Double Burden, Double Risk: Depression–Frailty Synergy and All‑Cause Mortality in U.S. Cancer Survivors

Background Depression and frailty each predict excess mortality in cancer survivors, but their combined effect is undefined. We quantified the independent and joint associations of depression and frailty with allcause mortality in a nationally representative cohort of U.S. cancer survivors. Methods We pooled 22 waves (1997–2018) of the National Health Interview Survey and linked records to the National Death Index (followup through December 31 2019). Depression was defined by selfreport of a clinician diagnosis; frailty was assessed with the fiveitem FRAIL scale (frail = score 3–5). Surveyweighted Cox models estimated hazard ratios (HRs) for allcause mortality after adjustment for demographic, socioeconomic, and clinical covariates. Effect modification by age and sex was examined. Results Among 55,751 cancer survivors (mean age, 62.8 ± 15.2 year; 54.4% women), 11,084 (19.9%) had depression, 12,437 (22.3%) were frail, and 1,592 (2.9%) had both conditions. Over 471,838 personyears, 17,603 deaths occurred. Depression was associated with higher mortality (multivariable HR, 1.34; 9 % CI, 1.18–1.53), as was frailty (HR, 1.18; 9 % CI, 1.08–1.30). Survivors with coexisting depression + frailty had the greatest risk (HR, 1.38; 9 % CI, 1.26–1.51) compared with all other survivors; the relative excess was largest in those < 60 years of age (HR, 2.60; 9 % CI, 2.10–3.23; P for interaction < 0.001) and similar in women and men. Absolute 10year survival was 12 percentage points lower in the combinedphenotype group than in controls. Conclusions Depression and frailty independently—and synergistically—elevate allcause mortality among U.S. cancer survivors, with the strongest relative effect in younger adults. Concurrent screening for both conditions and deployment of integrated exercise, nutritional, and psychosocial interventions may improve longterm survival in this growing population.