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Chapter12:CardiovascularDiseaseinCancerSurvivors
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CardiovascularDiseaseinCancerSurvivors

CardiotoxicityofRadiationTherapytotheThorax
Chestradiationtherapyisassociatedwithsignificantcardiotoxicity,whichcanmanifestasacomplex,
lifethreateningdisorder.Radiationinducedtoxicitycanaffectnearlyeverycomponentofthe
cardiovascularsystem,withmanifestationssuchaspericarditis(acuteorchronic),cardiomyopathy,
aortitis,conductionsystemdisease,valvulopathy,andcoronaryarterydisease(Table48).These
pathologicalterationsarelikelycausedbythegenerationofreactiveoxygenspeciesfromirradiation,
whichleadstobloodvesselinjuryandacascadeofinflammation,ischemiawithlossofcapillary
density,andfibrosisofthecardiovascularstructures.
Althoughpericarditismayoccuracutelywithchestradiation,manifestationsofradiationinduced
cardiotoxicityfrequentlydevelopafteralongindolentperiod(5to20yearsorlater)owingtothe
chronicnatureofthepathologyandthereforerequireahighindexofsuspicioninatriskpatients.The
clinicalmanifestationsarerelatedtotheaffectedportionofthecardiovascularsystem.Myocardial
fibrosisleadstoarestrictivecardiomyopathy,resultinginpoorchambercomplianceanddiastolic
heartfailure(seeMyocardialDisease).Signsofrestrictivecardiomyopathyhavebeenreportedin15%
to50%ofpatientswithpreviouslytreatedHodgkinlymphomaandaremoreevidentinthosewho
havereceivedtherapywithcardiotoxicdrugs.Constrictivepericarditisalsofrequentlyispresent.The
potentialforcoexistentconstrictivepericarditisandrestrictivecardiomyopathypresentssignificant
challengesinthemanagementofthesepatients,astheclinicalmanifestationsfrequentlyoverlapwhile
thetreatmentsforthesetwodisordersvaryconsiderably(thatis,pericardiectomyversuscardiac
transplantation).Pericardialeffusionisparticularlycommoninpatientstreatedforesophagealcancer
(approximately25%),withamedianpresentationtimeof5monthsaftertherapyinonereport.Any
cardiacvalvecanbeaffectedbyradiationinjury(5%40%ofpatients),althoughleftsidedlesions
predominateandfrequentlyoccurwithmixedstenosisandregurgitation.Coronaryarterydisease
typicallyisostialorproximalinlocationmicrovasculopathy(diseaseinvolvingvesselsthatarenot
epicardialinlocation)alsocanoccur.
Recognitionofthepotentialforcardiotoxicityhasledtoreductionsinradiationexposureinthe
treatmentofchestmalignancy.Mostcontemporarystudieshavedemonstratedsignificantdecreasesin
cardiacmortalityincomparisonwithhistoricalstudies.However,theincreasedriskofcardiotoxicity
anddeathduetovascularcomplicationsattributabletoradiationtherapyremains.Thus,lifetime
clinicalmonitoringforradiationinducedcardiotoxicityiswarrantedowingtothechronic,lethal
natureofthiscomplication.Propensityforradiationinducedinjuryisrelatedtoyoungerageat
treatment,femalesex,radiationexposure(totaldose,doseperfraction,andcardiacchamberaffected),
theuseofconcomitantcardiotoxicdrugs(suchasanthracyclines),andthepresenceofcardiacrisk
factors(hypertension,smoking,hyperlipidemia).Thereisnoclearlydefinedthresholdofradiation
exposureforcardiotoxicityrisk.Inallpatientswithahistoryofsignificantchestradiation,aggressive
managementofriskfactorsforatherosclerosisiswarrantedowingtotheheightenedriskofischemic
heartdiseaseinthesepatients.

Althoughcontemporarystudieshaveshownalowerincidenceofradiationinducedcardiotoxicity,the
followupinthesestudieshasbeenrelativelyshort(frequently5to10years)andthusmaybe
inadequatetoascertaintheindolenteffectsofradiationinducedcardiotoxicity.Recentanalyses
frequentlyhavefocusedonmortalityrateswithoutdetailedexaminationsofothercomplications,such
asmyopathy,valvulardisease,andconstrictivepericarditis.Thetimingandclinicalmethodsforserial
monitoringhavenotbeendefined,butcardiotoxicityshouldbeconsideredinanypatientwith
symptomsorsignsofcardiovasculardiseaseandahistoryofchestradiation.
Owingtothefrequentmultiplecardiacpathologiesinthesepatients,managementofradiation
inducedheartdiseasecanbechallenging.Treatmentisdirectedprimarilytowardthepredominant
pathology,althoughitisrecognizedthatconcomitantabnormalitiesincreasethesurgicalprocedural
risk.Forexample,patientsundergoingpericardiectomywillbeatsignificantoperativeriskowingto
thepropensityforincreasedsurgicalbleedingandmyopathyinthesepatients.Thus,ahighdegreeof
individualizationofthetreatmentplanforpatientswithradiationinducedheartdiseaseis
recommended.

KeyPoints
Inallpatientswithahistoryofsignificantchestradiation,aggressivemanagementofrisk
factorsforatherosclerosisiswarrantedowingtotheheightenedriskofischemicheartdiseasein
thesepatients.
Cardiotoxicityshouldbeconsideredinanypatientwithahistoryofchestradiationwho
developssymptomsorsignsofcardiovasculardisease.

CardiotoxicityofChemotherapy
RelatedQuestion
Question77
Cardiotoxicityfromchemotherapycanresultfromtraditionalcytotoxicchemotherapyagents,suchas
anthracyclines(doxorubicin,daunorubicin,mitoxantrone),aswellasfromneweragents,suchas
monoclonalantibodies(trastuzumab)andtyrosinekinaseinhibitors.Cardiotoxicitycanoccurin
patientswithnormalheartsbutismorecommoninpatientswithpreexistingcardiacdisease.
Cardiotoxicityfromtheseagentscanmanifestasdilatedcardiomyopathy,myocardialischemiafrom
coronaryvasospasm,orarrhythmias(Table49).
Thecardiotoxiceffectsofchemotherapycanbeshortterm,intermediate,orlongterm.5Fluorouracil
isassociatedwithahighincidenceofacutechestpainandelectrocardiographicchanges(70%within
72hoursofthefirsttreatmentcycle),resultingindeathin2%to8%ofpatientsaffectedby5
fluorouraciltoxicity.
Earlymanifestationsofanthracyclinetoxicityarerelativelyuncommon(3%)andincludehighgrade
heartblock,supraventricularandventriculararrhythmias,heartfailure,myocarditis,andpericarditis,
withresolutioninmanypatientsoccurringwithin1weekafterpresentation.Chroniccardiotoxicity
duetoanthracyclines,whichbeginswithasubclinicaldeclineinsystolicanddiastolicfunction,
manifestswithsymptomsusuallywithinmonthsaftercompletionofchemotherapy.However,
cardiotoxicityfromanthracyclinescanhavelonglatencyperiods(10yearsormore).
Thestrongestriskfactorforcardiotoxicityrelatedtoanthracyclineagentsiscumulativedose.The
incidenceofcardiotoxicityfordoxorubicinordaunorubicinhasbeenreportedtobelessthan1%for
cumulativedoseoflessthan400mg/m2,but26%forcumulativedosesof550mg/m2ormore.Itis
generallyacceptedthatmaximumcumulativedosesforthesedrugsshouldbelimitedto450to500

mg/m2,butthedosesthatleadtotoxicresponsesvaryconsiderablyamongindividualpatients.Other
riskfactorsforcardiotoxicityincludeageattreatment,concomitanttherapywithothercardiotoxic
agents,chestradiation,andpreexistingcardiacdisease.Thetoxicresponsestoanthracyclinescanbe
modifiedbyliposomeencapsulationofthemolecule,infusionalratherthanbolusadministration,use
ofstructuralanalogues(epirubicinandmitoxantrone),andadjunctivecardioprotectiveagents.
DexrazoxaneisanEDTAchelatorthatreducestheriskofchroniccardiotoxicityassociatedwith
doxorubicinandepirubicinandmaybeconsideredinpatientsbeingtreatedwithhighanthracycline
doses(>300mg/m2).
Cardiotoxicityduetotrastuzumabtypicallycausesachronic,asymptomaticdeclineinventricular
functionwithalowfrequencyofovertheartfailure(3%7%).Olderpatients(age>50years)and
thosewithpriororconcomitantexposuretoanthracyclinesareatincreasedriskoftrastuzumab
inducedcardiotoxicity.Inmostpatients,cardiotoxicityduetotrastuzumabisrelatedtochangesin
contractilityandisreversible.Unlikeanthracyclines,trastuzumabrelatedcardiotoxicityisnotdose
relatedandpatientscanbesuccessfullyrechallengedafterrecoveryofventricularfunction.
Kinaseinhibitors,suchastyrosinekinaseinhibitors,arearelativelynewapproachtotumorreceptor
targetedtherapy.Hypertensionisapotentialadverseeffectthatmayrequiredoseadjustmentor,in
patientswithseverehypertension,discontinuationofthekinaseinhibitor.
Inadultpatientsbeingconsideredforchemotherapywithanthracyclines,baselineevaluationofleft
ventricularfunctionshouldbeconsideredbeforeinitiationoftherapy,althoughtheneedforthis
assessmentiscontroversialinpatientswithnosymptomsorsignsofabnormalleftventricular
functionandinwhomthecumulativedoseisexpectedtobelow(<300mg/m2).Forpatientswho
receivetreatmentwithtrastuzumab,abaselineevaluationofleftventricularfunctionshouldbe
performed,particularlyifthereisahistoryofanthracyclineuse.Routinesurveillanceofcardiac
functionusingechocardiographyshouldbeperformedinallpatientswithassessmentofleft
ventricularejectionfractionaswellasindicesofdiastolicfunction.Thetimingintervalsforthese
assessmentsareindividualizedbasedonthepatient'sbaselinefunction,chemotherapeuticregimen,
riskprofile,andevidenceofchangeinfunctioninserialevaluations.
Inadultsundergoingdoxorubicintherapy,thedrugshouldbediscontinuedifthereisevidenceofheart
failure,a10%orgreaterdeclineinleftventricularejectionfractiontobelowthelowerlimitof
normal,anabsoluteleftventricularejectionfractionoflessthan45%,ora20%declineinleft
ventricularejectionfractiontoanylevel.Owingtothereversiblenatureofcardiotoxicityrelatedto
trastuzumab,thistherapycanberesumedafterrecoveryofleftventricularfunctioninselected
patients.
Althoughotherechocardiographicindices(suchasstrainimagingorvolumemeasurements)and
serummarkers(cardiactroponin,Btypenatriureticpeptide)havebeenproposedforserialmonitoring
ofpatientswhohaveundergonechemotherapy,thethresholdsforthesemarkersaswellasthe
appropriatetimingfortheirmeasurementremainuncertain.Patientswhohaveleftventricular
dysfunctionshouldreceiveappropriatetherapywithblockers,vasodilators,anddiureticsasin
patientswithheartfailuredisordersnotrelatedtochemotherapytoxicity.

KeyPoints
Hypertensionisapotentialadverseeffectofkinaseinhibitorsthatmayrequiredoseadjustment
or,inpatientswithseverehypertension,discontinuationofthekinaseinhibitor.
Cardiotoxicityrelatedtotrastuzumabisnotdoserelatedandisreversible.
Chroniccardiotoxicitywithanthracyclinesisdoserelatedandisnotreversible.
Inpatientswhohaveundergonechemotherapy,baselineevaluationandroutinesurveillanceof
cardiacfunctionusingechocardiographyshouldbeperformedwithassessmentofleft

ventricularejectionfractionaswellasindicesofdiastolicfunction.

Bibliography
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PerezEA,SumanVJ,DavidsonNE,etal.Cardiacsafetyanalysisofdoxorubicinand
cyclophosphamidefollowedbypaclitaxelwithorwithouttrastuzumabintheNorthCentral
CancerTreatmentGroupN9831adjuvantbreastcancertrial.JClinOncol.2008Mar
1026(8):12318.PMID:18250349
SlamonD,EiermannW,RobertN,etalBreastCancerInternationalResearchGroup.Adjuvant
trastuzumabinHER2positivebreastcancer.NEnglJMed.2011Oct6365(14):127383.
PMID:21991949
SwainSM,WhaleyFS,EwerMS.Congestiveheartfailureinpatientstreatedwithdoxorubicin:
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diagnosis,pathogenesis,andmanagement.Circulation.2004Jun29109(25):312231.PMID:
15226229
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