Early cancer therapy-related cardiovascular toxicities in children and adolescents: incidence and risk factors within five years from diagnosis

Abstract

Cancer therapy-related cardiovascular toxicities (CTR-CVT) are a major cause of morbidity in childhood, adolescent and young adult cancer survivors (CAYAcs). While late-onset cardiotoxicity has been extensively described, early CTR-CVT occurring during treatment and in the first years after diagnosis remain insufficiently characterised, particularly beyond anthracyclines and chest-directed radiotherapy. To evaluate the incidence, timing and risk factors for CTR-CVT and cancer therapy-related cardiac dysfunction (CTR-CD) from cancer diagnosis through the first five years of follow-up in children and adolescents receiving contemporary anticancer therapies. We retrospectively analysed patients aged 0–20 years treated with chemotherapy, radiotherapy, haematopoietic stem cell transplantation and/or targeted therapies. CTR-CVT, including CTR-CD and other cardiovascular events, were systematically recorded from treatment initiation to last follow-up, censored at five years. Univariable and multivariable Cox proportional hazards models were performed to identify independent risk factors. Among 383 patients included, 89 (23.4%) developed at least one CTR-CVT during follow-up. The majority of events occurred early, with 77% developing within the first two years from cancer diagnosis. CTR-CD was identified in 18 patients, accounting for 25% of all CTR-CVT cases. At univariable analysis, age >5 years at diagnosis, haematological malignancy, corticosteroid exposure, anthracyclines, antimetabolites, vinca alkaloids, etoposide, proteasome inhibitors, targeted therapies and haematopoietic stem cell transplantation were significantly associated with CTR-CVT. In multivariable Cox regression models, high cumulative anthracycline dose remained an independent predictor of both CTR-CVT and CTR-CD. Exposure to proteasome inhibitors independently increased the risk of CTR-CVT and CTR-CD, while haematopoietic stem cell transplantation emerged as an independent risk factor for CTR-CD. In addition, exposure to cytarabine and methotrexate was independently associated with the development of CTR-CVT. These findings highlight a heterogeneous and therapy-specific risk profile for early cardiovascular toxicity extending beyond traditional cardiotoxic agents. CTR-CVT and CTR-CD frequently occur during cancer treatment and early survivorship in children and adolescents. Beyond anthracyclines, stem cell transplantation, proteasome inhibitors and antimetabolites seem to significantly contribute to the development of early-onset cardiotoxicity. These findings support an early, individualised cardiovascular surveillance for CAYAcs, starting from cancer diagnosis, aimed to enable timely detection and prevention of long-term sequelae.