The risk of valvular heart disease in the French Childhood Cancer Survivors’ Study: Contribution of dose-volume histogram parameters

Background and purpose: Valvular Heart Disease (VHD) is a known complication of childhood cancer after radiotherapy treatment. However, the dose-volume-effect relationships have not been fully explored. Materials and methods: We obtained individual heart Dose Volume Histograms (DVH) for survivors of the French Childhood Cancer Survivors Study (FCCSS) who had received radiotherapy. We calculated the Mean Dose to the Heart (MHD) in Gy, as well as the heart DVH parameters (V_{d Gy}, which represents the percentage of heart volume receiving at least d Gy), fixing the thresholds to 0.1 Gy, 5 Gy, 20 Gy, and 40 Gy. We analyzed them furtherly in the subpopulation of the cohort that was treated with a dose lower than 5 Gy (V_0.1Gy|_V5Gy=0%), 20 Gy (V_5Gy|_V20Gy=0%), and 40 Gy (V_20Gy|_V40Gy=0%), respectively. We investigated their role in the occurrence of a VHD in this population-based observational cohort study using the Cox proportional hazard model, adjusting for age at cancer diagnosis and chemotherapy exposure. Results: Median follow-up was 30.6 years. Eighty-one patients out of the 7462 (1 %) with complete data experienced a severe VHD (grade ≥ 3). The risk of VHD increased along with the MHD, and it was associated with high doses to the heart (V_40Gy < 50 %, hazard ratio (HR) = 7.96, 95 % CI: 4.26–14.88 and V_20Gy|_V40Gy=0% >50 %, HR = 5.03, 95 % CI: [2.35–10.76]). Doses 5–20 Gy to more than 50 % (V_5Gy|_V20Gy=0% >50 %) of the heart induced a marginally non-significant estimated risk. We also observed a remarkable risk increase with attained age. Conclusions: Our results provide new insight into the VHD risk that may impact current treatments and long-term follow-up of childhood cancer survivors.