Background: Single-cancer screening strategies address only one component of the overall population cancer burden. Even high-risk populations in single-cancer screening trials experience a considerable burden of other cancer incidence; therefore, we assessed non-lung cancer incidence in the NLST to evaluate the proportion of unscreened cancers. Methods: The NLST was a randomized controlled trial of screening for lung cancer in adults aged 55–74 years with ≥30 pack-years of smoking history, enrolled in 2002–2004 and actively followed through 2009. Incident cancers were identified via participant questionnaires, death certificates, and direct notifications, and confirmed by medical record abstraction. The present analysis includes first invasive primary cancers diagnosed after study randomization. Non-lung cancer incidence was similar between the two trial arms, which were therefore combined for analysis. Results: Among 53 229 subjects (median follow-up 6.5 years), the incidence of any first primary cancer was 1941 per 100 000 person-years, of which 1327 per 100 000 (68%) was non-lung cancer. Non-lung cancer incidence rates exceeded that for lung cancer in all 5-year age categories (especially at younger ages) and all quintiles of smoking pack-years (especially with fewer pack-years). After lung cancer, the most common cancers were other leading cancer types in the general US population, as well as other smoking-related cancers (Table). No recommended population-based screens exist for 54% of observed cancer cases (3332 of 6142, excluding lung, colon/rectum, female breast, and cervix). Conclusions: In the NLST, only 32% of first primary cancer incidence was lung; non-lung cancer comprised 68%, and most cases were cancer types with no generally recommended screening strategy. Even in a high-risk population, a single-cancer screening test misses most cancers, illustrating the value of multi-cancer screening tests that can detect a broad spectrum of cancers and, therefore, have the potential to address a currently inaccessible portion of cancer morbidity and mortality.

*Smoking-related cancers