a lung cancer screening population.

OBJECTIVES: To longitudinally investigate smoking cessation-related changes of quantitative computed tomography (QCT)-based airway metrics in a group of heavy smokers. METHODS: CT scans were acquired in a lung cancer screening population over 4 years at 12-month intervals in 284 long-term ex-smokers (ES), 405 continuously active smokers (CS), and 31 subjects who quitted smoking within 2 years after baseline CT (recent quitters, RQ). Total diameter (TD), lumen area (LA), and wall percentage (WP) of 1st-8th generation airways were computed using airway analysis software. Inter-group comparison was performed using Mann-Whitney U test or Student's t test (two groups), and ANOVA or ANOVA on ranks with Dunn's multiple comparison test (more than two groups), while Fisher's exact test or chi-squared test was used for categorical data. Multiple linear regression was used for multivariable analysis. RESULTS: At any time, TD and LA were significantly higher in ES than CS, for example, in 5th-8th generation airways at baseline with 6.24 mm vs. 5.93 mm (p < 0.001) and 15.23 mm2 vs. 13.51 mm2 (p < 0.001), respectively. RQ showed higher TD (6.15 mm vs. 5.93 mm, n.s.) and significantly higher LA (14.77 mm2 vs. 13.51 mm2, p < 0.001) than CS after 3 years, and after 4 years. In multivariate analyses, smoking status independently predicted TD, LA, and WP at baseline, at 3 years and 4 years (p < 0.01-0.001), with stronger impact than pack years. CONCLUSIONS: Bronchial dimensions depend on the smoking status. Smoking-induced airway remodeling can be partially reversible after smoking cessation even in long-term heavy smokers. Therefore, QCT-based airway metrics in clinical trials should consider the current smoking status besides pack years. KEY POINTS: • Airway lumen and diameter are decreased in active smokers compared to ex-smokers, and there is a trend towards increased airway wall thickness in active smokers. • Smoking-related airway changes improve within 2 years after smoking cessation. • Smoking status is an independent predictor of airway dimensions.