Frailty and Sarcopenia within the Earliest Dutch Childhood Cancer Survivor Cohort (n=2,003): A Dccss-Later Study

Introduction: Childhood cancer survivors seem to be at increased risk of frailty and sarcopenia, two partly overlapping aging phenotypes that have been associated with adverse health outcomes. However, evidence about the prevalence of and risk factors for frailty and sarcopenia is limited. We investigated this in a well-defined national cohort of Dutch childhood cancer survivors diagnosed from 1963-2001.

Methods: 2,003 childhood cancer survivors aged 18-45 years at invitation were included (mean age at participation 33.1±7.2 years, 32.3% survivors of lymphoid leukemia, 5.1% myeloid and other leukemia, 18.6% lymphoma, 28.0% solid tumors, and 16.0% central nervous system and brain tumors). We defined prefrailty and frailty according to modified Fried criteria, and sarcopenia based on the EWGSOP2 definition (i.e. presence of both low lean mass and low muscle strength). Associations between demographic, treatment-related, endocrine, as well as lifestyle-related factors and (pre)frailty and sarcopenia were estimated with multivariable logistic regression models.

Results: In survivors with complete frailty measurements (n=1,114, 55.6% of participants) or complete sarcopenia measurements (n=1,472, 73.5%), the percentage of prefrailty, frailty, and sarcopenia was 20.3%, 7.4%, and 4.4%, respectively. In the model for prefrailty in the full cohort (n=2,003), underweight (odds ratio [OR]=3.38) and obesity (OR=1.67), cranial irradiation (CRT, OR=2.07), total body irradiation (TBI, OR=3.17), cisplatin dose ≥600 mg/m2 (OR=3.75), growth hormone deficiency (GHD, OR=2.25), hyperthyroidism (OR=3.72), BMD Z-score ≤-1 but >-2 (OR=1.80), BMD Z-score ≤-2 (OR=3.37), and folic acid deficiency (OR=1.87) were statistically significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR=1.94), underweight (OR=3.09), CRT (OR=2.65), TBI (OR=3.28), cisplatin dose ≥600 mg/m2 (OR=3.93), higher carboplatin doses (continuous, OR=1.15), cyclophosphamide equivalent dose ≥20 g/m2 (OR=3.90), hyperthyroidism (OR=2.87), BMD Z-score ≤-2 (OR=2.85), and folic acid deficiency (OR=2.04). Male sex (OR=4.56), lower body mass index (continuous, OR=0.52)), CRT (OR=3.87), TBI (OR=4.52), hypogonadism (OR=3.96), GHD (OR=4.66), and vitamin B12 deficiency (OR=6.26) were associated with sarcopenia.

Conclusion: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors, i.e., conceivably more than three decades earlier than in the general population. Early recognition and interventions for endocrine disorders and dietary deficiencies may be crucial in minimizing the risk of (pre)frailty and sarcopenia in this population.