Normal Tissue Complication Probability Estimation for Metabolic Syndrome in Survivors of the Dutch National Wilms Tumor Cohort: A DCCSS-LATER Study

PURPOSE: Wilms tumor (WT) survivors face increased mortality due to cardiovascular-related diseases. Cardiovascular risk factors include adiposity, insulin resistance, dyslipidemia, and hypertension, clustered as metabolic syndrome (MetS). We assessed the prevalence and determinants of MetS in the first XXXX national WT survivor cohort. METHOD: This cross-sectional 1:3 age and sex-matched case-control study, using the Lifelines-cohort, analyzed WT survivors treated between 1963-2002, recruited within XXXX study (2016-2020). MetS prevalence was assessed using the modified NCEP-ATP-III 2005 classification. Multivariable logistic regression models, adjusted for age and sex, assessed associations between the presence of MetS (components) and abdominal radiotherapy. Dosimetry was performed to estimate the mean dose to the abdominal fat, liver, pancreas (head ± tail), and contralateral kidney ± vessels and to estimate a normal tissue complication probability. RESULTS: Among 265/491 participating WT survivors (median age 33.9y; median follow-up: 29.8y), MetS prevalence was 18.8% and 7.3% in matched controls (OR:95%CI) (2.94:1.92-4.49). WT survivors showed increased levels of triglycerides (2.39:1.65-3.49) and fasting glucose (1.67:1.03-2.70), and decreased HDL-cholesterol (2.79:2.00-3.91). Univariable analyses identified abdominal radiotherapy to be the main determinant associated with increased risk for MetS (2.42:1.24-4.75). Multivariable analysis identified a significant increased risk of high fasting glucose levels (3.14:1.14-9.56) after abdominal radiotherapy. NTCP estimation identified radiation exposure of the pancreas and intra-abdominal fat as potential contributors to this association. A median dose between 10-20 Gy to the organs-at-risk results in a 5% risk of developing one or more components of MetS, increasing to 25% at 20-30 Gy. CONCLUSION: WT survivors, particularly those treated with abdominal radiotherapy >20 Gy, have an increased risk of developing components of the MetS.