10/4/18 1 Management of Chemotherapy Induced Nausea/Vomiting(CINV) in Adult Cancer Patients By Zahra Shaghaghi, Pharm-D, BCOP, PhC Prepared for 2018 NMSHP Balloon Fiesta Symposium
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ManagementofChemotherapyInducedNausea/Vomiting(CINV)
inAdultCancerPatientsByZahraShaghaghi,Pharm-D,BCOP,PhC
Preparedfor2018 NMSHPBalloonFiestaSymposium
10/4/18
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GoalsandObjectives:
• DescribedifferenttypeofCINV- acutevs.delayedandanticipatoryemesis.• Describepatient’sriskfactorsfordevelopingCINV.• Discusspotentialemetogenicity ofchemotherapyregimens.• DiscusspathophysiologyofCINV&Neurotransmittersinvolved• Recognizeroleof5HT3-RA&NK1-RAinpharmacologicapproachestomanagementofCINV.• Recommendoptimalantiemeticprophylaxisbasedonoverallemesisriskfactors&RecommendationsintheNCCNGuidelinesforAntiemesis.
AudienceQuestion#1
Whichoneisthemostcommonfearedsideeffectofchemotherapy?
1- Immunesuppression
2- Fatigue
3- FebrileNeutropenia
4- Vomiting
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ChemotherapyInducedNauseaVomiting(CINV)Fewsideeffectsofcancertreatmentaremorefearedbythepatientthannauseaandvomiting.
• Threephasesofemesisinclude:nausea,retching,andVomiting.
• GoalisPrevention.
TypesofEmesis
• ThreedistincttypesofCINVhavebeendefined:acute,delayed,andanticipatory.
• RecognizingthedifferencesbetweenthesetypesofCINVhasimportantimplicationsforbothpreventionandmanagementCINV.
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AcuteEmesis
• ItisthemostwidelystudiedformofCINV.• Intheabsenceofaneffectiveprophylaxisanti-emeticregimen:• Itoccursduringthefirst24hoursafterchemotherapy• Theonsetisusuallywithin1-2hoursofChemotherapy.• Itpeaksinthefirst4-6hours.•Mosteasilypreventedandtreatedwithcurrentanti-emeticdrugs.
DelayedEmesis
• Anyemesisoccurringafter24hourspostchemotherapy.• UnderlyingPathophysiologynotwellunderstood.• Bestexampleishighdosecisplatin,butcanoccurwithotheragentssuchascyclophosphamide,carboplatin,anthracyclines,andIfosfamide.• Itpeaksat48-72hoursintheabsenceofeffectiveprophylaxis.• Delayedemesisislesscontrolledwithcurrentanti-emetics.• Patientswhohavecompletecontrolofacuteemesisarelesspredisposedtodelayedsymptoms.
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AnticipatoryEmesis
• Aconditionedreflexinpatientswhohavedevelopedsignificantnauseaandvomitingduringpreviouscycles.• Veryimportanttoprovidemaximalcontrolofemesisearlierintreatment.• Usuallyoccurs24hourspriortotreatment.• Susceptiblepopulation:youngeradults,patientsreceivingchemotherapytreatmentforlongerperiodsoftime.
RiskFactorsforDevelopingCINV
• PatientRiskFactors(mayormaynotincreaseoverallemesisrisk)
• RegimenRiskFactors
OverallEmesisRisk=Patient’sriskfactors+Regimenriskfactors
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AudienceResponseQuestion#2
JDisa40-yearolddepressedwomanwhoisdiagnosedrecentlywithextensivestagesmallcelllungcancer.Sheisasocialdrinker,stoppedsmoking15yearsago.HerPMHissignificantformorningsicknesswithher2pregnanciesandmotionsickness.Heroncologistwishestousecisplatin75mg/m2IVD1,etoposide100mg/m2IVD1-3ofevery21daystimes6cyclesasherchemotherapytreatment.whatareJD’sspecificriskfactorsfordevelopingN/V?A- femaleB- AgeC- HistoryofmorningSicknessD- Historyofmotionsickness
PatientspecificriskfactorsfordevelopingCINV• Anxiety,expectationofnausea• Women>men• Psychosocialfactors(anxiety,depression,etc.)• Youngerage(i.e.,<50y/o)• Historyofmotionsickness• Pregnancy-inducednausea/vomiting• Historyofmoderatealcoholuse(protective)• Extentofdisease(stage)• Anti-emeticsinconsistentwithguidelines• Priorchemotherapyanddegreeofanti-emeticcontrol
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RegimenSpecificRiskFactors
• DoseandScheduleofregimen• Single-agentchemotherapyemetogeniccategories:– High– Moderate– Low– Minimal• Formulti-drugregimens:thedrugthathasthehighestlevelofemetogenicitydeterminestheregimen’semeticrisklevel.• Nolonger“calculate”emetogenicityofmultipledrugregimens
EMETOGENICPOTENTIALOFANTICANCERAGENTS
Itisbasedontheproportionofpatientswhoexperienceemesisintheabsenceofeffectiveantiemeticprophylaxis.
• HighEmeticriskèè over90%frequencyofemesis
• ModerateEmeticRiskèè 30-90%frequencyofemesis
• LowEmeticRiskèè 10-30%frequencyofemesis
• MinimalEmeticRiskèè lessthan10%frequencyofemesis
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EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis
HighlyEmetogenic- >90%incidenceinacuteanddelayedemesis– Cyclophosphamide/doxorubicincombination– Cisplatin– Higherdosesofspecificchemotherapyagents(e.g.CarboplatinAUC=4&>4)
EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis
ModeratelyEmetogenic- 30-90%riskofacuteanddelayedemesis– Carboplatin,Oxaliplatin– Anthracyclines(relativelylowerdoses)– Nitrogenmustards(e.g.Bendamustine,Ifosfamide,Cyclophosphamide,Irinotecan)
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EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis
LowEmetogenic- 10-30%riskofacuteemesis- Antimicrotubules (e.g.,Taxanes)- Antimetabolites&antifolates(e.g.Fluorouracil,Methotrexate,Pemetrexed)
EmetogenicPotentialofIVAnticancerAgentsintheabsenceofeffectiveantiemeticprophylaxis
Minimaly Emetogenic- <10%riskofacuteemesis– Monoclonalantibodies,Vinca Alkaloids
SeeNCCNGuidelinesforAntiemesis (availableat:www.nccn.org)forcompletelist
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EMETOGENICPOTENTIALOFORALANTICANCERAGENTS
Moderatetohighemeticrisk(≥30%frequencyofemesis):• Cytotoxicchemotherapy- Cyclophosphamide≥100mg/m2/d,Temozolomide>75mg/m2/d• Crizotinib• PARPinhibitors- Olaparib,Rucaparib,Niraparib
Minimaltolow(<30%frequencyofemesis):• Capecitabine• Temozolomide<75mg/m2/d• “-nibs”– Gefitinib,Afatinib,Suntinib,Regorafenib• CDK4/6inhibitors- Palbociclib,Ribociclib,AbemaciclibSeeNCCNGuidelinesforAntiemesis (availableat:www.nccn.org)forcompletelist
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PathophysiologyofCINV
• Vomitingistriggeredbyafferentimpulsestothevomitingcenter,anucleusofcellsinthemedulla.• Impulsesarereceivedfromsensorycenters,suchasthechemoreceptortriggerzone(CTZ),cerebralcortex,andvisceralafferentsfromthepharynxandGItract.• Whenexcited,afferentimpulsesareintegratedbythevomitingcenter,resultinginefferentimpulsestothesalivationcenter,respiratorycenter,andthepharyngeal,GI,andabdominalmuscles,leadingtovomiting.
PathophysiologyofNausea/Vomiting
• Thevomitingreflexistriggeredbyafferentimpulsestothevomitingcenterfromvagus nerveterminalsinthewallofthesmallbowel,thechemoreceptortriggerzone,orthecerebralcortex.• Theactofvomitingoccurswhenefferentimpulsesaresenttoanumberoforgansandtissuessuchastheabdominalmuscles,salivaryglands,cranialnerves,andrespiratorycenter
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NeurotransmittersInvolvedinCINV
• ManyneurotransmittersarepotentiallyinvolvedinCINV,buttheserotoninreceptors--type3[5-(hydroxytryptamine)HT3]--andthesubstancePreceptors(NK1 receptors)aremostimportant.• DopamineD2 receptorsareoflesserimportancebutprovidedthekeytocurrentunderstandingof5-HT3 receptor.• Otherneurotransmitters(H1,M,GABA,CB)mayhavesomeeffectonnausea,withalessereffectonvomiting.
PathophysiologyofEmesis
• Fear,Dread,Anticipationè Higherlevelofcortexè5HT3,NK1,D2,GABAèEmeticCenterInMedullaè Vomiting
• InnerEar,Motionè CerebellumèH1,Mè EmeticCenterInMedulla(NK1)èVomiting
• BloodBornEmeticsèChemoreceptorTriggerZone(CTZ)è5HT,D2,M,CB,Opioidè EmeticCenterInMedulla(NK1)è Vomiting
• Vagal,sympatheticstimulationsè 5HT3,NK1,D2,M,CB,H1è EmeticCenterInMedulla(NK1)è Vomiting
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Anti-emeticsDrugClasses- basedontargetingreceptor
• Histamine(H1)• Diphenhydramine(++++)• Promethazine(++++)• Prochlorperazine(++)
• Dopamine(D2)• Haloperidol(++++)•Metoclopramide(+++)• Olanzapine(++++)• Prochlorperazine(++++)• Promethazine(++)
Anti-emeticsDrugClasses- basedontargetingreceptor
• Muscarinicacetylcholinereceptors(M)• Scopolamine(++++)• Diphenhydramine(++)• Promethazine(++)
• Cannabinoid(CB)• Dronabinol• Nabilone
• GABA• Lorazepam
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Corticosteroids:Dexamethasone
• CornerstoneofAntiemetictherapy(bothAcute&DelayedN/V)
• MOAnotwellunderstood,possiblyprostaglandinblockingactivityinthecerebralcortexandchangesincellularpermeability.
• Notrecommendedassingleagentforhigh/moderateCINV• Notrecommendedwithimmunotherapiesandcellulartherapies.• SE:insomnia,agitation,increasedenergy,increasedappetite,agitation,moodchanges,Hyperglycemiaw/prolongeduse,dyspepsia&abdominaldiscomfort.
• Clinicalpearl:considerextendingthecourseforpatientssufferingfromextendeddelayedCINV
• NK1receptorantagonists(withtheexceptionofRolapitant)inhibitmetabolismofDexamethasone,reducedoseofdexamethasone.
SerotoninReceptorAntagonists
• TherevolutionincontrolofCINVhappenedwhenrecognizedtheroleof5-HT3receptorsubtype.• Developmentofselective5-HT3antagonistledtosignificantsuccessincontrolofCINV.• The5-HT3receptorsarelocatedbothcentrally(NTSandAP)andintheperiphery(GI)vomitingreflexarc.• Oralandintravenousserotoninreceptorantagonists(5-HT3RA)haveequivalentefficacywhenusedattheappropriatedosesandintervals.• Clinicalpearl:Afterreceivingpalonosetron,granisetron transdermalpatch,orextended-releaseinjection,breakthrough5-HT3RAsplayalimitedroleinthedelayedinfusionperiodandbreakthroughantiemeticshouldfocusonadifferentmechanismofaction.
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5HT3ReceptorAntagonists
• Dolasetron 100mgPOonce.• Granisetron 10mgSQonceor2mgPOonce,or0.01mg/kg(max1mg)IVonce,or3.1mg/24-htransdermalpatchapplied24–48hpriortofirstdoseofchemotherapy.• Ondansetron16–24mgPOonce,or8-16mgIVonce• Palonosetron0.25mgIVonce
Neurokinin-1(NK1)receptorantagonistsPlaceintherapyisforpreventionandnottreatmentofCINV.LargestbenefitseenindelayedCINVsetting.• Aprepitant- 125mgPOD1,then80mgD2&3;Aprepitantinjectableemulsion130mgIVonce.Fosaprepitant- 150mgIVonce.• Netupitant300mg/palonosetron0.5mg(availableasfixedcombinationproductonly)POonce.• Rolapitant- 180mgPOonce(hasanextendedhalf-lifeandshouldnotbeadministeredatlessthan2-weekintervals)
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D2- DOPAMINETYPE2RECEPTORANTAGONIST(METOCLOPROMIDE)
• Itwasthe1stgroupofantiemeticthatwasusedforthepreventionofCINV.• InitialAntiemetictherapywerefocusedondopamineD2receptorsanddopaminergicantagonistsuchasmetoclopramide• ThreeproposedMOAcontributingtoitsantiemeticproperties:
• Blocksdopamineatthechemoreceptortriggerzone(CTZ)• Stimulatescholinergicactivityinthegut,causingincreasedgutmotility• BlocksperipheralserotoninreceptorsintheGI&CTZ(high- doseonly)
• MetoclopramidehadlimitedefficacyincontrollingCINVevenwhenusedinhighdoseandwassignificantlyassociatedwithsideeffectmainlyextrapyramidalsymptoms.
Olanzapine- Atypicalantipsychotic
• Olanzapine5-10mgPOoncedailyX4days.• SE:sedation,EPS,QTcprolongation• CNSdepression/sedationmostnotableonday2&improvesovertime• Consider5mgdoseforelderlyorover-sedatedpatients• MayincreasetheriskofdevelopingQTcprolongation,whenusedincombinationwithotherQT-prolongingagents.
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NEPA-Netupitant+Palonosetron
• Netupitanthashalf-lifeof80hours(vs.aprepitant half-life9-13hours)• InhibitsCYP3A4upto4daysfollowingdose• Phase3studiesinhighly- andmoderately- emetogenicchemotherapyregimensdemonstratedimprovedcontrolofCINVinacute,delayedandoverallphases
• UsewithcautioninpatientsreceivingconcomitantmedicationsprimarilymetabolizedbyCYP3A4.TheplasmaconcentrationsofCYP3A4substratescanincreasewhenco-administered.TheinhibitoryeffectonCYP3A4canlastformultipledays.• Atwo-foldincreaseinthesystemicexposureofdexamethasonewasobserved4daysaftersingledoseofNetupitant,reduceddoseofDexamethasoneshouldbegiven.
• ConsiderthepotentialeffectsofincreasedplasmaconcentrationsofmidazolamorotherbenzodiazepinesmetabolizedviaCYP3A4(alprazolam,triazolam).whenadministeringwithNetupitant,thesystemicexposuretomidazolamwassignificantlyincreased
• AvoidconcomitantusewithastrongCYP3A4inducersuchasrifampin.
PRINCIPLESOFEMESISCONTROLinCANCERPATIENT
Preventionofnausea/vomitingisthegoal
• Evaluatetheriskfornausea/vomiting.• Considerotherpotentialcausesofemesis:brainmetastasis,gastroparesis,etc.• Reviewconcomitantdrugsincludingopioids• Multidrugregimenvssingledrugregimen• Acute≤24hoursvs.delayednausea>24hours.• Highemetogenicpotentialchemotherapyvs.moderateemeticrisk.• Beawareofthepotentialfortheoveruseofprophylacticantiemetics• UnwantedpotentialAdverseeffects&poseundueeconomicburden
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NCCNGuidelineForAnti-emesisRecommendation- SingleDayHighlyEmetogenicRegimens,Acute• NK1-RA+5HT3-RA+DexamethasoneORPalonosetron0.25mgIV+Olanzapine10mgPO+Dexamethasone12OROlanzapine+NK1-RA+5H3-RA+Dexamethasone
NCCNGuidelinesforAntiemesis:RecommendationsforDelayed,Highly EmetogenicofsingledayregimenUsedD1forAcuteN/V UseforDelayedN/V
Aprepitant125+5HT3+Dex12 Aprepitant80Days2-3+Dexamethasone8Days2-4
Olanzapine10PO+Dex12PO/IV+Palonosetron0.25IV
Olanzapine10mgPOdailyondays2,3,4
Olanzapine10+5HT3+NK1+Dex Olanzapine10mgPOdailyondays2,3,4.Aprepitant80mgPOdailyondays2,3(ifAprepitantPOusedonday1)Dexamethasone8mgPO/IVdailyondays2,3,4
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NCCNGuidelinesforAntiemesis :RecommendationsforAcute&Delayed, ModeratelyEmetogenic
UsedforAcuteN/VDay1 UseforDelayedN/VDays2-3
5HT3 +Dex(Palonosetron0.25mgIVoncepreferred)
• Dex8mgPO/IVDays2&3• NothingifPalonosetronwasusedin
acutesetting
NK1-RA+5HT3+Dexamethasone Aprepitant80D2-3+/- DexamethasoneD2,D3
Olanzapine+Palonosetron+Dex Olanzapine10mgPOdailyondays2,3
NCCNGuidelinesforAntiemesis:RecommendationsforpreventionofemesiswithLOW ANDMINIMAL emeticriskagents
Low EmeticRisk- Startbeforechemotherapy,Repeatdailyformultidaydosesofchemotherapy.Selectone:• Dexamethasone8–12mgPO/IVonce• Metoclopramide10–20mgPO/IVonce• 5-HT3RAMinimal EmetogenicRisk:• NoRoutineProphylaxis
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ORALCHEMOTHERAPY- EMESISPREVENTION
Hightomoderateemeticrisk:• Selectoneofthe5-HT3RA• Startbeforechemotherapyandcontinuedaily.
Lowtominimalemeticrisk:PrnRecommendationonly,unlessN/Voccurs,thenselectanyagent&continuedaily
MultidayRegimens
• MultidaychemotherapyregimensarecommonandintroduceachallengeinthemanagementofCINVbecauseoftheoverlapbetweenacuteanddelayedCINV.• Afterchemotherapyadministrationconcludes,theperiodofriskfordelayedemesisalsodependsonthespecificregimenandtheemetogenicpotentialofthelastchemotherapyagentadministeredintheregimen.• Practicalissues:takeintoaccounttheadministrationsetting(eg,inpatientversusoutpatient),preferredrouteofadministration(parenteral,oral,ortransdermal),durationofactionofthe5-HT3RAandappropriateassociateddosingintervals,tolerabilityofdailyantiemetics(eg,steroids),adherence/complianceissues,andindividualriskfactor(s).• Dexamethasonedosemaybemodifiedoromittedwhenthechemotherapyregimenalreadyincludesasteroid• Ifpatientscannottoleratedexamethasone,considerreplacingwitholanzapine.
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BreakthroughCINV- OccursdespiteProperprophylaxis,Measuresbymeansof“prn”medications
Thegeneralprincipleofbreakthroughtreatmentistoaddoneagentfromadifferentdrugclasstothecurrentregimen• Addanxiolytic• AddH2-blocker/PPI• AddAprepitant• Addolanzapine• Adddopamineantagonist• Changedose/scheduleofserotoninantagonist• Ifpalliative,changechemotherapy• IfcontrolledN/V,thencontinuebreakthroughmedications,onaschedule&PRN
• IfN/Vnotcontrolled:Re-evaluateandconsiderdoseadjustmentsand/orsequentiallyaddoneagentfromadifferentdrugclass
AudienceResponseQuestion#3
JDisa40-yearolddepressedwomanwhowasrecentlydiagnosedwithextensivestagesmallcelllungcancer.Sheisasocialdrinker,stoppedsmoking15yearsago.HerPMHissignificantformorningsicknesswithher2pregnanciesandmotionsickness.Heroncologistwishestousecisplatin75mg/m2IVD1,etoposide100mg/m2IVD1-3ofevery28daysfor6cycles.WhatshouldshereceiveforpreventionofacuteCINV?A- Fosaprepitant150mgIVpluspalonosetron0.25mgIVplusdexamethasone20mgPOB- Fosaprepitant150mgIVpluspalonosetron0.25mgIVplusdexamethasone12mgPOC- Fosaprepitant150mgIVplusondansetron8mgPOplusdexamethasone20mgPOD- Fosaprepitant150mgIVplusondansetron8mgPOplusdexamethasone12mgPO
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AnswertoAudienceQuestion#3
CorrectanswerisB• CurrentNCCNGuidelines:3drugs(NK1antagonist,5HT3agonist&dexamethasone)forthepreventionofacuteemesisduetohighlyemetogenicchemotherapy.• Fosaprepitant150mgIVissingledoseonD1.• DuetoaninteractionbetweenAprepitant/Fosaprepitantanddexamethasone,itisrecommendedthatthedoseofdexamethasonebedecreasedfrom20mgto12mgpriortochemotherapy.• ThecorrectdoseforPOondansetronis16to24mg.Note:Olanzapineregimensmayalsobeusedforhighlyemeticchemotherapy(itwasnotlistedasoneofthechoices)
AudienceResponseQuestion#4
BasedonyouranswerforantiemeticregimenforacuteN/VonD1,whatshouldJDreceiveforpreventionofdelayednauseaandvomiting?A- Dexamethasone8mgPOQDondays2to4B- Dexamethasone8mgPOQDdays2to4plusondansetron8mgPOdays2to4C- Aprepitant80mgPOondays2and3plusdexamethasone8mgPOQDondays2to4D- Aprepitant80mgPOondays2and3plusdexamethasone8mgPOQDdays2to4plusondansetron8mgPOdays2to4
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AnswertoAudienceResponseQuestion#4
• CorrectanswerisA.• SinceJDreceivedfosaprepitant150mgonday1,noadditionalAprepitantisnecessaryforthiscycle.Therefore,singledexamethasone8mgPOQDondays2to4isthecorrectanswer.• 5HT3notrecommendedingeneralforpreventionofdelayednauseaandvomitingduetohighlyemetogenicchemotherapies
Conclusion
• CINVcansignificantlyaffectpatient’squalityoflife,compliance,andprovider’sabilitytoadministerfurtherchemotherapytreatment.• Appropriateuseofantiemetics&adherencetoevidencebasedconsensusguidelinesdecreasesincidenceofCINV.• Theadventof5-HT3andNK1antagoniststhatspecificallytargetneuroreceptorsimplicatedinCINVhasdramaticallyimprovedthepreventionandacutecontrolofsymptoms.• However,delayedCINVremainsdifficulttocontrolandposesasubstantialburdenforpatients.• ProperassessmentofCINVriskanditsmanagementallowpharmaciststheopportunitiestobecomemoredirectlyinvolvedinthecareofcancerpatientsreceivingchemotherapy• Pharmacists&Pharmacytechnicianscanensurethatpatientsaregivenappropriateprescriptionsandcanfacilitatepatientsobtainingthemedications.
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Questions?
References
• ReferencedwithpermissionfromtheNCCNClinicalPracticeGuidelinesinOncology(NCCNGuidelines®)forAntiemesis V.3.2018©NationalComprehensiveCancerNetwork,Inc 2018.Allrightsreserved.AccessedSeptember,2018.• Hesketh PJ,Aapro M,StreetJC,CaridesAD.Evaluationofriskfactorspredictiveofnauseaandvomitingwithcurrentstandard-of-careantiemetictreatment:analysisoftwophaseIIItrialsofaprepitant inpatientsreceivingcisplatin-basedchemotherapy.SupportiveCareinCancer2010;18:1171-7• Yanai T,Iwasa S,HashimotoH,etal.Adouble-blindrandomizedphaseIIdose-findingstudyofolanzapine10mgor5mgfortheprophylaxisofemesisinducedbyhighlyemetogeniccisplatin-basedchemotherapy.Int JClin Oncol2018;23:382-388
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Refrences
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• Navari RM,etal.Olanzapineforpreventionofchemotherapyinducednauseaandvomiting.NEngl JMed.2016;375:134-142
• Antiemetics:AmericanSocietyofClinicalOncologyClinicalPracticeGuidelineUpdate,www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki.
• PieterH.M.etal.AMulticenter,Randomized,Double-Blind,CrossoverStudyofOndansetronComparedwithHigh-DoseMetoclopramideinProphylaxisofAcute&DelayedCisplatinInducedNausea/Vomiting.AnnalsofInternalMedicineDecember1990;Volume113:834-840
• Cunningham,D.etal.PreventionofemesisinpatientsreceivingcytotoxicdrugsbyGR38032F,Aselective5-HT,ReceptorAntagonist.TheLancet,June27,1987.