Cardiotoxicity and Cardioprotection in Childhood Cancer

Abstract

Children diagnosed with cancer are now living longer as a result of advances in treatment. However, some commonly used anticancer drugs, although effective in curing cancer, can also cause adverse late effects. The cardiotoxic effects of anthracycline chemotherapy, such as doxorubicin, and radiation can cause persistent and progressive cardiovascular damage, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Examples of risk factors for cardiotoxicity in children include higher anthracycline cumulative dose, higher dose of radiation, younger age at diagnosis, female sex, trisomy 21 and black race. However, not all who are exposed to toxic treatments experience cardiotoxicity, suggesting the possibility of a genetic predisposition. Cardioprotective strategies under investigation include the use of dexrazoxane, which provides short- and long-term cardioprotection in children treated with doxorubicin without interfering with oncological efficacy, the use of less toxic anthracycline derivatives and nutritional supplements. Evidence-based monitoring and screening are needed to identify early signs of cardiotoxicity that have been validated as surrogates of subsequent clinically significant cardiovascular disease before the occurrence of cardiac damage, in patients who may be at higher risk.

Role of ACE inhibitors in anthracycline‐induced cardiotoxicity: A randomized, double‐blind, placebo‐controlled trial

“…The authors concluded that enalapril appeared efficacious in preserving systolic and diastolic functions . On the other hand, a small study conducted on childhood cancer survivors questioned whether or not use of ACE inhibitors improves the long‐term outcome of anthracycline‐induced cardiomyopathy . In that same study, improvements in echocardiographic parameters after enalapril initiation did not persist after 6 years of treatment.…”

“…Early identification of cardiotoxicity and the measures to reduce it have been an area of research in recent years. There are few studies that have shown a beneficial effect of the angiotensin converting enzyme (ACE) inhibitor enalapril in anthracycline‐induced cardiotoxicity, but these were not randomized controlled trials carried out exclusively in pediatric patients.…”

Cardioprotective effect of metformin against doxorubicin cardiotoxicity in rats

“…Thus, it is important to define cardiotoxic risk factors. Elevation of serum levels of cardiac troponin T ve NT Pro-BNP at the beginning of doxorubicin treatment was observed to predict clinical cardiotoxicity (20-22). …”

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

“…The exact mechanism of DOX-induced cardiotoxicity is not fully elucidated; however, oxidative stress, mitochondrial dysfunction, derailed molecular signaling, inflammation, and apoptotic cell death are believed to be important players [3]. Since cardiac dysfunction does not occur in every DOX-treated cancer patient, there is a growing interest in identifying risk factors that predispose some patients to DOX-induced cardiotoxicity [4, 5]. Several factors have been shown to increase the risk of DOX-induced cardiotoxicity including total cumulative dose, pre-existing cardiovascular disease, and combination treatment with other cardiotoxic chemotherapeutic agents such as trastuzumab [5].…”