Andersons pediatric cardiology 1695
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CardioprotectionandPrevention
StrategiesfortheprimarypreventionofCTCrangefrommodifieddosing
strategiestoalternativeanthracyclineformulationstouseofmedicationsthought
topreventmyocardialdamage.Closemonitoringduringtherapymayafforda
chancetostarttherapywhenissuesariseasopposedtoafterthefact.Secondary
prevention(i.e.,oncemeasurableCTChasdeveloped)generallyfollows
standardtherapiesforcardiovasculardisease.
AlternateDosingSchedulesandAnthracycline
Derivatives
Theeffectsofdosingscheduleandvariousanthracyclinederivativeson
developmentofCTChavebeenelegantlysummarizedinasystematicreviewby
vanDalenetal.55Anthracyclineinfusiondurationof6hoursorlongerreduced
theriskofdevelopingsubclinicalcardiacinjuryorheartfailure,andliposomalencapsulateddoxorubicinhadafavorableprofileregardingthedevelopmentof
CTCwhencomparedwithstandarddoxorubicin;however,therewasno
protectivebenefitwithlowerpeakdosesofanthracycline.Thereviewofdosing
scheduleincludedpediatricstudies,56–59althoughthemajoritywereadult,
whereasthatinanthracyclinederivativesdidnotincludeanypediatricreports.
Thereforecautionmustbetakeninapplyingconclusionstopediatric
populations.
Dexrazoxane
Dexrazoxane(Zinecard)isaderivativeofEDTAandactsasachelatorofiron,
decreasingtheformationofsuperoxidefreeradicalsandpreventingtheactionof
anthracyclinesontopoisomerase2β(seeFig.62.2).Dexrazoxanewasfirst
approvedbytheFoodandDrugAdministration(UnitedStates)forpreventionof
CTCassociatedwithdoxorubicininbreastcancerpatientsin1991,andin2014
itwasdesignatedanorphandrugforpreventionofCTCinchildrenand
adolescents(age0to16years)treatedwithanthracyclines.Theuseof
dexrazoxanetopreventCTCinchildrenhasbeenreportedinclinicaltrialsas
earlyastwodecadesago.60Severalkeystudiesillustratethepotentially
protectiveeffectsofdexrazoxane,evidencedbyreducedelevationsintroponin,
natriureticpeptides,andventricularremodelingwithoutnegativelyimpacting
long-termsurvival.34,36,37However,despitetheevidenceforcardioprotection,
dexrazoxaneisusedinonly2%to2.5%ofpediatricpatientswithacute
lymphoblasticandmyeloidleukemia.61Concernsoverimpactonthetreatment
effectofanthracyclinesandriskofsecondarymalignanciesmaybelimitingits
use,althoughregistrystudieshavearguedagainsttheseclaimsinpatientswitha
varietyofchildhoodcancers.62–64Thisisnottosaythereshouldbeuniversaluse
oftheagentbecauseameta-analysisindicatedthatthebalanceofriskforCTC
versussecondarymalignantneoplasmsshouldbeconsideredinmakingthe
decision.65
OtherMedicalTherapiesandInterventions
CommoncardiovascularmedicationshavedemonstratedprotectionagainstCTC
inadults.Angiotensin-convertingenzyme(ACE)inhibitors,66β-blockers,66,67
andHMG-CoAreductaseinhibitors(statins)allshowsomebenefit.68Datain
pediatricandadolescentpatientsaremorelimitedandlessconvincing.In
survivorsofpediatriccancerplacedonanACEinhibitor,echocardiographic
indiceswereinitiallypreservedbutthebenefitwaslostafter6yearson
therapy.69Thismaybeduetolaterinitiationofthemedications.Wallstresswas
reducedinpatientstreatedwithACEinhibitorfor5years,althoughwithoutany
otherfunctionalbenefit.70Inasmallstudyofpatientswithacutelymphoblastic
leukemiareceivinganthracyclines,pretreatmentwithaβ-blockerpreserved
echocardiographicindicesandserumcardiactroponinconcentrationswerenot
increased.71Currently,astudyisongoingtoassesstheeffectoftheβ-blocker
carvedilolinpreventingdevelopmentofleftventriculardysfunctioninsurvivors
ofchildhoodcancer.72Therearenodataonthecardioprotectiveeffectofstatins
inchildren.
Inadditiontopharmacologicmethodsofcardioprotection,thereisevidencein
animalmodelsthataerobicexercisecanmitigatethecardiovasculareffectsof
cancertherapieswhenusedbefore,during,oraftertherapy.Severalmechanisms
forthisbenefithavebeenproposed,butoverallthepathwaysremainunlcear.73
Inpatients,thebenefitsofexerciseincludeimprovementincardiovascular
function,bodycomposition,immunefunction,chemotherapycompletionrates,
musclestrengthandflexibility,andmood;andreductioninmedicationside
effects,stress,andanxiety.16
ActivityRestrictionsandModifiableRiskFactors
GuidelinesfromtheCOGincludetheneedtocounselcancersurvivorsregarding
dietandexerciseandthattheymaybeathigherriskfrommodifiable
cardiovascularriskfactors.74Aerobicexerciseisconsideredsafeinmostcases
andshouldbeencouraged.Intensiveisometricactivitiesshouldbeavoided,
whilehigher-repetition,lighter-weightexercisesareconsideredmorelikelytobe
safe.Forpatientswhowishtoengageincompetitivesports,ongoingmonitoring
withacardiologistisrecommended.InpatientswhohavedemonstrableCTC,
standardguidelinesforactivityrestrictionshouldbefollowed.75
