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Cardioprotection and Prevention Strategies for the primary prevention of CTC range from modified dosing strategies to alternative anthracycline formulations to use of medications thought to prevent myocardial damage Close monitoring during therapy may afford a chance to start therapy when issues arise as opposed to after the fact Secondary prevention (i.e., once measurable CTC has developed) generally follows standard therapies for cardiovascular disease Alternate Dosing Schedules and Anthracycline Derivatives The effects of dosing schedule and various anthracycline derivatives on development of CTC have been elegantly summarized in a systematic review by van Dalen et al.55 Anthracycline infusion duration of 6 hours or longer reduced the risk of developing subclinical cardiac injury or heart failure, and liposomalencapsulated doxorubicin had a favorable profile regarding the development of CTC when compared with standard doxorubicin; however, there was no protective benefit with lower peak doses of anthracycline The review of dosing schedule included pediatric studies,56–59 although the majority were adult, whereas that in anthracycline derivatives did not include any pediatric reports Therefore caution must be taken in applying conclusions to pediatric populations Dexrazoxane Dexrazoxane (Zinecard) is a derivative of EDTA and acts as a chelator of iron, decreasing the formation of superoxide free radicals and preventing the action of anthracyclines on topoisomerase 2β (see Fig 62.2) Dexrazoxane was first approved by the Food and Drug Administration (United States) for prevention of CTC associated with doxorubicin in breast cancer patients in 1991, and in 2014 it was designated an orphan drug for prevention of CTC in children and adolescents (age 0 to 16 years) treated with anthracyclines The use of dexrazoxane to prevent CTC in children has been reported in clinical trials as early as two decades ago.60 Several key studies illustrate the potentially protective effects of dexrazoxane, evidenced by reduced elevations in troponin, natriuretic peptides, and ventricular remodeling without negatively impacting long-term survival.34,36,37 However, despite the evidence for cardioprotection, dexrazoxane is used in only 2% to 2.5% of pediatric patients with acute lymphoblastic and myeloid leukemia.61 Concerns over impact on the treatment effect of anthracyclines and risk of secondary malignancies may be limiting its use, although registry studies have argued against these claims in patients with a variety of childhood cancers.62–64 This is not to say there should be universal use of the agent because a meta-analysis indicated that the balance of risk for CTC versus secondary malignant neoplasms should be considered in making the decision.65 Other Medical Therapies and Interventions Common cardiovascular medications have demonstrated protection against CTC in adults Angiotensin-converting enzyme (ACE) inhibitors,66 β-blockers,66,67 and HMG-CoA reductase inhibitors (statins) all show some benefit.68 Data in pediatric and adolescent patients are more limited and less convincing In survivors of pediatric cancer placed on an ACE inhibitor, echocardiographic indices were initially preserved but the benefit was lost after 6 years on therapy.69 This may be due to later initiation of the medications Wall stress was reduced in patients treated with ACE inhibitor for 5 years, although without any other functional benefit.70 In a small study of patients with acute lymphoblastic leukemia receiving anthracyclines, pretreatment with a β-blocker preserved echocardiographic indices and serum cardiac troponin concentrations were not increased.71 Currently, a study is ongoing to assess the effect of the β-blocker carvedilol in preventing development of left ventricular dysfunction in survivors of childhood cancer.72 There are no data on the cardioprotective effect of statins in children In addition to pharmacologic methods of cardioprotection, there is evidence in animal models that aerobic exercise can mitigate the cardiovascular effects of cancer therapies when used before, during, or after therapy Several mechanisms for this benefit have been proposed, but overall the pathways remain unlcear.73 In patients, the benefits of exercise include improvement in cardiovascular function, body composition, immune function, chemotherapy completion rates, muscle strength and flexibility, and mood; and reduction in medication side effects, stress, and anxiety.16 Activity Restrictions and Modifiable Risk Factors Guidelines from the COG include the need to counsel cancer survivors regarding diet and exercise and that they may be at higher risk from modifiable cardiovascular risk factors.74 Aerobic exercise is considered safe in most cases and should be encouraged Intensive isometric activities should be avoided, while higher-repetition, lighter-weight exercises are considered more likely to be safe For patients who wish to engage in competitive sports, ongoing monitoring with a cardiologist is recommended In patients who have demonstrable CTC, standard guidelines for activity restriction should be followed.75 ... and HMG-CoA reductase inhibitors (statins) all show some benefit.68 Data in pediatric and adolescent patients are more limited and less convincing In survivors of pediatric cancer placed on an ACE inhibitor, echocardiographic... long-term survival.34,36,37 However, despite the evidence for cardioprotection, dexrazoxane is used in only 2% to 2.5% of pediatric patients with acute lymphoblastic and myeloid leukemia.61 Concerns over impact on the treatment