Andersons pediatric cardiology 1692
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FIG.62.1 Anthracycline-associatedacutecancertreatment-related
cardiotoxicity.Echocardiogramafterasingledoseofdoxorubicin(60
mg/m2),includingpretreatmentwithdexrazoxane,in13-year-oldpatient
diagnosedwithanaplasticlargecelllymphoma.Ventricularfunctionwas
normal2weeksprior.Theparasternalshortviewshowshypokinesisinthe
anteriorleftventricularwallwhencomparingdiastole(A)andsystole(B).
Theapicalfour-chamberviewshowsminimalchangeinventricular
dimensionbetweendiastole(C)andsystole(D).Thereisalsoapericardial
effusionpresent.AlsoseeVideos62.1and62.2.(CourtesyDr.Callie
Rzasa.)
MechanismsofCancerTreatment–Related
Cardiotoxicity
Amongtheagentsfoundtocausecardiotoxiceffectsare:anthracyclines,
antimetabolites(e.g.,5-fluorouracil,methotrexate),antimicrotubuleagents(e.g.,
paclitaxel),alkylatingagents(e.g.,cyclophosphamide,busulfan),small
molecules(e.g.,sorafenib),monoclonalantibodies(e.g.,trastuzamab,
rituximab),interleukins,andothermiscellaneousagentsusedlessfrequently.8
Successfulpediatriccancertreatmentrequiresarisk-adapted,multimodal
approach.Specifictherapyregimenchoicesaredeterminedbythepatient's
specificmoleculardiagnosis,clinicalfeatures,siteofdisease,andrisk
determinants(e.g.,stage,grade)(seeTable62.1).Thepreponderanceofdata
pertainingtomechanismhavebeengeneratedinrelationtotheanthracyclines.A
numberofwidelydisparatepathwaysareinvolved,includingmitochondrial
DNAdamage,apoptosisfromgenerationofreactiveoxygenspecies,and
damagetonuclearDNAthroughdirectinteractionofanthracyclineson
topoisomerase2β(Fig.62.2).8–11Overtimethe“safe”thresholdfor
anthracyclineexposurehassteadilydecreased,withstudiesdemonstrating
structuralchangesdetectablebyechocardiographyevenaftersingle
treatments.12,13However,thecurrentgenerallyaccepteddefinitionoflowversushigh-doseanthracyclineexposureis250mg/m2doxorubicinequivalent.
FIG.62.2 Mechanismofanthracycline-inducedcardiotoxicity.
Anthracyclines(A)interactdirectlywithtopoisomerase2β,disruptingits
normalfunctionandinducingbreaksinDNA.Thisleadstodefectsin
mitochondriaandincreaseinproductionofreactiveoxygenspecies(ROS).
Inset,Dexrazoxane(D)exertingaprotectiveeffectbyblockingthebinding
ofanthracyclinetotopoisomerase2β.(FromVejpongsaP,YehET.
Preventionofanthracycline-inducedcardiotoxicity:challengesand
opportunities.JAmCollCardiol.2014;64[9]:938–945.)
RadiationtherapyalsoposesincreasedriskforCTC,accountingforinjuryto
thepericardium,coronaryarteries,conductionpathways,andthemyocardium—
oftenmanifestasdiastolicdysfunction.5Similartoanthracyclines,thereisadose
dependenceofinjury;however,thisseemsmostlytoaffecttimingof
manifestation,andithasnotbeenestablishedwhetherthereisalowerlimit
belowwhichinjurydoesnotoccur.14Mechanismsofinjuryincludeinductionof
proinflammatorycascades,endothelialinjury,generationoffibrosis,and
initiationofoxidativestress.5,14
PatientandTreatmentRiskFactors
ThemajorityofinformationondevelopmentofCTCinchildrencomesfrom
studiesonadultlong-termsurvivorsofpediatriccancers.TheChildhoodCancer
SurvivorStudy(CCSS),acohortofmorethan35,000survivorsofchildhood
cancerand5000siblingcontrols,hasbeenawealthofinformationinthisregard.
BasedontheCCSSandotherstudies,patient-andtreatment-relatedriskfactors
havebeenidentified(Box62.1).4,5,15,16Patientfactorsincludeyoungerage,
femalegender,African-Americanrace,andunderlyingheartdisease.Someof
thestrongesttreatmentfactorsaretotalanthracyclinedose,concomitant
radiationexposure,andtimesincetherapy.DatafromtheCCSSreportthat
survivorsofchildhoodcancerarefivetosixtimesmorelikelythancontrolsto
developcongestiveheartfailure,pericardialdisease,myocardialinfarction,or
valvarabnormalities(Fig.62.3).4Theincidenceofsymptomaticheartfailureis
ashighas12%inpatientswithmultipleriskfactorsandreceivinghigherdose
anthracyclines.17Whencardiomyopathyisdefinedasleftventricularejection
fraction(EF)lessthan50%,7.5%ofallsurvivorsareaffectedwithmostbeing
asymptomatic.18
Box62.1
PatientandTreatmentRiskFactorsinthe
