Abstract

HomeCirculationVol. 128, No. 17Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLong-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research DirectionsA Scientific Statement From the American Heart Association Steven E. Lipshultz, MD, FAHA, M. Jacob Adams, MD, MPH, Steven D. Colan, MD, FAHA, Louis S. Constine, MD, Eugene H. Herman, PhD, Daphne T. Hsu, MD, FAHA, Melissa M. Hudson, MD, Leontien C. Kremer, MD, PhD, David C. Landy, PhD, Tracie L. Miller, MD, Kevin C. Oeffinger, MD, David N. Rosenthal, MD, Craig A. Sable, MD, FAHA, Stephen E. Sallan, MD, Gautam K. Singh, MD, Julia Steinberger, MD, MS, FAHA, Thomas R. Cochran, BA and James D. Wilkinson, MD, MPH Steven E. LipshultzSteven E. Lipshultz Search for more papers by this author , M. Jacob AdamsM. Jacob Adams Search for more papers by this author , Steven D. ColanSteven D. Colan Search for more papers by this author , Louis S. ConstineLouis S. Constine Search for more papers by this author , Eugene H. HermanEugene H. Herman Search for more papers by this author , Daphne T. HsuDaphne T. Hsu Search for more papers by this author , Melissa M. HudsonMelissa M. Hudson Search for more papers by this author , Leontien C. KremerLeontien C. Kremer Search for more papers by this author , David C. LandyDavid C. Landy Search for more papers by this author , Tracie L. MillerTracie L. Miller Search for more papers by this author , Kevin C. OeffingerKevin C. Oeffinger Search for more papers by this author , David N. RosenthalDavid N. Rosenthal Search for more papers by this author , Craig A. SableCraig A. Sable Search for more papers by this author , Stephen E. SallanStephen E. Sallan Search for more papers by this author , Gautam K. SinghGautam K. Singh Search for more papers by this author , Julia SteinbergerJulia Steinberger Search for more papers by this author , Thomas R. CochranThomas R. Cochran Search for more papers by this author and James D. WilkinsonJames D. Wilkinson Search for more papers by this author Search for more papers by this author and on behalf of the American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Basic Cardiovascular Sciences, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity and Metabolism Originally published30 Sep 2013https://doi.org/10.1161/CIR.0b013e3182a88099Circulation. 2013;128:1927–1995is corrected byCorrectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes other than recurrence (eg, second malignancies, cardiac and pulmonary disease) exceeded that from recurrence or progression of the original cancer, and these other causes did not plateau with time.7,8 These findings have been confirmed in other large cohort studies and among survivors treated with more current therapy.9–15Early in the study of late effects after cancer therapy, the developing cardiovascular system of children and adolescents was recognized as being particularly vulnerable.15a In the proceedings of the first National Cancer Institute’s Conference on the Delayed Consequences of Cancer Therapy in 1975, Gilladoga et al16 reported that 9 of 110 children receiving a cumulative dose of either doxorubicin or daunorubicin >500 mg/m2 experienced severe cardiomyopathy with congestive heart failure (CHF) while undergoing therapy or soon thereafter. Not long afterward, Brosius et al17 described the necropsy findings of 16 cancer survivors diagnosed in childhood or young adulthood who had received >35 Gy of cardiac radiation. All had evidence of radiation-induced cardiac damage, and 6 had at least 1 coronary artery with severe stenosis. Since these early studies, the incidence and risk factors of cardiovascular disease (CVD) have been studied intensely, as described in the present article. Indeed, cardiac-specific disease is the most common noncancer cause of death among long-term childhood cancer survivors.7,8,11These investigations, which linked specific treatment and host factors to adverse outcomes, have guided pediatric cancer treatments and health monitoring during and after therapy. For example, in the aforementioned 1975 proceedings, Gilladoga and colleagues16 recommended maximum cumulative anthracycline doses of 500 and 600 mg/m2 in children treated with or without cardiac radiation, respectively. Subsequently, newer protocols have sought to balance the benefits of treatment with the risk of anthracycline-related cardiomyopathy by testing lower cumulative doses18 and alternative dosing schedules and methods of administration,19,20 as well as by adding potentially cardioprotective agents.21–23 Similarly, to reduce the risk of cardiac disease and second malignant neoplasms (eg, breast cancer), the use, dose, and volume of radiation to the heart has decreased substantially in frontline trials for children with hematological and low-stage, biologically favorable solid malignancies.Current therapy for childhood malignancies has evolved into a risk-adapted approach that bases the intensity of therapy on clinical, biological, and genetic factors and on treatment response (Table 1). Most pediatric cancer protocols still rely on cytotoxic chemotherapy and radiation, with few integrating new biological and molecularly targeted agents.18 Research establishing dose-related toxicity profiles for specific chemotherapeutic agents (eg, anthracyclines; alkylating agents) and radiation has guided their risk-adapted use in current protocols. The universal objective of all pediatric cancer trials is to prescribe treatments at cumulative doses that balance cancer control with preserved health and function of normal tissues.Table 1. Trends in the Use of Cardiotoxic Treatment Modalities for Common Childhood CancersHistologyAnthracycline ChemotherapyCardiac RadiationAcute lymphoblastic leukemiaFrequency: 18.7%• Increased use of anthracyclines in high-risk patients since 1970s, with cumulative doses ranging from 45 mg/m2 (low risk) to 350 mg/m2 (high risk)• Introduction of craniospinal irradiation to treat and prevent CNS leukemia in 1960s–1970s• Increasing use of cranial irradiation (18–24 Gy) and intrathecal + high-dose chemotherapy for CNS-directed therapy in 1970s• Decline in use of craniospinal radiation for CNS-directed therapy since 1970s and now limited to cases of relapseAcute myeloid leukemiaFrequency: 4.5%• Introduction of anthracyclines into remission induction regimens in 1970s• Not applicable• Escalation of anthracycline doses (320–450 mg/m2) in 1990sHodgkin lymphomaFrequency: 8.8%• Introduction of anthracyclines in ABVD combination in 1970s (6–8 cycles, 300–400 mg/m2)• Introduction of extended-field high-dose (35–44 Gy) mantle/mediastinal irradiation in 1960s• Introduction of risk-adapted regimens in 1980s restricting anthracycline dose to ≤200 mg/m2 for low-risk and ≤300 mg/m2 for high-risk disease presentations• Introduction of involved-field low-dose (15–25.5 Gy) mantle/mediastinal irradiation in pediatric combined-modality regimens in 1970s• Selected use of radiation in 2000s for favorable and intermediate- or high-risk patients achieving complete remission to chemotherapyNon-Hodgkin lymphomaFrequency: 6.7%• Use of anthracyclines for all histological subtypes since 1960s with dose ranging from 120 to 300 mg/m2 based on stage and histology• Variable use of radiation to involved nodes from 1960s to 1980s• Use of cranial irradiation for CNS prophylaxis from 1970s to 1990s• Selected use of involved-field irradiation therapy for cases with relapsed/refractory diseaseCNS tumorsFrequency: 16.7%• Not applicable• Use of craniospinal irradiation therapy as standard of care for specific histological subtypes (eg, medulloblastoma) since 1960s• Use of cranial irradiation for most brain tumors, with only indirect impact on cardiovascular disease risk via neuroendocrine effectsNeuroblastomaFrequency: 5.1%• Use of doxorubicin in combination chemotherapy regimens since 1970s (105–175 mg/m2)• Use of radiation for localized and regional disease (20–40 Gy) from 1960s to 1990s• Escalation of doxorubicin dose (300 mg/m2) in selected trials for high-risk disease• Use of local radiation to high-risk primary site even for resected disease; no RT to low-risk disease after 1990sWilms tumorFrequency: 4.2%• Introduction of doxorubicin (300 mg/m2) into combination chemotherapy regimens in 1970s• Use of age-based radiation (18–40 Gy) to whole abdomen and flank in 1970s• Use of doxorubicin limited to advanced-stage disease since 1980s and dose reduced to 150 mg/m2• Reduction of flank or whole abdominal radiation dose to 20 Gy in 1980s and limited to advanced stage• Reduction of flank or whole abdominal radiation dose to 10.8 Gy in 1990s for advanced stage• Use of whole lung radiation (15 Gy) to pulmonary metastatic disease since 1960s; reduction of dose to 12 Gy in 1980sRhabdomyosarcomaFrequency: 2.9%• Introduction of doxorubicin into combination chemotherapy regimens in 1970s• Whole lung radiation (18 Gy) to pulmonary metastatic disease from 1970s to 1980s• Use of doxorubicin limited to high-risk patients in selected contemporary regimens (375 mg/m2)• Reduction of whole lung radiation to 14.4 Gy for pulmonary metastatic disease in 1990s• Standard use of whole lung radiation dose of 15 Gy for pulmonary metastatic disease since 2000sOsteosarcomaFrequency: 3.1%• Use of doxorubicin (450 mg/m2) in combination chemotherapy regimens since 1970s• Not applicableEwing sarcomaFrequency: 1.9%• Use of doxorubicin (375 mg/m2) in combination chemotherapy regimens since 1970s• Use of whole lung radiation (15–18 Gy) for pulmonary and 15 Gy for pleural involvement (or effusion)• Use of up to 55 Gy for mediastinal, chest wall, or rib involvementFrequencies noted represent percent distribution of childhood cancers by ICCC category for age group <20 years, all races, both sexes, SEER, 1975–1995.24ABVD indicates chemotherapy regimen of Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine; CNS, central nervous system; ICCC, International Classification of Childhood Cancer; RT, radiation therapy; and SEER, Surveillance, Epidemiology, and End Results.Although some adverse effects of cytotoxic therapy may be unavoidable, the evolution of pediatric cancer treatments has already changed the prevalence and spectrum of adverse treatment effects. Because threshold doses for vital organ toxicity have been recognized, acute life-threatening treatment effects are relatively uncommon after current therapy, except in survivors who require intensive multimodal therapy for aggressive and refractory or relapsed malignancies. However, life-altering toxicities affecting endocrine, reproductive, musculoskeletal, and neurological function still occur after specific treatments (eg, infertility after high-dose alkylating agent chemotherapy or gonadal radiation). Of increasing concern are the subclinical changes observed after cancer treatment that may contribute to the premature onset of common diseases associated with aging, such as obesity,25,26 diabetes mellitus,27 CVD,28–30 hypertension,31–33 and cancer.34,35 These data underscore the need for research to evaluate the impact of aging and health behaviors on health outcomes of adults treated for cancer during childhood.This scientific statement is targeted to pediatric oncologists, general pediatricians, adolescent and young adult specialists and practitioners, as well as the number of other healthcare providers who may care for survivors of childhood cancer.Pathophysiology of Cardiovascular ToxicityPathophysiology of Cardiovascular Toxicity From Chemotherapeutic AgentsAnticancer drugs are designed to interfere with rapidly dividing neoplastic cells; however, these same drugs can also have adverse effects on multiple organs and normal tissues. The most frequently reported toxicities occur in tissues composed of rapidly dividing cells, the capacity of which for recovery tends to minimize long-term consequences. In contrast, the cardiovascular system consists of many cells that have limited regenerative capability, a consequence of which is the potential for increased susceptibility to long-term adverse effects from chemotherapeutic agents. In the cardiovascular system, chemotherapeutic agents may cause adverse effects by directly compromising myocardial function or peripherally by changing vascular hemodynamics. These adverse effects may be predictable or unpredictable, set or cumulative, and potentiated or ameliorated by the use of concomitant antineoplastic agents. However, it is not always possible to predict drug toxicity in children from adult clinical experience.36Anthracyclines, such as doxorubicin, are frequently used to treat the most common form of cancer in children, ALL. Anthracyclines are among the most notorious chemotherapeutic agents that cause cardiotoxicity in both adult-onset and childhood malignancies. Except for anthracyclines, the use of chemotherapeutic agents and reports of associated cardiotoxic events are less extensive in children than in adults. Examples of nonanthracycline agents used in adult and pediatric populations that have been associated with cardiotoxicity include cyclophosphamide, cytarabine, cisplatin, and ifosfamide (Table 2).37,38 Other compounds (paclitaxel, 5-fluorouracil [5-FU], and amsacrine), also reported to induce cardiotoxicity in adults, have been used infrequently as first-line agents to treat pediatric tumors.37 Children are also being treated with newer types of antineoplastic compounds (tyrosine kinase inhibitors), some of which have been reported to cause cardiotoxic activity in adult patients.39 In children, cardiac toxicity can be an important complication both during and after cancer treatment. Clinically, cardiac toxicity is an important issue because many children responding to treatment may subsequently experience acute or chronic cardiovascular adverse effects that could impact their quality of life, as well as limit future treatment options.Table 2. Examples of Pediatric Chemotherapeutic Agents Associated With CardiotoxicityAdverse EffectClass/CompoundPathogenesisBradycardiaTaxanes/paclitaxelHypersensitivityArrhythmias/QT prolongationAmsacrineAnthracyclines (doxorubicin)Sunitinib Anthracyclines (doxorubicin)Interference with HERG currentsInhibition of cardiac kinasesInterference of ion channelsMyocardial ischemiaAntimetabolites/5-fluorouracilCoronary vasospasmLeft ventricular dysfunction/CHFAnthracyclines (doxorubicin)Tyrosine kinase inhibitors (imatinib/sunitinib)Alkylating agents (cyclophosphamide/ifosfamide)CisplatinOxidative stressInhibition of Abl kinase mitochondrial dysfunctionVascular endothelial cell injuryHypomagnesia, coronary artery fibrosisCHF indicates congestive heart failure; and HERG, human ether-a-go-go related.The types of chemotherapy-induced cardiovascular alterations reported primarily, but not exclusively, in adults include the following: Acute cardiac rhythm abnormalities (arrhythmias including QT prolongation), myocardial ischemia or infarction, hypertension, and significant left ventricular (LV) contractile dysfunction.37,38 The pathogenesis of these diverse cardiovascular effects varies and may involve multiple mechanisms.Cardiovascular Alterations Induced by Chemotherapeutic AgentsBradycardiaIn adults, both paclitaxel and thalidomide cause reversible sinus bradycardia, with an incidence ranging from 0.1% to 31% and from 5% to 55%, respectively.40–43 Paclitaxel has been used to treat breast and ovarian cancer in adults and has been suggested for use in children.38 Paclitaxel may induce bradycardia directly through actions on the Purkinje system or indirectly through its formulation vehicle, Cremophor EL (polyoxyethylated castor oil). When used in combination, paclitaxel appears to enhance doxorubicin cardiotoxicity by altering doxorubicin pharmacokinetics and increasing the myocyte formation of doxorubicinol, the major metabolite of doxorubicin.44 Although paclitaxel has been found to be ineffective in children, new taxanes such as cabazitaxel require further investigation to determine their effect on children.Thalidomide is infrequently used in pediatric cancer treatment. The mechanism that reduces heart rate with thalidomide treatment has not been determined. The effect could be the result of central sedative actions or enhanced vasovagal activity.42 Thalidomide may also cause deep venous thrombosis, edema, and pulmonary hypertension.45 Further pediatric clinical trials are needed to determine the mechanism and efficacy of thalidomide.Arrhythmias and QT Interval ProlongationAmsacrine.Two acute forms of cardiotoxicity have been associated with amsacrine therapy in adults and children.38,46,47 The more common toxicities are arrhythmias (atrial and ventricular tachycardia) and ECG alterations (prolonged QT intervals and nonspecific ST-segment and T-wave changes) that occur within minutes to hours after treatment.47 Both types of cardiac alterations have been observed in children treated with amsacrine.46,47 It is possible that the cardiotoxic potential of amsacrine may be enhanced by prior exposure to anthracyclines.46,47 Amsacrine is not frequently used in children.Arsenic Trioxide.Prolonged QT intervals (a potential precursor to serious arrhythmias, such as torsade de pointes and ventricular fibrillation) has been reported in adults undergoing therapy with arsenic trioxide, with an incidence ranging from 26% to 93%.48 The QT interval returned to normal 8 weeks after arsenic trioxide treatment.48 Arsenic trioxide is highly efficacious in treatment of both newly diagnosed and relapsed acute promyelocytic leukemia; however, a number of studies describe the occurrence of cardiotoxicity when this drug is used in children.49–52Tyrosine Kinase Inhibitors.Tyrosine kinase inhibitors such as dasatinib, lapatinib, imatinib, and nilotinib have been implicated in prolonging the QT interval in adults, with an incidence of 1% to 10%.43 These drugs are commonly used for chronic myelogenous leukemia and ALL. Uses of tyrosine kinase inhibitors in pediatric oncology are still limited; however, Dubois et al53 reported QT-interval prolongation in 2 of 23 children treated with sunitinib in a phase 1 study of refractory solid tumors.The mechanism and the structural characteristics of drugs most likely to change the duration of the QT interval have not been determined completely. The QT interval is presumed to increase when HERG (human ether-a-go-go) potassium channel activity (delayed rectifier potassium current) is altered. By interfering with these channels, drugs slow potassium ion entry into the myocyte and thereby prolong repolarization.54 Additional mechanisms may also be involved, because not all drugs that impede HERG potassium channel activity induce QT prolongation. Both adults and children with cancer may be more susceptible to QT prolongation because of comorbid conditions, disease-related electrolyte disturbances, or concomitant treatment with potentially proarrhythmic medications.Anthracyclines.Anthracyclines, such as doxorubicin, daunorubicin, epirubicin, and idarubicin, have been associated with prolonged corrected QT (QTc) intervals as measured by surface electrocardiography, a finding that indicates a risk of ventricular tachycardia.55,56 They have also been directly associated with premature ventricular contractions, sinus node dysfunction, ventricular late potentials, and decreased QRS voltage. The incidence of these findings ranges from 10% to 30%.55,57,58 The mechanism of the electrophysiological cardiotoxicity is unknown, although the efficacy of dexrazoxane in attenuating this injury suggests that the toxicity may be mediated through free radicals. Acute changes that occur during infusion therapy range from fatal ventricular arrhythmias to minor abnormalities. Some patients at higher cumulative doses have permanent damage, whereas most others recover, at least temporarily. Cumulative toxicity is generally a result of damage such as cardiomyocyte death and dysfunction caused during therapy but that is not serious enough to cause symptoms immediately.In most instances, arrhythmias associated with anthracyclines are transient and do not require specific intervention. However, Kilickap et al58 reported serious consequences in a patient with syncope and complete heart block who required pacemaker implantation during anthracycline therapy at only modest doses (cumulative dose of 120 mg/m2). This response has also been described for epirubicin, which is thought to have a more favorable cardiovascular toxicity profile.59 Pirarubicin, when evaluated in adults with non-Hodgkin lymphoma, was marginally less cardiotoxic than doxorubicin, with the risk of arrhythmia being 9% versus 14%, respectively.60 However, in that same study, both agents were associated with a similar risk of ischemic cardiac injury.The relationship between myocyte dysfunction and arrhythmogenesis in cancer cardiotoxicity is not completely determined; however, an investigation by Nakamae et al61 of 72 adults receiving anthracycline therapy suggests a link between these problems. In that study, the QTc interval during anthracycline therapy correlated moderately well with the degree of LV enlargement (r=0.43) and even more strongly with ejection fraction (r=−0.46), the negative correlation indicating that the reduction in ejection fraction was associated with longer QTc intervals. Interestingly, the QTc interval was not associated with LV diastolic function, which some investigators believe to be the first step in myocardial injury after anthracycline administration. A 1981 case report describes sudden cardiac death in a patient who had received a high cumulative dose of doxorubicin (490 mg/m2) ≈8 months before and who had no evidence of CHF or history of arrhythmia.62 There was postmortem evidence of cardiac fibrosis and hypertrophy, so perhaps the absence of recognized clinical heart failure did not exclude marked myocardial dysfunction at the time of the (presumed) arrhythmic death.Other cancer therapies have been associated with a variety of electrophysiological disorders that arise during therapy. Mitoxantrone can cause arrhythmia during infusion (in conjunction with myocarditis), and 5-FU may cause ischemic changes in addition to prolonging the QTc interval.55,56 Preexisting coronary artery disease (CAD) and chest radiation are risk factors for 5-FU toxicity.38 Newer agents used mainly in adults are also proving to have marked cardiotoxicity, including arrhythmogenesis. The tyrosine kinase inhibitors (eg, imatinib and sunitinib) prolong the QT interval, as do protein kinase C inhibitors.55,63 The mechanism is unknown, but the effect is great and is often dose-limiting. Additionally, the cardiotoxicity of trastuzumab, a monoclonal antibody that acts through the HER2 receptor, is potentiated by coadministration of anthracyclines. The cardiotoxicity is typically expressed as reversible myocardial dysfunction but may manifest as conduction block and ischemia, as described in a recent case report.64Myocardial IschemiaThe chemotherapeutic drugs noted below can cause ischemia in localized areas of the myocardium or a coronary artery syndrome.Antimetabolites (5-FU and Capecitabine).An ischemic syndrome (symptoms vary from angina pectoris to acute myocardial infarction [MI]) has been reported in up to 68% of adults after treatment with 5-FU.65 Signs of ischemia were observed within 2 to 5 days after patients began treatment and persisted for up to 48 hours after treatment.65 The risk of ischemia appears to be greater in patients with preexisting CAD. The incidence of ischemic events was also increased in patients whose treatment regimens included high doses of 5-FU administered with or without continuous infusion.43 5-FU is not commonly used to treat pediatric tumors; however, 2 separate pediatric case reports describe cardiotoxic activity after exposure to 5-FU. In 1 case, the combination of 5-FU with cisplatin and methotrexate caused severe but reversible cardiotoxicity characterized by tachycardia, hypotension, and reduced LV contractility in a 14-year-old boy.66 The second case was also a 14-year-old patient in whom acute dilated cardiomyopathy developed after 1 cycle of 5-FU and cisplatin therapy. This patient stabilized but died suddenly during the fifth treatment cycle (possibly of arrhythmia).67Capecitabine, a derivative of 5-FU, appears to cause a similar but less frequent incidence of ischemic toxicity in 3% to 9% of patients.68 The mechanisms responsible for 5-FU– and capecitabine-induced myocardial ischemia are not delineated completely. Adverse effects, such as coronary artery spasm, direct myocyte injury, coronary thrombosis resulting from activated coagulation, and autoimmune responses, have all been proposed as possible causative factors.69 5-FU has also been reported to affect vascular endothelial function by decreasing nitric oxide synthase activity. This action can facilitate coronary vessel spasm and protein kinase C–mediated vasoconstriction.69Microtubule-Targeting Agents (Paclitaxel).In adults, paclitaxel occasionally causes myocardial ischemia and infarction.43 Coexisting factors, such as concomitant drug treatment and CAD, appear to increase the occurrence of this toxicity.43 The release of histamine by polyoxyethylated castor oil (the paclitaxel vehicle) may contribute to the onset of ischemia.43 Paclitaxel can also exert direct toxic effects on cardiac myocytes. A related compound, docetaxel, has also been reported to cause myocardial ischemia.68Monoclonal Antibody-Based Tyrosine Kinase Inhibitors (Bevacizumab).Vascular endothelial growth factor (VEGF) is highly expressed in solid tumors and is critical in modulating important cellular and vascular processes. Bevacizumab binds to and inhibits VEGF activity. This drug can promote arterial thrombotic activity, and in a few patients (3.8% in 1 study), it induces MI, angina, heart failure, stroke, and transient ischemic attacks (TIAs).70 These adverse effects were not dose related and occurred any time during treatment (median time, 3 months).70The increased risk of arterial thrombotic events is thought to be caused by disturbances in endothelial regeneration.71 The pathogenesis of bevacizumab-induced heart failure is probably multifactorial and likely involves hypertension, reduced capillary density, the presence of cardiac fibrosis, an overall decline in contractile function, or some combination of these factors.72 Further research is required to determine the mechanism and efficacy of bevacizumab in children.Small-Molecule Tyrosine Kinase Inhibitors (Sorafenib and Erlotinib).Sorafenib caused myocardial ischemia in 3% of patients in 1 study.73 This multikinase inhibitor targets VEGF receptors and other important kinase pathways. Sorafenib-induced ischemic cardiotoxic activity could result from VEGF receptor inhibition or decreased Raf kinase activity. Cardiac ischemia has also been noted after exposure to erlotinib.43 The incidence of myocardial ischemia or infarction was slig