Original Abstract
BACKGROUND: The clinical value of a negative low-dose computed tomography (LDCT) screen for long-term risk stratification remains unclear, leading to uncertainties in rescreening intervals. RESEARCH QUESTION: What are the long-term risks of lung cancer incidence and mortality among screening-negative individuals? STUDY DESIGN AND METHODS: This prospective cohort study utilized data from provincial initiatives (2012-2019) within China's National Lung Cancer Screening Program. Participants aged 40-74 years were categorized as non-screened, screening-negative, screening-positive, or low-risk. Inverse probability weighting integrated with Cox proportional hazard models was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer incidence and mortality. RESULTS: During a median follow-up of 8.61 years, 3,173 incident lung cancers and 2,083 lung cancer deaths occurred among 269,173 participants. Compared with the non-screened group, the screening-negative group exhibited a significantly lower risk of lung cancer incidence (HR = 0.80, 95% CI: 0.65-0.97) and all-cause mortality (HR = 0.77, 95% CI: 0.70-0.85), whereas lung cancer-specific mortality did not differ significantly (HR = 0.88, 95% CI: 0.69-1.12). The reduced risk of lung cancer persisted throughout follow-up and was most pronounced during the first three years. While the screening-negative group exhibited lung cancer incidence (HR = 0.84, 95% CI: 0.68-1.03), lung cancer mortality (HR = 0.89, 95% CI: 0.69-1.15), and all-cause mortality (HR = 0.91, 95% CI: 0.80-1.05) comparable to those in the low-risk group, a slightly lower risk of lung cancer was observed in the screening-negative group at the 9-year cumulative follow-up. In stratified analyses, currently smoking individuals with negative screening results had a higher long-term risk of lung cancer incidence than those in the low-risk group. INTERPRETATION: Individuals with negative LDCT screening results had generally comparable long-term risks of lung cancer incidence, mortality, and all-cause mortality to the low-risk population, supporting risk-stratified follow-up rather than uniform annual rescreening.