Year: 2025
Type: article
Study design: Observational Study
Abstract: 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.
Source: JAMA Oncology
Authors: Rivalin Aho Glele, Elizabeth A. M. Feijen, Brice Fresneau, Raoul C. Reulen, Rodrigue S. Allodji, Giao Vu-Bezin, Boris Schwartz, Neige Journy, Véronique Minard-Colin, Francesca Bagnasco, Edit Bardi, Fabiën N. Belle, Julianne Byrne, Elvira C. van Dalen, Jop C. Teepen, Desiree Grabow, Peter Kaatsch, Lars Hjorth, Momcilo Jankovic, Claudia E. Kuehni, Gillian Levitt, Cristina Veres, Isabelle Aerts, Lorna Zadravec Zaletel, Helena J. H. van der Pal, Cecile Ronckers, Carlotta Sacerdote, Roderick Skinner, Zsuzsanna Jakab, Gisela Michel, Monica Terenziani, Nadia Haddy, Isabelle Thierry-Chef, Elisabeth Cardis, Ibrahima Diallo, David L. Winter, Leontien C. M. Kremer, Mike M. Hawkins, Florent de Vathaire
Institutions: Inserm, Université Paris-Saclay, Institut Gustave Roussy, Centre de recherche en Epidémiologie et Santé des Populations, Princess Máxima Center, Fondation Gustave Roussy, University of Birmingham, Istituto Giannina Gaslini, Johannes Kepler University of Linz, Kepler Universitätsklinikum, St Anna Children's Hospital, St. Anna Children's Cancer Research Institute, University of Bern, Institute of Social and Preventive Medicine, Boyne Research Institute, University Medical Center of the Johannes Gutenberg University Mainz, Lund University, Skåne University Hospital, Azienda Ospedaliera San Gerardo, University Hospital of Bern, Great North Children's Hospital, Université Paris Sciences et Lettres, Institut Curie, University of Ljubljana, Institute of Oncology Ljubljana, Piedmont Reference Center for Epidemiology and Cancer Prevention, University of Turin, Royal Victoria Infirmary, Newcastle University, Markusovszky Egyetemi Oktatókórház, University of Lucerne, Fondazione IRCCS Istituto Nazionale dei Tumori, Universitat Pompeu Fabra, Instituto de Salud Carlos III, Barcelona Institute for Global Health, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4414987121