Chemotherapy-induced cardiotoxicity in children

ABSTRACT

Introduction: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents.

Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology.

Expert opinion: There is no ‘safe’ anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.

KEYWORDS:

• Childhood cancer
• anthracycline
• cardiotoxicity
• survivorship
• cardio-oncology

Article highlights

• The number of survivors of childhood cancers has increased exponentially; survivors are at substantially increased long-term risk of morbidity and mortality from treatment-related cardiotoxicity

• There is no ‘safe’ dose of anthracycline but higher lifetime cumulative doses of anthracyclines, higher dose rates, younger age at treatment, longer follow-up after treatment, female sex, and cardiac irradiation are associated with more severe cardiotoxicity.

• There is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications.

• Treatment-related cardiac damage is progressive and often difficult to reverse.

• The key points in management of these toxicities are: mitigation by primary prevention and then effective management of the toxicity, which has already occurred, in order to minimize ongoing morbidity.

• With deeper understanding of the mechanisms of the adverse cardiac effects and identifications of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects may be achieved.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The contents in this review chapter were supported in part by grants from the National Institutes of Health (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, HD52102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, and HD80002), the National Heart, Lung, and Blood Institute (R01 HL53392, R01 HL111459, R01 HL109090), the Children’s Cardiomyopathy Foundation, the Women’s Cancer Association, the Lance Armstrong Foundation, the STOP Children’s Cancer Foundation, the Parker Family Foundation, the Scott Howard Fund, the Michael Garil Fund, Sofia’s Hope, the Kyle John Rymiszewski Foundation.