Prediagnosis frailty and survival after cancer in middle-aged and older adults: a population-based cohort study

Frailty is a multidimensional syndrome reflecting diminished physiological reserve and has been associated with adverse outcomes in middle-aged and older adults with cancer. However, its long-term prognostic significance when assessed prior to cancer diagnosis remains insufficiently characterized.

We conducted a population-based prospective cohort study using data from the 2006 wave of the Health and Retirement Study (HRS), with follow-up through December 31, 2020. Participants were middle-aged and older adults aged 52 years or older, were cancer-free at baseline, and subsequently developed incident cancer. Frailty was assessed a median of 6.0 years before diagnosis using a 33-item deficit accumulation frailty index (FI) and categorized as non-frail (≤ 0.10), pre-frail (> 0.10 to ≤ 0.21), and frail (> 0.21). The primary outcome was all-cause mortality after cancer diagnosis. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for age, sex, race/ethnicity, education, residential setting, smoking status, alcohol consumption, hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, psychiatric disorders, rheumatic disease, and persistent pain.

Among 1,882 participants, 819 deaths occurred over a median follow-up of 8.7 years after diagnosis. In the fully adjusted model, both pre-frailty and frailty were independently associated with higher mortality compared with non-frailty (HR 1.35, 95% CI 1.05-1.73; and HR 1.87, 95% CI 1.34-2.59, respectively). When modeled continuously, each 0.01-unit increase in FI was associated with an approximately 2% higher mortality risk (HR 1.02, 95% CI 1.01-1.03). At baseline, 740 participants (39.3%) were younger than 65 years, whereas 1,142 participants (60.7%) were aged 65 years or older. Age-stratified fully adjusted weighted Cox analyses demonstrated that each 0.01-unit increment in FI was associated with elevated mortality in the total population (HR 1.022, 95% CI 1.015-1.030; P < 0.001), adults aged ≥ 65 years (HR 1.017, 95% CI 1.008-1.026; P < 0.001), and participants < 65 years (HR 1.023, 95% CI 1.011-1.036; P = 0.003). Significant nonlinear associations were observed for the total population and those aged ≥ 65 years (both P-nonlinear < 0.001), whereas nonlinearity was not statistically significant among participants < 65 years (P-nonlinear = 0.124; Fig. 3, Supplementary Table S10).

These findings suggest that prediagnosis frailty may serve as a marker of underlying vulnerability and may provide modest incremental prognostic information for longitudinal risk assessment in geriatric oncology. Future interventional studies are needed to test whether frailty-targeted assessment and management before or after cancer diagnosis can improve survival, functional outcomes, or quality of life.