Safety profile and evaluation of secondary malignant neoplasms

Multiple studies support the cardioprotective efficacy of dexrazoxane in paediatric patients treated with anthracyclines. In a retrospective cohort of 258 children, dose-limiting cardiotoxicity occurred significantly more frequently in patients who did not receive dexrazoxane (p = 0.006).^{Reference Kang, Kim and Song14} Among patients receiving cumulative anthracycline doses of 200–300 mg/m², left ventricular ejection fraction and fractional shortening z-scores were significantly better preserved in dexrazoxane-treated patients (p < 0.04).

In patients with osteosarcoma exposed to very high cumulative doxorubicin doses (600 mg/m²), dexrazoxane was associated with only minimal reductions in fractional shortening and predominantly transient, low-grade ventricular dysfunction.^{Reference Schwartz, Wexler and Krailo15}

Notably, long-term data from Chow et al. demonstrated that dexrazoxane use was associated with improved ventricular function and lower myocardial stress nearly two decades after cancer diagnosis, particularly among patients exposed to cumulative doxorubicin doses ≥250 mg/m².^{Reference Chow, Aggarwal and Doody16} These findings suggest not only short-term myocardial protection but also durable long-term benefits.

Concerns regarding second primary malignancies largely originate from a single analysis in paediatric Hodgkin lymphoma, in which a higher number of second primary malignancies was observed in the dexrazoxane arm.^{Reference Tebbi, London and Friedman17,Reference Hellmann18} However, subsequent large observational studies and clinical trials have failed to corroborate this association.

A retrospective analysis of over 15,000 paediatric cancer patients demonstrated lower, not higher, rates of secondary acute myeloid leukaemia among dexrazoxane-exposed patients.^{Reference Seif, Walker and Li19} Additional cohort studies and meta-analyses likewise failed to show a statistically significant increase in second primary malignancies risk.^{Reference Vrooman, Neuberg and Stevenson20}

The 2022 Cochrane review did, however, conclude that a potential association cannot be definitively excluded in paediatric populations,^{Reference Baat, Mulder and Armenian21} emphasising ongoing uncertainty rather than confirmed causal risk.

Dexrazoxane is generally well tolerated. While some studies report increased haematologic toxicity, major randomised trials have shown comparable rates of infection, myelosuppression, and neurologic toxicity in dexrazoxane-treated and control patients.^{Reference Asselin, Devidas and Chen9}

Initial regulatory concerns regarding excess mortality were not substantiated by later analyses. Long-term pooled data from randomised trials demonstrated no adverse effect on 10-year overall survival, a finding corroborated by subsequent meta-analyses and guideline reviews.^{Reference Asselin, Devidas and Chen9,Reference Baat, van Dalen and Mulder12,Reference Chow, Asselin and Schwartz22}

Across multiple randomised trials and systematic reviews, dexrazoxane has not been associated with increased relapse or inferior event-free or overall survival.^{Reference Baat, van Dalen and Mulder12,Reference Chow, Asselin and Schwartz22,Reference Shaikh, Dupuis and Alexander23} These data collectively indicate that dexrazoxane does not attenuate the antitumour efficacy of anthracycline-based chemotherapy.

The cost–benefit profile of dexrazoxane must be interpreted in the context of cumulative anthracycline exposure and expected lifetime cardiovascular risk. Its primary benefit lies in the prevention of subclinical myocardial injury, which may otherwise progress silently for years before manifesting as irreversible heart failure.

Potential risks include uncertain protocol-dependent associations with secondary malignancies and transient haematologic toxicity. However, in patients expected to receive cumulative anthracycline doses ≥250 mg/m²—particularly those with long anticipated survival—the balance increasingly favours cardioprotection.

Predicament of Latin America

In high-income countries, contemporary paediatric oncology and cardio-oncology guidelines increasingly endorse a risk-stratified use of dexrazoxane in children expected to receive high cumulative anthracycline doses, supported by access to advanced cardiac imaging, biomarker surveillance, and long-term survivorship programs. In contrast, much of Latin America faces structural limitations, including restricted access to serial echocardiography, cardiac MRI, and specialised survivorship care, as well as greater sensitivity to upfront drug costs within publicly funded health systems. Consequently, while high-income settings may rely on intensive monitoring to detect and manage early cardiotoxicity, Latin American health systems must place greater emphasis on primary prevention strategies that reduce irreversible late cardiac damage in the absence of robust long-term follow-up infrastructure. This divergence highlights the need to interpret international guidelines through a regional lens, adapting recommendations on dexrazoxane use to local clinical capacity, economic constraints, and survivorship realities rather than applying high-income country paradigms uncritically.^{Reference Gonzalez-Ramella, Freigeiro and Castellanos24,Reference Izurieta Pacheco, Noyd and Challinor25}

From a public health perspective, Ministries of Health in Latin America should consider incorporating dexrazoxane into national paediatric oncology protocols for clearly defined high-risk patients, as targeted cardioprotection may reduce long-term heart failure-related morbidity and downstream healthcare costs in survivorship despite higher upfront drug expenditure.