The use of dexrazoxane in CAYA cancer to prevent cardiovascular toxicity

Over the past few decades, as survival rates for paediatric cancers have significantly improved, a focus has turned to minimising long-term cardiovascular toxicities of standard treatment modalities

Over the past few decades, treatments for malignancies of children, adolescents, and young adults (CAYA) have advanced and there is an exponential increase in survivors. In the Irish context, Alken et al in 2020 reported cancer survival from 2004–2013 showing a five-year overall survival of 88 per cent for adolescents and young adults (16–24 years) and 82 per cent for children (0–15 years).¹ There is an ever-increasing cohort of CAYA cancer survivors who are living decades beyond their cancer treatment. There is an ongoing emphasis on the importance of minimising toxicities of therapy and subsequent late effects experienced by this group. At present, although more targeted therapies are emerging, the mainstay of treatment modalities remain surgery, radiotherapy, and cytotoxic chemotherapy.

Late effects are multisystem and can present at any time following cancer treatment and the importance of long-term follow-up care and lifelong surveillance therefore cannot be underestimated. Oeffinger et al published results of the Childhood Cancer Survivor Study in The New England Journal of Medicine in 2006, which was a seminal study in the new era of survivorship care for CAYA cancer survivors.² It demonstrated that two-thirds of survivors had at least one chronic health condition and 27.5 per cent had a severe or life-threatening condition. Compared with their siblings, this risk was three-times greater for any chronic condition and eight-times more likely if the condition was severe. The incidence of chronic conditions was cumulative and increased year on year. This study also demonstrated that paediatric cancer survivors are eight-times more likely than their sibling controls to develop cardiovascular conditions.² A study by Kero et al reported that cancer survivors diagnosed between the ages of 0–19 years had an overall hazard ratio of 13.5 (95% CI 8.9–20.5) to develop cardiovascular compromise compared to their sibling-matched controls, with increased cumulative risk up to 25 years after diagnosis.³ As a result, focus turned to minimising the cardiovascular complications of chemotherapy, specifically those of anthracycline chemotherapy, to reduce long-term toxicities in survivors.

Anthracycline-induced cardiotoxicity

Anthracyclines, including doxorubicin, daunorubicin, idarubicin, and epirubicin, are important chemotherapeutic agents used in many paediatric malignancies including sarcoma, leukaemia, and lymphoma. Unfortunately, anthracycline-induced cardiotoxicity (AIC) is a well-recognised long-term consequence of anthracycline use, which is associated with the overall cumulative dose of anthracycline and results in cardiac damage. Over the past few decades, as survival rates for paediatric cancers have significantly improved,^1,4 efforts to address the long-term toxicities of treatment modalities, and in particular, methods to minimise AIC, have increased.⁵ One such intervention, which has been developed to minimise AIC, is dexrazoxane.

There is no one consensus definition for AIC; however, it is usually defined by clinical features of heart failure or subclinical evidence of left ventricular dysfunction (a decrease in left ventricular ejection fraction by 10 points or an overall ejection fraction less than 50 per cent) on imaging modalities.⁶ AIC can be subdivided into acute, early and late cardiotoxicity. Early AIC occurs in the 12 months following exposure to anthracycline chemotherapy and late AIC occurs after this period.⁷

Acute cardiotoxicity typically occurs during treatment and manifests as arrhythmias with ECG changes or a pericarditis picture. Early-onset cardiotoxicity occurs within the first 12 months after treatment and late onset beyond 12 months, but often emerging decades later. Features of AIC can range from asymptomatic left ventricular systolic dysfunction to clinically-symptomatic heart failure, reduced exercise tolerance, and fatigue.

The mechanisms of AIC have not been fully elucidated, however, it is thought to be multifactorial in origin. The original hypothesis for AIC is that damage occurs to cardiomyocytes due to the formation of reactive oxygen species because of oxidative stress.^8,9 More recently, topoisomerase 2β has been elucidated to play an important role in AIC.⁹ Topoisomerase 2β is expressed in cardiomyocytes. Anthracyclines bind to DNA strands, topoisomerase isoenzymes, which cause DNA breakages and cell death. The target is typically the malignant cells, however, due to the abundance of topoisomerase 2β in cardiomyocytes it affects their cell replication. Another mechanism of AIC is thought to be related to neuregulin-Erbβ (NRG), which disrupts downstream signalling regulation for cardiomyocyte survival. Studies have shown that anthracyclines reduce Erbβ4 expression in acute anthracycline exposure and increase Erbβ2 expression in chronic anthracycline exposure, which may partly explain mechanisms of early and late cardiotoxicity related to anthracyclines.⁹ As a result of known mechanisms of AIC, cumulative dose limitations have been put on anthracyclines to prevent this cardiac muscle damage.

Studies to alleviate the impact of AIC have examined multiple potential cardioprotective measures including dexrazoxane, co-enzyme Q10, L-carnitine, N-acetylcysteine, as well as liposomal anthracycline formulations and more prolonged anthracycline infusion times. Dexrazoxane has been the only agent with demonstrated consistent efficacy against AIC.

Lifestyle education remains a mainstay against modifiable risk factors for survivors of CAYA cancer for their ongoing sustained cardiovascular health.

Dexrazoxane

Dexrazoxane is currently the only approved pharmacological agent to prevent AIC. It is administered intravenously. Its mechanism of action is thought to work through dual function of inhibiting the reactive oxidative stress generation, as well as inhibiting the DNA topoisomerase II, which rapidly breaks down topoisomerase 2β.⁸

A Cochrane review in 2022,¹⁰ looked at dexrazoxane use in both adults and children. Five paediatric randomised controlled trials, with a total of 1,252 children and adolescents, were included with heterogeneous diagnoses (leukaemia, lymphoma, and solid tumours), all of whom received doxorubicin. The control groups received doxorubicin alone, while the intervention group received dexrazoxane alongside doxorubicin. The overall findings of these studies were a reduction in clinical heart failure and subclinical myocardial dysfunction combined with a RR of 0.33 (0.13–0.85). There was no difference in overall mortality nor tumour response rates.

Looking specifically at longer-term outcomes, a prospective multi-site study by Chow et al (JCO, 2023)¹⁸ looked at 195 participants with a mean time since doxorubicin-containing cancer treatment of 18.1 years. Half (50.8 per cent) of the group had received dexrazoxane alongside their doxorubicin. Over 70 per cent of both groups had received a cumulative equivalent dose of doxorubicin >250mg/m². The study showed those who received dexrazoxane alongside their anthracycline chemotherapy had better left ventricular systolic function and lower blood biomarker levels (troponin-T, BNP, NT-proBNP) of myocardial stress compared with those who did not receive it. This study demonstrates the sustained impact on minimising long-term toxicity in this group.

Despite the known benefits, dexrazoxane is associated with adverse effects including the risk of myelotoxicity, transient increase in liver enzymes and the risk of secondary malignant neoplasms (SMNs).¹¹ In 2011, the European Medicines Agency (EMA) contraindicated the use of dexrazoxane in children, awaiting further evidence and support for use in the paediatric population.¹² Some studies have shown an increase in SMNs,¹³ while others have refuted this claim.^14,15 Systematic reviews by Cochrane have demonstrated no increase in SMNs.

Dexrazoxane in current practice

Due to the EMA change in licensing, European institutions have been slower to adopt ubiquitous dexrazoxane use with doxorubicin. The contraindications for dexrazoxane were changed by the EMA in 2017.¹² Current EMA labelling allows for use of dexrazoxane in paediatric patients with high cumulative anthracycline doses (usually >300mg/m² doxorubicin or equivalent anthracycline dose such as in osteosarcoma and Ewing sarcoma). However, use remains institution dependent and it typically remains an option in protocols in Europe. In the Children’s Oncology Group in North America, adoption of dexrazoxane in protocols have been more widespread with a number of protocols – P9754 for osteosarcoma, POG9404 for leukaemia, and AEWS1031 for Ewing sarcoma – incorporating it as standard of care.

Long-term surveillance

Cardiovascular complications are the second leading cause of death in paediatric cancer survivors, second only to secondary malignancies. Cardiomyopathy, arrhythmias, pericardial disease and valvular heart disease can occur typically following high doses of anthracyclines and/or a radiotherapy field exposing the heart. Cardiac dysfunction can be symptomatic with features of heart failure or asymptomatic cardiac dysfunction found on imaging. PanCare, the European group for survivorship in paediatric cancer, has recommended surveillance strategies for at-risk patients, which include a cardiac history, physical examination, and ECG at entry to long-term follow-up care and an echo every two to five years, depending on cumulative anthracycline dose and radiotherapy exposure.¹⁶

Any female patients who have had a total cumulative dose >100mg/m² of anthracycline are recommended to have an echo in the first trimester and should have regular echos throughout pregnancy if there is any history of left ventricular systolic dysfunction, even with normal baseline ejection fraction in the first trimester. Alongside this cardiovascular surveillance, patients should be screened and educated on modifiable cardiovascular risk factors.

ACE inhibitors and beta blockers have demonstrated efficacy in AIC,¹⁰ and should be initiated as early as possible if a reduction in ejection fraction is seen with concern for AIC, as there is demonstrated benefit in overall outcomes.^6,17

Conclusion

At present, dexrazoxane is our only known agent to prevent AIC in CAYA with cancer. As our survival rates increase, we must seek to minimise late toxicities, particularly in cardiovascular compromise which remains the second leading cause of death. Further studies with dexrazoxane are needed to strengthen the evidence-base. Alongside prevention, long-term follow-up strategies, early initiation of treatment, and lifestyle modification is essential to maximising cardiovascular outcomes in CAYA cancer survivors.

References

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16. PanCare Guidelines Group. Recommendations for long-term follow-up care of childhood, adolescent, and young adult cancer survivors. 2024. Available at: www.pancare.eu/wp-content/uploads/2025/02/Updated-PanCareFollowUp-Recommendations-for-long-term-follow-up-April-2024_Final-3.0.pdf 

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18. Chow EJ, et al. Dexrazoxane and long-term heart function in survivors of childhood cancer. J Clin Oncol. 2023 Apr 20;41(12):2248–2257