Risk Factors for Valvulopathy Among Childhood Cancer Survivors.
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IMPORTANCE: Substantial improvements in childhood cancer survival have created a critical need to address serious long-term health complications, such as valvular heart disease (VHD). OBJECTIVE: To identify treatment-related risk factors for VHD in a large European cohort of long-term childhood cancer survivors. DESIGN, SETTING, AND PARTICIPANTS: This nested case-control study used data from the PanCareSurFup (PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies) and ProCardio cohorts, including detailed radiation dose reconstruction and chemotherapy exposure, for childhood cancer survivors from 7 European countries, diagnosed between 1940 and 2009, who survived at least 5 years after cancer diagnosis. Case patients, defined as having symptomatic VHD, were matched with controls 1:2 by subcohort, sex, age at cancer diagnosis, and calendar year of initial diagnosis. Data were analyzed from October 2023 to June 2025. EXPOSURES: Doses were calculated by performing a whole-body dosimetric reconstruction using a voxel-based anthropomorphic phantom with more than 200 delineated anatomic structures or substructures. Cumulative dose to cytotoxic agents was also assessed. MAIN OUTCOME AND MEASURE: Development of symptomatic VHD (grade ≥3 per the Common Terminology and Criteria for Adverse Events, version 4.03). RESULTS: Of the 225 cases, 136 participants (60.4%) were male, and 195 (86.7%) were diagnosed with VHD beyond 20 years from childhood cancer. Survivors receiving a mean heart radiation therapy (RT) dose of 5 to less than 15 Gy had an increased risk of VHD (odds ratio [OR], 4.7; 95% CI, 2.1-10.7) compared to those without heart RT, with higher risk when more than half of the heart was exposed. The heart RT dose response appeared exponential, with the OR being 104.1 (95% CI, 27.8-389.6) for mean heart dose of 30 Gy or more, increasing considerably with follow-up from 6.0 (95% CI, 1.4-26.5) after 5 to 19 years to 71.4 (95% CI, 20.4-250.0) after 30 or more years. Cumulative anthracycline doses of 400 mg/m2 or higher were also associated with increased VHD risk (OR, 3.8; 95% CI, 1.4-10.3), showing an exponential dose-response pattern. Cumulative exposure to platinum agents was associated with VHD risk in a linear manner. No statistically significant associations were found for other chemotherapy agents or radiation to the spleen. CONCLUSION AND RELEVANCE: In this case-control study, heart RT, anthracyclines, and platinum agents were associated with increased VHD risk in childhood cancer survivors. Risks from both RT and anthracyclines were amplified with age and follow-up, underscoring the need for long-term cardiac surveillance.