Dexrazoxane makes doxorubicin-induced heart failure a rare event in sarcoma patients receiving high cumulative doses.

Doxorubicin remains a cornerstone in sarcoma treatment, but its dose-dependent cardiotoxicity limits its clinical use and therapeutic potential. Dexrazoxane, the only FDA-approved cardioprotective agent, has demonstrated substantial efficacy in preventing doxorubicin-induced cardiotoxicity. However, despite its proven benefits, dexrazoxane remains underutilized not only in clinical practice but also in contemporary trials. This review examines the role of dexrazoxane in recent oncology trials involving sarcoma patients treated with high cumulative doses of doxorubicin. The LMS 04 trial, a contemporary phase 3 sarcoma trial in which dexrazoxane use was prohibited, reported a 5.4% heart failure incidence at cumulative doxorubicin doses of 360-450 mg/m². In contrast, the trials, where dexrazoxane was used early or upfront, demonstrated rare heart failure incidences even at cumulative doses exceeding 600 mg/m², which is well beyond the conventional maximal limit. Additionally, dexrazoxane enables the safe administration of cumulative doxorubicin doses exceeding 1000 mg/m² without increasing cardiotoxicity. Concerns about secondary malignancies and reduced anti-tumor efficacy have not been supported by clinical trials and meta-analyses. The routine upfront use of dexrazoxane should be considered with doxorubicin treatment, especially in those requiring high cumulative doses or patients at high risk of cardiotoxicity, as each dose of doxorubicin incrementally contributes to the development of cardiotoxicity. Dexrazoxane not only mitigates cardiotoxicity but also allows for extended doxorubicin dosing, maximizing its therapeutic potential. Awareness and guideline updates are necessary to ensure its broader adoption in clinical practice.