Over a 5-year follow-up interval, frail young adult survivors of childhood cancers experienced significantly larger declines than nonfrail survivors in memory, attention, processing speed, and executive function domains. Prefrail survivors also experienced significant declines in attention. Kirsten K. Ness, PhD, PT of the Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital in Memphis, TN, US and colleagues published on 20 July 2021 in the Journal of Clinical Oncology the findings from a prospective study from the St Jude Lifetime Cohort which aimed to determine if the frailty phenotype predicts future neurocognitive decline among young adult survivors of childhood cancer. The data suggest that interventions designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.

The authors explained in the background that cancer-related neurocognitive impairment is present among up to 35% of childhood cancer survivors. It interferes with quality of life, employment, educational attainment, independence in life roles, social engagement, and work productivity. 

Onset of clinically apparent neurocognitive impairment may persist or worsen over time. This suggests a cellular process that either interrupts neuronal processes or permanently damages brain structure and function. However, even children who do not receive therapies directed to the central nervous system (CNS) experience neurocognitive impairment and those who do not have neurocognitive impairment in the immediate post-therapy period may develop it later in survivorship. This suggests that either subclinical damage is present and becomes clinically relevant when demand exceeds structural reserve, or adverse cellular processes continue after exposure ends or are reinitiated, exacerbated, or accelerated by aging.

The latter hypothesis is supported by evidence that an aging phenotype, physiologic frailty, is prevalent in childhood cancer survivors in their fourth decade of life at rates (7.9%) similar to those reported among persons in the general population three decades older.

Frailty has been characterised among childhood cancer survivors as a physical phenomenon including three or more criteria of low lean muscle mass, weakness, slow walking speed, low energy expenditure, and fatigue, but associations of frailty and neurocognitive impairment or decline are not known among childhood cancer survivors.

The aims of this analysis were to characterise the cross-sectional association between frailty and neurocognitive impairment and the prospective association between frailty and neurocognitive decline over a period of approximately 5 years in young adult survivors of childhood cancer.

Childhood cancer survivors 18 to 45 years old and at least 10 years from diagnosis were clinically evaluated for prefrailty or frailty according Fried criteria and completed neuropsychologic assessments at enrolment and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS–directed therapy and baseline neurocognitive performance.

Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrolment. Frail survivors declined an average of 0.54 standard deviation (95% confidence interval [CI] −0.93 to −0.15) in short-term verbal recall, whereas nonfrail survivors did not decline. Frail survivors declined more than nonfrail survivors on visual-motor processing speed (β = −.40; 95% CI −0.67 to −0.12), cognitive flexibility (β = −.62; 95% CI −1.02 to −0.22), and verbal fluency (β = −.23; 95% CI −0.41 to −0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail β = −.35; 95% CI −0.53 to −0.17; frail β = −.48; 95% CI −0.83 to −0.12) compared with nonfrail survivors.

The authors concluded that over approximately 5 years, prefrail and frail young adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Future research is needed to understand the shared biologic pathways underlying frailty and neurocognitive function to inform interventions suitable to this population.

The study was supported by grants from the US National Cancer Institute and the American Lebanese Syrian Associated Charities.


Williams ALM, Krull KR, Howell CR, et al. Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort. JCO; Published online 20 July 2021. DOI: 10.1200/JCO.21.00194