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  126 S.Barnietal./CriticalReviewsinOncology/Hematology102(2016)125–134 1.Introduction Patientswithadvancedcancerareoftenexposedtomultipledrugsthatareusedforthetreatmentoftheirdisease,theassociatedcomplications(e.g.pain)andcomorbidities(e.g.cardiovasculardis-ease,diabetes,dyslipidemia),aswellasforthepreventionandtreatmentoftheadverseeventscausedbycancertherapy(e.g.nauseaandvomitinginducedbychemotherapyandfebrileneu-tropenia).Thisinevitablyinvolvesanincreasedriskofpotentiallyharmfuldrug–druginteractions,whichmay   befurthercomplicatedbyreducedorganfunction(heart,liver,andkidney)typicallyseeninelderlypatients,andparticularlyincancerpatients.ArecentEuropeanmulticenteranalysisconductedin11countriesinover2000patientswhoweretakingopioiddrugstotreatcancerpainhasshownthatmorethanone-fourthofpatientswereusing10ormoredrugs.Approximately45%ofpatientsreceivedunnecessaryorpotentiallyunnecessarydrugs,andpotentialinteractionsshowedtoincreasetheriskofsedation,gastriculcerations,bleedings,andneuropsychiatricandcardiaccomplications(Kotlinska-Lemieszeketal.,2014).Cardiaccomplicationsincancerpatientshavebeenasignificantmedicalprobleminthelastfewyears(Salvatorellietal.,2015).The complexityoftreatmentofcancerpatients,theknowncardiotoxiceffectsofbothchemotherapeuticdrugsandsupportivetherapy,aswellastheincreaseinthemeanlifeexpectancyofthegeneralpopulationandcancerpatients,haveprovidedaclinicalrelevancetothisissue(Salvatorellietal.,2015;Bhaveetal.,2014;Accordinoetal.,2014).Drugscanexpresstheircardiotoxicpotentialeitherdirectlyonmyocardialmuscleorbyinducingapro-arrhythmiceffectthroughaninflammatoryprocessthatcausesthedevelopmentofarrhyth-mogenicfoci,orbyactingdirectlyoncardiacconductiontissue(Bagnesetal.,2010).Bloodhypertensionstatesarefrequentlyasso- ciatedwiththeuseofantiangiogenicagents,withacardiotoxiceffectresultingfromhemodynamicchangesandhypertension-relatedorgandamage;thisdamageisalsoexpressedinthekidneys,brain,andperipheralvascularcirculationingeneral.Moreover,acuteandchroniccardiacischemiceventscanbeobserved,whicharenotnecessarilyrelatedtoathromboticcoronarydisease.Car-diotoxicityeventsandsymptomsmay   occurbothatanacuteandadelayedphaseandcanbeeithertransientorchronicallypersistent(Salvatorellietal.,2015;Bhaveetal.,2014;Accordinoetal.,2014;Bagnesetal.,2010).Thecurrentanticancerandsupportivetherapiesoftenrequirecomplexandcompositeassociationsofdifferentactiveprinciples.Thisobviouslyentailsthat,inordertoevaluatetheircardiotoxicpotential,ameredescriptionoftheiatrogenicpotentialofeachclassofdrugsisnotsufficient,andthatgreatattentionshouldbepaidtothepotential(cardiotoxic)synergiesbetweendrugsofdifferentclasses(polypharmacy-basedassessment)withinthecontextofamultifactorialstrategy(Salvatorellietal.,2015).Since2005,theregulatoryauthoritieshaverequiredthattheriskofproarrhythmiceffectassociatedwithanewdrugasaresultofitsdirectactiononheartconductiontissueshouldbeevalu-atedinagreementwithICHE14guidelines(Shah,2005a,b)before thedrugismarketed.Thepurposeoftheseguidelinesistoeval-uateadrug’sliabilitytoincreasetheQTintervalasrecordedintheelectrocardiogram.TheQTintervalrepresentsthedurationof ventriculardepolarizationandsubsequentrepolarizationandismeasuredfromthebeginningoftheQRScomplextotheendoftheTwave.Adelayincardiacrepolarizationcreatesanelectrophysi-ologicalenvironmentthatfavorsthedevelopmentoffatalcardiacarrhythmias,mostclearlyTorsadedePointes(TdP),butpossiblyotherventriculartachyarrhythmiasaswell(Shah,2005a,b).TdPis arareanddistinctiveformofpolymorphicventriculartachycardiacharacterizedbyagradualandprogressivechangeintheamplitudeandtorsionoftheQRScomplexaroundtheisoelectricline.TheQTintervalisameasureofthetimetakenforventriculardepolarizationandrepolarizationandisexpressedastimeunits(usuallymilliseconds).SinceQTintervalisdependentonheartrate,inordertocompareQTvaluesovertimeatdifferentrates,itisusually“corrected”(correctedQTintervalorQTc)byestimatingthevalueatanidealheartrateof60b.p.m.usingBazett’sformula(Bagnesetal.,2010).Today,theeffectofQTprolongationcausedbysomedrugsandobservedintheinternalmedicinesettingiswellknown.Inpartic-ular,thisistrueforcytotoxicagents,targetedtherapies(Table1)orclinicalconditions(e.g.dystonia).Itisknownthatsomeclassesofnewmolecularagents,suchassmallmoleculeinhibitorsoftheintracellulartyrosine-kinasedomain(e.g.vandetanib,pazopanib,nilotinib,lapatinib,sorafenib,cabozantinib,andsunitinib)areasso-ciatedwithQTprolongationandthattheiruseshouldbecloselymonitoredtopreventfatalarrhythmiceventssuchassuddencar-diacdeathandTdP(Naingetal.,2012;LenihanandKowey,2013).TheuseofdrugsthatprolongQTintervalrequiresclosemonitor-ing/doseadjustmentinpatientswithrenaland/orliverfunctionimpairment,cardiovascularcomorbidities,concomitantuseofsev-eraldrugsthatpotentiallyprolongQTinterval,water-electrolyteimbalanceorcongenitallongQTsyndrome(Salvatorellietal.,2015;Bhaveetal.,2014;Accordinoetal.,2014;Bagnesetal.,2010;Naingetal.,2012;LenihanandKowey,2013).Theadministrationoftargeteddrugsoftenoccursinassociationwithchemotherapeuticagentsthatarewellknownfortheircar-diotoxiceffects(e.g.anthracyclines,taxanes,antimetabolites,etc.).However,lessisknownaboutthecardiotoxicprofileofsupport-ivetherapies,whicharealmostinvariablyusedinassociationwithchemotherapyand/ortargetedtherapyandmightcontributetocreatingsynergiesregardingcardiotoxicity(Bagnesetal.,2010).Inthelastfewyears,newinformationhasbecomeavailableaboutthecardiotoxicprofileofsupportivetherapies;suchinformationmainlycomesfromchangesintheprescribinginformationofsomeproducts(e.g.ondansetron,dolasetron,metoclopramide),andfromspecificinformationfrompharmaceuticalcompanies(e.g.“DearDoctorLetter”)orregulatoryauthorities(e.g.FDAalerts,informa-tionnotesfromEMA   orAIFA).Acategoryofmainstaydrugsusedinsupportivetherapyisthatofantiemeticsfortheprophylaxisofnauseaandvomiting.Intheearly90’sstandardtherapyforantiemeticprophylaxiswerebasedonmetoclopramide,haloperidol,prochlorperazineand/orsteroids.Then,bettercontrolofemesiswasobtainedwiththeintro-ductionofnewagentssuchas5-Hydroxytryptamine(3)receptorantagonists(5-HT3-RAs).Inthelastfewyears,thepost-marketingexperiencewiththesedrugs(e.gondansetron)hasshownthattheyareassociatedwitharareanddifficult-to-quantifyriskofacutearrhythmogeniceventssuchastachyarrhythmias,especiallyintheacutephasefollowingintravenous(i.v.)administration,andQTpro-longation(BryggerandHerrstedt,2014).Therefore,itisessential foramedicaloncologisttohaveacomprehensiveknowledgeofthecardiotoxicityrisksassociatedwiththeantiemeticdrugs.TheaimofthisoverviewissotoprovideacurrentoverviewofthedataaboutriskofQTprolongationwitholderandnewestantiemeticsagentscommonlyusedforthepreventionofchemotherapy-inducednau-seaandvomiting. 2.Methods AsystematicsearchofPubmedwasperformedwiththeterms(palonosetronorgranisetronorondansetronortropisetronordolasetronormetoclopramideoraprepitantorolanzapineordex-amethasoneorsteroidorhaloperidolorantiemeticor“5HT3  S.Barnietal./CriticalReviewsinOncology/Hematology102(2016)125–134 127  Table   1 QT-prolongingdrugs.Anti-cancerdrugsGenericnameBrandnameClassUseDoxorubicinAdriblastinAnti-cancerdrugsBreast,lymphomasEpirubicinFarmorubicinAnti-cancerdrugsBreast,lymphomas5-florouracilFluorouracilAnti-cancerdrugs GastroentericCapecitabineXelodaAnti-cancerdrugsGastroenteric,breastCyclophosphamide,highdosesEndoxanAnti-cancerdrugsLymphomas,myelomasIfosfamide,highdosesHoloxanAnti-cancerdrugsSarcomaArsenictrioxideTrisenoxAnti-cancerdrugsLeukemiaBortezomibVelcadeProteosomeinhibitorsMultiplemyeloma,lymphomasBosutinibBosulifTyrosinekinaseinhibitors LeukemiaDabrafenibTafinlarSelectiveBRAFinhibitors MelanomaDasatinibSpryceTyrosinekinaseinhibitorsLeukemiaEribulinHalavenAnti-cancerdrugsBreastLapatinibTyverbAnti-cancerdrugsBreastNilotinibTasignaAnti-cancerdrugsLeukemiaPazopanibVotrientTyrosinekinaseinhibitorsKidney,sarcomaSorafenibNexavarTyrosinekinaseinhibitorsKidney,hepatocellularcarcinomaSunitinibSutentTyrosinekinaseinhibitorsKidney,GISTTamoxifenTamoxifenSelectiveestrogenreceptormodulatorsBreastToremifeneFarestonEstrogenagonists/antagonists BreastVandetanibCaprelsaTyrosinekinaseinhibitorsThyroidVemurafenibZelborafSelectiveBRAFinhibitorsMelanomaOther   drugsGenericname BrandnameClassUseHaloperidolSerenaseAnti-psychoticdrugsSchizophrenia,agitationAmitriptylineLaroxylTricyclicantidepressantsDepressionAmoxapineParoxetineTetracyclicantidepressantsDepressionAripiprazoleAripiprexAnti-psychoticdrugsPsychosis,asanadd-ontoantidepressantsChlorpromazineLargactilAnti-psychotic/antiemeticdrugsSchizophrenia,nauseaCitalopramCitalopramSSRIsDepressionClomipraminehydrochlorideAnafranilTricyclicantidepressantsDepressionClozapineLeponexAnti-psychoticdrugsSchizophreniaDesipramineNortimilTricyclicantidepressantsDepressionDoxepinSinepinTricyclicantidepressants DepressionEscitalopramCipralexSSRIsMajordepression,anxietyFluoxetineProzacSSRIsDepressionMirtazapineRemeronTricyclicantidepressantsDepressionNortriptylineNoritrenTricyclicantidepressantsDepressionOlanzapineZyprexaAnti-psychoticdrugsSchizophrenia,bipolarsyndromeParoxetineSereupinSSRIsDepressionProtriptylineConcordinTricyclicantidepressants DepressionQuetiapineSeroquelAnti-psychoticdrugsSchizophreniaSertralineZoloftSSRIsDepressionTrazodoneTritticoSARIsDepression,insomniaTrimipramineSurmontilTricyclicantidepressantsDepressionVenlafaxineEfexorSNRIsDepressionPaliperidon/risperdonInvega,xeplion/risperdalAnti-psycoticdrugsSchizophreniaVoriconazoleVfendAnti-fungalAspergillosis,candidemia,otherfungalinfectionrefractorytoothertherapyFoscavirFoscarnetAntiviralCMV   retinitisHydroxyzineAtaraxAntihistaminicPruritusTacrolimusPrografImmunosuppressivedrugProphylaxisoforganrejectionintransplantatedpatientsAzithromycinZitromaxMacrolidesChlamydia,gonorrhea,acne,sinusitis,bronchitis,otitis,pneumoniaCiprofloxacinCiproxinFluoroquinolonesInfectionsoftherespiratorytract,genitaltract,gastroenterictract,biliarytract,urinarytract,earnoseandthroat,skinandsofttissues,osteo-articularapparatus,orsystemicinfectionsClarithromycinKlacidMacrolidesUpperandlowerrespiratorytractinfections,acuteotitismedia,odontostomatologicinfections,skinandsofttissueinfections,mycobacterialinfections,eradicationof HelicobacterpyloriErithromycinErithromycinMacrolidesInfectiousprocessesofupperandlowerairways,skin,softtissues;prophylaxisofbacterialendocarditisLevofloxacinTavanicFluoroquinolonesUpperandlowerrespiratorytractinfections,urinarytractinfections,prostateinfections,softtissueinfectionsMetronidazoleFlagylNitroimidazolesAnaerobicinfectionsMoxifloxacinAvaloxFluoroquinolonesBronchitis,sinusitis,pneumonia;multidrug-resistantTBNorfloxacinNoroxinFluoroquinolonesUpperandlowerurinarytractinfectionsOfloxacinOflocinFluoroquinolonesRespiratoryandurinarytractinfectionsPentamidinePentacarinatAnti-infectiveagentsPneumocystispneumoniaTelavancinVibativGlycopeptidesNosocomialpneumoniaTelithromycinKetekKetolidesUpperandlowerrespiratorytract  128 S.Barnietal./CriticalReviewsinOncology/Hematology102(2016)125–134 Table   1( Continued )OtherdrugsGenericnameBrandnameClassUseTrimethoprimsulfamethoxazoleBactrimCombinationof2bacteriostaticdrugsUTI,chronicbacterialprostatitis,pneumoniacausedbyP.carinii,typhoidfever,shigellosis,diarrheacausedbyE.Coli,nocardiosis,otitismedia,gonorrhea,COPDexacerbationsSalbutamolVentolinBronchodilatorsAsthmaAmiodaroneCordaroneAnti-arrhythmicdrugsCardiacarrhythmiasDiphenhydraminehydrochlorideBenadrilAnti-histaminesAllergicrhinitis,insomniaFluconazoleDiflucanAzoleantifungalagentsFungalinfectionsFurosemideLasixLoopdiureticsOedema,acuteorchronicrenalfailure,nephroticsyndrome,hypertensionItraconazoleSporanoxAzolederivative FungalinfectionsTolterodineDetrusitolMusclerelaxantsOveractivebladderMethadonehydrochlorideEptadoneOpioidsPaintreatment;drugaddiction receptor”orNK-1orNEPAornetupitant)AND(“heartrate”orQTcorQTorarrhythmiasorcardiactoxicityorcardiotoxicityorcar-diovasculartoxicity)frominceptiontoJune2015.Alsowebsitesof EMA,AIFAandFDAweresearchedforclinicalrecommendationsoralerts.Articles(prospectivetrialsorretrospectiveseriesorclinicalpracticeguidelinesorreviewarticles)inEnglishlanguagereportingdataoncardiactoxicity,inparticularregardingarrhythmiaspoten-tiallyrelatedtoantiemeticdrugs,wereretrievedandanalyzedforcardiaccomplications. 3.Results  3.1.Antiemeticdrugs:classificationandcardiotoxicitydata(Table2 ) Fiveneurotransmitterreceptorsitesareofprimaryimportanceinthevomitingreflex: ã  M1—muscarinic ã  D2—dopamine ã  H1—histamine ã  5-hydroxytryptamine(HT)—3—serotonin ã  neurokinin1(NK1)receptor—substanceP.TheareapostremaisanimportantsiteforM1,D2,5-HT3,andNK1receptors,althoughothercentralandperipheralsitesplayaroleinmodulatingthevomitingreflex,includingH1receptorsinthevestibularnucleusand5-HT3receptorsonvagalaffer-entneurons(BryggerandHerrstedt,2014).Thesereceptorsmay somehowinterferewithimpulseconduction,andthereforewithheartfunction,andmay   beresponsibleforthepathogenesisof antiemetics-inducedcardiotoxicity.Thethreegroupsofdrugsmostfrequentlyusedforthetreatmentofchemotherapy-inducednauseaandvomiting(CINV)include5-HT3-RAs,NK1receptorantago-nists,andglucocorticoids.Literaturedataareavailableonthecardiotoxicpotentialofthesedrugs.Otherlesscommondrugsincludedopaminereceptorantagonists(e.g.haloperidolandmeto-clopramide),benzodiazepines(e.g.lorazepam)andolanzapine;forthesedrugs,too,informationisavailableregardingtheircardiotox-icityprofile(BryggerandHerrstedt,2014).In2001,theUSFoodandDrugAdministrationissueda“blackbox”warningfordroperidolregardingitspotentialtoinduceQTprolongationand,therefore,tocauseapro-arrhythmicrisk.Likedroperidol,5-HT3-RAsarealsoabletoblockKCNH2potassiumchannel,whichisessentialforrepolarizationPhase3ofcardiacmonophasicactionpotential.Inhibitionofthesecurrentsistherea-sonforpotentialQTprolongationofthesedrugs.Moreover,sodiumchannelblockadeby5-HT3-RAsinducesaprolongationinthedepo-larizationandrepolarizationtimesofactionpotential(Kuryshevetal.,2000;Schwoereretal.,2007).Thecardiotoxiceventsobservedduringtheuseofthesedrugstypicallydeveloptwo   hoursafterasin-gledose–anintravenous(i.v.)doseinmostcases–,withareturntobaselinevalueswithin24h.However,potentiallyfatalcardiacarrhythmias,includingTdP,havebeenreportedinassociationwithQTprolongation.Giventhepaucityofinformationavailableaboutthecardiologicalsafetyandtheextensiveuseoffirst-generation5-HT3-RAsintheclinicalpractice,theregulatoryauthoritieshaverequiredthatappropriatestudiesbeconductedtodeterminethecardiotoxicpotentialofantiemeticdrugs.Theprovisionsissuedbyregulatoryauthorities(FDA,EMA,AIFA)(NotaInformativeDolasetron,2015;FDASafetyCommunication,2014),inthelastfewyears(2011–2013),torestricttheuseoffirst-generation5-HT3-RAs(ondansetron,granisetron,tropisetronanddolasetron)wasbasedontheresultsofsuchstudies.Toperformaproperassessmentofthecardiotoxicimpactofnewantiemeticdrugs,theregulatoryauthoritieshaverequiredspecificstudiesfortheseagents(e.g.5-HT3-RA,NK1-RA ... )   inagreementwiththeabove-identifiedICHguidelines(Shah,2005b).Thecardiactoxicityprofilesofthedifferentclassesofantiemeticdrugsaredescribedbelow.  3.2.5-HT3-RA 3.2.1.Ondansetron Followingtheresultsofanad-hocstudyonthecardiotoxicityprofileofondansetron,somerestrictionstotheuseofondansetronbyi.v.routewerefirstissuedbytheFDAandthenbytheEMA   andtheAIFA(theItalianMedicinesAgency)(Anon.,2016a) ã  In2011,thesingle-dosevialofondansetron32mgi.v.waswithdrawnfromthemarket.Thisdecisionwastakenafteraclin-icalstudyhadshownthattheelectricalactivityoftheheart(QTprolongation)wasaffectedbyondansetron32mg   i.v.inadose-dependentmanner.Inparticular,ECGabnormalitieshadbeenobserved,includingQTprolongation,inpatientsreceiv-ingondansetron.CasesofTorsadesdePointes,anabnormalandpotentiallyfatalformofcardiacarrhythmias,werealsoreportedinsomepatients(Anon.,2016a). ã  In2012,thesingle-dosevialofondansetron24mg   i.v.waswith-drawnfromthemarket.Thisrestrictionwas   basedonthefinaldatareviewofthefindingsfromthesamestudythathadresultedinthewithdrawalofthe32-mgi.v.dosein2011(Anon.,2016a). ã  In2013,basedonareviewoftheavailableliterature,onthepublicationofCanadianguidelines(June2014)thatrestrictedtheuseofondansetroninelderlypatientstoreducetherisksofQTprolongation,(Anon.,2014)andonEUpost-marketing pharmacovigilancedata,theAIFArecommendedthefollowingrestrictionstotheuseofondansetroninItaly(Anon.,2016b):
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