Colorectal Cancer in the U.S., 1999–2021: Declining Rates, Rising Concerns, and Persistent Disparities

<b>Background:</b> Colorectal cancer (CRC) incidence and mortality have declined in the United States over the past two decades, yet disparities persist by age, sex, race/ethnicity, and geography. To characterize population-level survival signals, we examined trends in age-adjusted incidence rates (AAIR), mortality rates (AAMR), and the mortality-to-incidence ratio (AAMIR) from 1999 to 2021, stratified by key subgroups. <b>Methods:</b> This retrospective analysis utilized de-identified data from the CDC WONDER United States Cancer Statistics database, encompassing incident CRC cases (SEER codes 21041-21052) and deaths (ICD-10 codes C18-C20) in adults aged 20 years and older. Age-adjusted rates (per 100,000, 2000 U.S. standard population) and AAMIR were calculated using Stata 17.0. Joinpoint regression identified trends (annual or average annual percent change [APC/AAPC], <i>p</i> < 0.05). <b>Results:</b> Among 3,489,881 cases and 1,225,986 deaths, AAIR decreased from 78.24 (1999) to 50.79 (2021; AAPC: -2.20%, 95% CI: -2.52 to -1.89), AAMR decreased from 29.34 to 17.92 (AAPC: -2.33%, -2.46 to -2.20), and AAMIR from 0.375 to 0.353 (AAPC: -0.08%, -0.47 to 0.30; <i>p</i> = 0.669). Women showed a significant AAMIR decline (AAPC: -0.29%), unlike men (AAPC: 0.07%). Young adults (20-39 years) had rising AAIR (AAPC: 2.42%) and AAMR (0.87%) but improving AAMIR (AAPC: -1.71%). Non-Hispanic Black individuals had the highest AAMIR (0.400 in 2021; AAPC: -0.54%). The Northeast had the most favorable AAMIR trend (AAPC: -0.40%), while the Midwest, South, and West were stable. States like New Jersey and Massachusetts achieved low AAMIR (0.292 and 0.304 in 2021), contrasting with Nebraska and Arizona (0.402 in both). <b>Conclusions:</b> Although colorectal cancer incidence and mortality have declined substantially in the United States from 1999 to 2021, the mortality-to-incidence ratio improved only marginally and remained markedly uneven across subgroups. Targeted interventions-enhancing screening and treatment access for men, racial/ethnic minorities, younger adults, and high-burden regions and states-can promote equitable outcomes.