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2016

Systemictreatmentofmetastaticbreastcancerinwomen:Chemotherapy

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Systemictreatmentofmetastaticbreastcancerinwomen:Chemotherapy
Author
AnneFSchott,MD

SectionEditor
DanielFHayes,MD

DeputyEditor
SadhnaRVora,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Dec2015.|Thistopiclastupdated:Aug21,2015.
INTRODUCTIONBreastcanceristhemostfrequentlydiagnosedcancerandtheleadingcauseofcancer
relateddeathamongfemalesworldwide[1].Despitethegainsinearlydetection,uptofivepercentofwomen
diagnosedwithbreastcancerintheUnitedStateshavemetastaticdiseaseatthetimeoffirstpresentation.In
addition,upto30percentofwomenwithearlystage,nonmetastaticbreastcanceratdiagnosiswilldevelop
distantmetastaticdisease[2].Althoughmetastaticbreastcancerisnotcurable,meaningfulimprovementsin
survivalhavebeenseen,coincidentwiththeintroductionofnewersystemictherapies[35].
Theroleofchemotherapyforthetreatmentofmetastaticbreastcancerwillbereviewedhere.Ageneraloverview
oftheapproachtometastaticbreastcancer,endocrinetherapyforhormonereceptorpositivemetastaticbreast
cancer,HumanEpidermalGrowthFactorReceptor2(HER2)directedagentsandothermolecularlytargeted
therapy,andbreastcancerinmenarereviewedseparately.Inaddition,commonlyusedtreatmentregimensused
inthetreatmentofbreastcancerarealsocompiledinaseparatetopic.
(See"Systemictreatmentformetastaticbreastcancer:Generalprinciples".)
(See"Treatmentapproachtometastatichormonereceptorpositivebreastcancer:Endocrinetherapy".)
(See"SystemictreatmentforHER2positivemetastaticbreastcancer".)
(See"Breastcancerinmen".)
(See"Treatmentprotocolsforbreastcancer".)
INDICATIONSThegoalsoftreatmentofmetastaticbreastcanceraretoprolongsurvivalandimprovequality
oflifebyreducingcancerrelatedsymptoms.Inordertoachievethesegoals,anindividualizedapproachisneeded
sincenoonestrategycanbeappliedforallwomen.Cytotoxicchemotherapymaybeusedtoachievethesegoals
inthefollowingsituations:
HormonereceptornegativebreastcancerUnlikepatientswithhormonereceptorpositivebreastcancer,
thesepatientsarenotcandidatesforendocrinetherapy.
Patientswithsymptomatichormonereceptorpositivebreastcancer,inwhomendocrinetherapyisunlikelyto
resultinapromptclinicalresponse[6].Theseincludepatientswhopresentwith:
Rapiddiseaseprogressionfollowingmorethanoneendocrinetherapy(ie,endocrineresistantdisease)
Alargetumorburdeninvolvingvisceralorgans
PatientswithHumanEpidermalGrowthFactorReceptor2(HER2)positivediseaseshouldhaveaHER2directed
agentincludedaspartoftheirtreatment.AdiscussionontheapproachtotreatmentofHER2positivebreast
canceriscoveredseparately.(See"SystemictreatmentforHER2positivemetastaticbreastcancer".)
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Ingeneral,weprefernottoadministerchemotherapywithendocrinetherapyforwomenwithhormonereceptor
positivediseaseinordertominimizesideeffects,includinganincreasedriskofthromboembolicevents[7].In
addition,a1998metaanalysisshowedthatcombiningthesetreatmentswasnotmoreeffectivethantheuseof
chemotherapyalone[8].Theadministrationofendocrinetherapyforpatientswithhormonereceptorpositive
metastaticbreastcanceriscoveredseparately.(See"Systemictreatmentformetastaticbreastcancer:General
principles",sectionon'Endocrinetherapyversuschemotherapy'and"Treatmentapproachtometastatichormone
receptorpositivebreastcancer:Endocrinetherapy".)
FACTORSINFLUENCINGCHEMOTHERAPYCHOICEForpatientsinwhomchemotherapyis
recommended,thechoicebetweenasingleagentoracombinationregimen,andtheselectionofaspecific
therapy,shouldtakeintoaccountseveralfactorsinanefforttoindividualizetherapyasmuchaspossible.
Becauseoftheavailabilityofmanyagentstotreatmetastaticbreastcancer,thereisnoidealsequenceof
treatmentsthatcanbeappliedtoallpatients.Itislikelythatpatientswithmetastaticbreastcancerwillreceive
many(ifnotall)ofthesetreatmentsthroughoutthecourseoftheirdisease.However,belowweillustratethe
principlesthatcanguidethechoiceoftherapyinthefirstorlaterlinesetting.Giventhatcurrentlyavailable
systemictreatmentsformetastaticbreastcancerarenotcurative,weencourageparticipationinwelldesigned
clinicaltrials.
TumorburdenTumorburden(theextentofdiseasedetectedonimagingorclinicalexamand/orthepresence
oftumorrelatedsymptoms)canimpactonwhethersingleagentchemotherapyoracombinationregimenis
administered:
Wepreferthesequentialuseofsingleagentchemotherapy,especiallyforpatientswithalimitedtumor
burdenand/orlimitedorminimalcancerrelatedsymptoms.Sequentialsingleagenttreatmentisoftenless
toxicandresultsinsimilaroverallsurvivalcomparedwithcombinationchemotherapy[9].(See'Singleagent
chemotherapy'below.)
Forselectpatients,wefavortheuseofacombinationregimenratherthanasingleagentbecause
combinationtherapyresultsinahigherresponserate,whichmayjustifytherisksoftreatment[10].
Appropriatepatientsincludethosewithsymptomaticdiseaseduetothelocationofspecificmetastatic
lesions(eg,rightupperquadrantpainduetoexpandinglivermetastases,ordyspnearelatedtodiffuselung
metastases),alargetumorburden,andthosewithrapidlyprogressivedisease.(See'Combination
chemotherapy'below.)
Forpatientswithbrainmetastases,systemictreatmentmaynotberequiredifthereisnoevidenceof
systemicdisease.Inthepresenceofsystemicdisease,treatmentofboththecentralnervoussystemand
systemicdiseaseshouldbeindividualized.(See"Managementofbrainmetastasesinbreastcancer".)
GeneralhealthstatusTreatmentdecisionsshouldtakeintoaccounttheoverallhealthstatusofthepatient,
whichcanbegaugedbytheperformancestatus(table1)or,inthecaseofolderwomen,acomprehensive
geriatricanalysis(CGA).(See"Comprehensivegeriatricassessmentforpatientswithcancer"and"Treatmentof
metastaticbreastcancerinolderwomen".)
Forpatientsinwhomasingleagentisrecommended,anunderstandingofthepatientshealthstatusalsomay
influencetheappropriateselectionofagents.Asexamples(see'Singleagentchemotherapy'below):
Patientswithahistoryofcardiacdiseaseorheartfailureandthosewhoarefelttobeatagreaterriskfor
cardiacinjury(eg,elderlypatients)shouldnotbetreatedwithananthracycline.Therearemultipleappropriate
alternatives(eg,paclitaxelorcapecitabine).
Patientswithsymptomaticperitonealmetastases,thosewhohavedifficultyswallowingpills,orthosewho
arenotabletofollowinstructionsrequiredtouseadailyregimenmaynotbegoodcandidatesfororal
therapies(eg,capecitabine).
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Patientsatriskforhyperglycemia(eg,patientswithdiabetes)andthosewhocannottoleratesteroidsfor
whateverreasonmayderivemoreofabenefitfromagentsthatdonotrequirepremedication(eg,nanoparticle
albuminbound[nAb]paclitaxel,capecitabine,andgemcitabine).
Patientswithapoorperformancestatusorthosewithsignificantcompetingcomorbiditiesmaynotbenefit
fromtreatmentatall,especiallyiftheyhaveahigherriskofdyingfromacauseotherthanbreastcancer.
Therefore,thebenefitsandrisksofsingleagenttherapyshouldbebalancedagainstoverallprognosis.
Forpatientsinwhomacombinationregimenispreferred,thepatientshealthstatusalsocanhelpchoosethe
mostappropriateregimen.Asexamples(see'Combinationchemotherapy'below):
Idealcandidatesforananthracyclinecontainingregimenincludewomenwithchemotherapynaive,stageIV
breastcancer(ie,nopriorcytotoxictherapyandthosewhoreceivedendocrinetherapyinitially)andthose
whodidnotpreviouslyreceiveananthracycline(eg,thosewhoreceiveddocetaxelpluscyclophosphamidein
theadjuvantsetting).Theseareamongofthemostactiveregimensformetastaticbreastcancer.(See
'Anthracyclinecontainingregimens'below.)
Patientswithacardiachistory(includingprioranthracyclineinducedcardiacinjury)shouldnotbetreatedwith
ananthracycline.Ourpreferenceistoadministerataxanebasedregimen(eg,gemcitabinepluspaclitaxelor
docetaxel).(See'Nonanthracycline,taxanebasedregimens'below.)
PriortreatmentandtoxicitiesForthepatientwhohasbeenpreviouslyexposedtochemotherapy(eg,as
adjuvanttreatmentorprevioustherapyformetastaticbreastcancer),thereisnooptimalsequenceof
administrationofchemotherapyagentsusedtotreatmetastaticbreastcancer.Ingeneral,treatmentwith
chemotherapydrugsofdifferentclasses(noncrossresistantagents)mayresultinahigherprobabilityof
response,especiallyifdiseaseprogressionoccurredwithinsixmonthsfollowingthepreviouslyadministered
regimen[11].However,thetreatmenthistory(ie,agentsusedandanyprevioustoxicityexperiencedorpersisting)
shouldbereviewedtohelpinformthechoiceofasubsequentregimen.Asexamples:
Patientswhoreceiveddoxorubicinorepirubicinintheadjuvantsetting,evenyearspreviously,maynotbe
goodcandidatesforrepeatanthracyclinetherapyduetoincreasingriskofcardiactoxicityathigher
cumulativedoses.Oftheavailablealternativeagents,wetypicallyadministerataxaneinthesepatients.
(See'Taxanes'below.)
Patientswithahistoryofmyelosuppressionwithpriortherapythatresultedindosemodificationortreatment
delaymaynotbegoodcandidatesforcombinationchemotherapy,particularlythoseusingagentsor
scheduleswithsignificantmyelotoxicityrisks(eg,ixabepilone,gemcitabine,andeverythreeweek
docetaxel).Inthesesituations,singleagenttreatmentusingaweeklyanthracycline,capecitabine,ora
weeklytaxanemaybemoreappropriate.(See'Taxanes'belowand'Anthracyclines'below.)
Patientswithbaselineorahistoryofserious(grade3/4)neuropathymaynotbegoodcandidatesfor
microtubulindirectedagents(eg,taxanes,ixabepilone,eribulin,orvinorelbine).Thesepatientsareappropriate
candidatesforanthracyclines,especiallyinthefirstlinesettinginapatientwhowasnevertreatedwithan
anthracycline.Alternativestoanthracyclinesincludecapecitabine,etoposide,orgemcitabine.(See
'Anthracyclines'belowand'Otheragents'below.)
PatientpreferencesPatientpreferenceshelptoindividualizetreatmentplansformetastaticbreastcancer.For
example,somepatientsmaynotaccepttheadditionalrisksoftoxicityassociatedwithcombinationchemotherapy
ifthegoaloftreatmentisnotcure(orremission).Ontheotherhand,othersmayacceptahigherchanceofa
treatmentresponsedespitetheadditionaltoxicityrisksandmayoptforcombinationchemotherapy.
Additionalexamplesinclude:
Patientswhopreferlessfrequentvisitsforintravenoustreatmentsmayoptfortreatmentadministeredevery
threeweeks,ratherthanweekly.Appropriateregimensthatcanbeadministeredeverythreeweeksinclude
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singleagenttaxanes,anthracyclines,orixabepilone,orcombinationtherapyusingcyclophosphamide,
methotrexate,andfluorouracil(CMF)ordoxorubicinpluscyclophosphamide(AC).(See'Taxanes'belowand
'Anthracyclines'belowand'Otheragents'belowand'Cyclophosphamide,methotrexate,andfluorouracil
(CMF)'belowand'Anthracyclinecontainingregimens'below.)
Patientswhopreferalowriskofalopeciamaywanttoavoidtaxanesandanthracyclines(wheretheriskof
alopeciaiscloseto90percent).Optionsinthiscircumstanceincludeagentswithalowerriskofalopecia,
suchasgemcitabine(upto15percent)andcapecitabine(lessthan10percent).(See'Otheragents'below.)
Patientswhopreferlessintrusionontheirlifestylemayoptforanorallyadministeredagent,suchas
capecitabine,ratherthantreatmentsthatrequireintravenousinfusion.(See'Capecitabine'below.)
SINGLEAGENTCHEMOTHERAPYThereareanumberofagentswithactivityinmetastaticbreastcancer.
Becausethetaxanesandanthracyclinesaremostcommonlyadministered,especiallyinthefirstlinetreatmentof
metastaticbreastcancer,theyarepresentedfirst.(See'Indications'above.)
TaxanesTaxanesareamongthemostactiveagentsformetastaticbreastcancer.Agentsinthisclassinclude:
DocetaxelDocetaxelcanbeadministeredeverythreeweeks(80to100mg/m2)orweekly(30to40mg/m2
weeklyforthreeweeksfollowedbyoneweekoff)[12].Oftheseschedules,wepreferdosingeverythree
weeksbasedontheresultsofarandomizedtrialintheadjuvantsettingthatshowedeverythreeweek
dosingresultsinanimprovementindiseasefreesurvival(DFS)comparedwithweeklydosing[13].
Docetaxelisassociatedwithasignificantriskoffluidretention,whichisreducedbypremedicationwith
dexamethasone[14].
PaclitaxelPaclitaxelcanbeadministeredweekly(80to100mg/m2ondays1,8,and15ofa28daycycle)
oreverythreeweeks(175mg/m2)[12,13,15].Wheneverpossible,wepreferweeklyschedulingbasedonthe
resultsofa2010metaanalysis,whichshowedthatcomparedwitheverythreeweektreatment,weekly
administrationofpaclitaxelresultedinanimprovementinoverallsurvival(OS,hazardratio[HR]0.78,95%
CI0.670.89)[12].
Itshouldbenotedthatpatientstreatedwithpaclitaxelareatriskforallergicreactionsasaresultofthe
compositionofpaclitaxel,whichismixedwithCremophor.Atmostinstitutions,steroidpremedication
(dexamethasone20mgthenightbeforeandmorningofinfusion)isadministered,althoughitcanusuallybe
discontinuedifthefirsttwoorthreedosesaretolerated.However,thescheduleandadministrationof
dexamethasonevariesbyinstitution.
NabpaclitaxelNabpaclitaxelhasactivityinmetastaticbreastcancersimilartoothertaxanes[1618].It
maybeofparticularbenefittopatientswhoareatriskforhyperglycemiaandthosewhocannottolerate
steroids.Nabpaclitaxelhasalowerriskofallergicreactionscomparedwithothertaxanes,whichnegates
therequirementforsteroidpremedicationsandtheriskofsteroidinducedhyperglycemia.
ComparingtaxanesForpatientsinwhomataxaneisindicated,thechoicebetweentaxanescanbebased
ontheircomparativesafetyprofilesandpatientpreferencesregardingschedulingoftreatments.Forexample:
Therisksofneuropathyandmyalgiaaregreaterwithpaclitaxelthanwithdocetaxel.
Paclitaxelcanbeadministeredinthesettingofmildmoderatehepaticdysfunction.Incontrast,docetaxel
shouldnotbeadministeredinthiscontext.
Docetaxelgiveneverythreeweeksisthemoremyelosuppressivetaxaneagent.Risksfromdocetaxelalso
includefebrileneutropenia,edema,andgastrointestinaltoxicities.
Therearelimiteddatacomparingeachofthetaxanesagainsteachother.However,theyshowthattheactivity
andtoxicitydifferbywhichschedulewasused(ie,weeklyoreverythreeweeks)andbyagent.Asexamples:
Docetaxelwascomparedwithpaclitaxel(bothona21daycycle)inatrialof449patientswithadvanced
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breastcancerthathadprogressedafterananthracyclinecontainingchemotherapyregimen.Docetaxel
producedasignificantlybettermediantimetoprogression(TTP,5.7versus3.6months)andOS(15.4versus
12.7months)comparedwithpaclitaxel[19].However,bothhematologicandnonhematologictoxicitywere
worsewithdocetaxel.
Althoughthisstudyfoundthateverythreeweekdosingofdocetaxelissuperiortothesamescheduleusing
paclitaxel,weeklypaclitaxel(whichisthepreferredmethodofadministration)hasnotbeencomparedwith
everythreeweekdocetaxelinthemetastaticsetting.
Paclitaxelandnabpaclitaxelwereevaluatedasafirstlinetreatment(assingleagentsorwithoptional
administrationwithbevacizumab)intheAlliancetrial,conductedbyCancerandLeukemiaGroupB(CALGB)
andtheNorthCentralClinicalTrialsGroup(NCCTG)(CALGB40502/NCCTGN063H)[20].Thestudy
randomized799patients(44percentwhowerepreviouslytreatedwithadjuvantpaclitaxel)tobevacizumab
witheitherweeklytreatmentwithpaclitaxel(90mg/m2)ornabpaclitaxel(150mg/m2)onathreeweekon,
oneweekoffschedule.Athirdarmincludingweeklyixabepilone(16mg/m2)wasclosedforfutilityatthefirst
interimanalysis.Theresultsforpaclitaxelversusnabpaclitaxelarediscussedbelow.(See'Ixabepilone'
below.)
Nosignificantdifferenceinprogressionfreesurvivalbetweenpaclitaxelandnabpaclitaxel(11versus
9.3months,respectivelyHR1.2095%CI1.001.40).
Nosignificantdifferenceinoverallsurvivalbetweenpaclitaxelandnabpaclitaxel(26.5versus23.5
months,respectively,HR1.17,95%CI0.921.47).
Ahigherrateofserioustoxicity(grade3orhigher)inthenabpaclitaxelversuspaclitaxelarms,
includingsensoryneuropathy(27versus18percent,respectively)andhematologictoxicity(55versus
22percent).
AnthracyclinesTheanthracyclinesareimportantagentsforthetreatmentofbreastcancer.However,theiruse
intheadjuvantcontextoftenlimitstheirapplicationinwomenwithmetastaticdisease.Despitethis,
anthracyclinesmaybeappropriateinselectpatients,particularlythosewhoarechemotherapynaiveandthose
whowerenottreatedwithananthracyclineinthepast.Inaddition,anthracyclinescanbeusedinpatientswith
mildtomoderatehepaticdysfunctionwithdosemodification.
Theanthracyclinesusedinthetreatmentofmetastaticbreastcancerare:
Doxorubicin(60to75mg/m2everythreeweeks,or20mg/m2weeklyforthreeweeksfollowedbyoneweek
off)ORR30to47percent[21,22]
Epirubicin(75to100mg/m2everythreeweeks,or20to30mg/m2weeklyforthreeweeksfollowedbyone
weekoff)ORR42to50percent[2325]
Pegylatedliposomaldoxorubicin(40mg/m2everyfourweeks)ORR10to33percent[26,27]
Onepotentialdownsideofusinganthracyclineregimensistheriskforcumulativecardiactoxicity,whichmaylimit
thedurationofanthracyclinebasedtherapy.However,forpatientswhoarerespondingtotreatmentandotherwise
aretoleratingtherapy,theuseofdexrazoxanemayminimizetheriskoftreatmentrelatedcardiacdamage.For
patientstreatedwithdoxorubicin,dexrazoxaneisindicatedafteracumulativedoxorubicindoseof300mg/m2.
(See"Cardiotoxicityofanthracyclinelikechemotherapyagents",sectionon'Dexrazoxane'.)
ComparinganthracyclinesOurpreferredanthracyclineisdoxorubicinorepirubicinbecausetheyareboth
relativelyeasytoadminister.Achoicebetweenthemisbasedongeographicandinstitutionalpreferences.For
example,doxorubicinismorecommonlyusedintheUnitedStateswhileepirubicinismorecommonlyusedin
Europe.Althoughtherearenoprospectivetrialscomparingittostandarddosingeverythreeweeks,wepreferthe
useofweeklyanthracyclinedosinginthemetastaticsettingbecauseitisbettertolerated.
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Forpatientswhodesirealessfrequentadministrationschedule,pegylatedliposomaldoxorubicinadministered
everyfourweeksappearstobeequallyactiveandlesstoxiccomparedwithdoxorubicinadministeredeverythree
weeks.Thiswasshowninatrialof509patientswithmetastaticbreastcancer(56percentwhohadpreviously
receivedanthracyclines)whowererandomlyassignedtreatmentwithpegylatedliposomaldoxorubicin50mg/m2
giveneveryfourweeksordoxorubicin60mg/m2giveneverythreeweeks[26].Comparedwithpegylated
liposomaldoxorubicin,doxorubicinresultedin:
SlightlyhigherORR(38versus33percent)
SimilarPFS(median,7.8versus6.9monthsHR1.0,95%CI0.821.22)andOS(median,22versus21
monthsHR,0.94,95%CI0.741.19),thoughPFSmeasureswereconfoundedbymorefrequent
assessmentsintheeverythreeweekdoxorubicinarm.
Anincreaseintheriskcardiotoxicity(26versus7percent,HR3.1695%CI1.586.31).
Higherratesofalopecia(66versus20percent),nausea(53versus37percent),vomiting(31versus19
percent),andneutropenia(10versus4).Incontrast,pegylatedliposomaldoxorubicinwasassociatedwitha
higherrateofplantarplantarerythrodysesthesia(48versus2percent),stomatitis(22versus15percent),and
mucositis(23versus13percent).
AnthracyclineversustaxaneThereisnoevidenceofsuperiorityofeitheranthracyclinesortaxanesinthe
metastaticsetting,althoughthedurationoftreatmentusinganthracyclinesismorelikelytobelimitedduetothe
cumulativeriskofcardiactoxicity.(See'Anthracyclines'above.)
Whilea2008metaanalysisofindividualpatientdata(n=919patients)foundthatadministrationofan
anthracyclineresultedinanimprovementintheORR(38versus33percent)andPFS(median,7versus5
months)comparedwithtaxanes[28],wedonotfeelthatthesesmalldifferencesinORRandPFSareclinically
significantinthecurrenterainwhichmultipleothertherapiesareavailable.Inaddition,theanalysiswaslimitedby
multiplefactorsincluding:
Heterogeneitybetweentheincludedtrials
Differencesinadministrationschedulesforthetaxaneused(includingthelackofinclusionoftrialsusing
weeklyadministrationofpaclitaxel)
Theinclusionofpatientswithorwithoutpriorexposuretoendocrinetherapy
Lackofinclusionofpatientstreatedwithadjuvanttaxanes
CapecitabineInourpractice,singleagentcapecitabine(1000to1250mg/m2twicedailyfor14daysfollowed
bysevendaysofrest)isafrequentchoiceasafirstlinetreatmentformetastaticbreastcancer,particularlyin
patientswithbonepredominant,estrogenreceptorpositivemetastaticdiseasewhohaveprogresseddespiteat
leasttwotrialsofendocrinetherapy.Inaddition,capecitabinealsoappearstocrossthebloodbrainbarrierbetter
thansomeagentsandmaybeagoodconsiderationinpatientswithahistoryofcentralnervoussystem
metastases[29].(See"Managementofbrainmetastasesinbreastcancer".)
Capecitabineisaprodrugoftheantimetabolitefluorouracil.Itisorallyavailable,andunlikemanyagentsusedin
thetreatmentofbreastcancer,itcausesverylittlealopeciaorneuropathy.Itsprimarytoxicitiesarehandfoot
syndromeanddiarrhea,anditcanbeusedinsettingsofhepaticdysfunction.Thebenefitofcapecitabinewas
shownintwomulticentersinglearmphaseIItrials[30,31]:
Inonestudy,126patientsweretreatedwithcapecitabine(1250mg/m2dose).ThemedianTTPwas5
monthsandtheORRwas28percent.MedianOSwas15months[30].
Inasecondstudy,95womenwererandomlyassignedtocapecitabineorcyclophosphamide,methotrexate,
plusfluorouracil(CMF).CapecitabineresultedinahigherORRcomparedwithCMF(30versus16percent,
respectively).ThemedianTTPwassimilar(4versus3months)butcapecitabineresultedinaslightlylonger
medianOS(20versus17months)[31].
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OtheragentsForpatientswhoarenotcandidatesfortheagentsabove,othersareavailableandhave
documentedactivityagainstbreastcancer.
EribulinEribulinmesylate(1.4mg/m2days1and8every21days)isderivedfromamarinespongeand
inhibitsthepolymerizationoftubulinandmicrotubules.Itresultsinlessneuropathythanothermicrotubuledirected
agentsandcanbeadministeredwithdoseadjustmentformildtomoderatehepaticdysfunction.Therefore,itisa
goodagenttoadministerinthesesituations.
TheactivityoferibulinwasshowninaphaseIIItrialof762heavilypretreatedpatientswhowererandomly
assignedtotreatmentwitheribulinorotherchemotherapy(basedonphysiciansandpatientschoice)[32].
TreatmentwitheribulinsignificantlyimprovedOS(median,13.1versus10.6months).Theprimarytoxicitywith
eribulinwasneutropenia,withgrade3and4neutropeniain45percentofpatients,andgrade3and4febrile
neutropeniain5percent.Peripheralneuropathywasthemostcommonadverseeventleadingtodiscontinuationof
eribulin,occurringin5percentofpatients.(See"Overviewofneurologiccomplicationsofnonplatinumcancer
chemotherapy",sectionon'Eribulin'.)
Ofnote,asubsequentrandomizedtrialwasperformedinwomenwithmetastaticbreastcancerwhohadreceived
prioranthracyclineandtaxanetherapywithanaimtoformerlyevaluateeribulinversuscapecitabineasfirst,
second,orthirdlinetherapy[33].Unlikethetrialabove,therewasnodifferencebetweeneribulinandcapecitabine
intermsofPFS(fourmonthsineach)oroverallresponserates(11and11.5percent,respectively).Inaddition,
therewasnoclinicallymeaningfuldifferenceinOS(15.9versus14.5months,respectivelyHR0.88,95%CI0.77
1.00).
VinorelbineVinorelbineisanintravenouslyadministeredagentusuallydosedat30mg/m2onaweekly
schedule(days1and8every21days)[34].Vinorelbinecauseslittlenausea,vomiting,andhairloss,andisactive
asasingleagent(ORR25to45percent),eveninheavilypretreatedpatients[3537].
GemcitabineAlthoughdatasuggestgemcitabineisactiveincombinationwithpaclitaxelinfirstline
metastaticbreastcancer,gemcitabine(commonly1000mg/m2days1and8ofa21daycycle)isfrequentlyused
asasingleagent.(See'Gemcitabinepluspaclitaxelordocetaxel'below.)
Gemcitabineappearstocrossthebloodbrainbarrierandmaybeagoodoptioninpatientswithahistoryofcentral
nervoussystemmetastases[38].Alopeciaandgastrointestinaltoxicityaremild,anditisnotassociatedwith
significantneuropathy.Gemcitabineiswelltoleratedandactiveinmetastaticbreastcancer,thoughwhen
gemcitabinewasdirectlycomparedwithweeklyepirubicinasfirstlinechemotherapyinwomennotpreviously
exposedtoananthracycline,itresultedinasignificantlyshortertimetoprogressivediseaseandalowerOS[39
41].Thrombocytopeniacanbeadoselimitingtoxicity,especiallyinheavilypretreatedpatients.
IxabepiloneIxabepiloneisanepothilone,aclassofnontaxanetubulinpolymerizingagentsthathave
activityintaxaneresistantpatients.Assingleagenttreatment,ixabepilone(40mg/m2every21days)resultedin
anORRof19percentwithamediandurationofresponseof5.7monthsinaclinicaltrial[42].MedianOSwas8.6
months.Grade3and4peripheralsensoryneuropathyoccurredin14percentofpatients.
Somedatasuggestthatixabepilonemayhavelessactivitywhencomparedwiththetaxanes,althoughitmaybe
bettertolerated.IntheCALGB40502trialdiscussedearlier,weeklyixabepiloneresultedinashortermedianPFS
comparedwithtaxanes(7.6monthsversus10monthswithpaclitaxelandnabpaclitaxel)andOS(21versus26
and27months,respectively)butresultedinalowerincidenceofhematologictoxicity(12versus21and51
percent)[43].Ofnote,theincidenceofserious(grade3/4)sensoryneuropathywasequivalentbetween
ixabepiloneandnabpaclitaxel(25percentinbotharms).FurtherresultsofCALGB40502arediscussedabove.
(See'Comparingtaxanes'above.)
Inthepresenceofmildtomoderatehepaticimpairment,ixabepilonedosesshouldbeadjusted.Itsusefulnessin
laterlinetherapyisoftenlimitedbyitstoxicitiesofneuropathy,anemia,andfatigue.However,epothilonesmay
crossthebloodbrainbarrier[44],suggestingitmaybeanoptionforpatientswithcentralnervoussystemdisease.
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(See"Managementofbrainmetastasesinbreastcancer".)
DespiteFDAapproval,itisnotavailableinEuropebecausetheEuropeanMedicinesAgency(EMA)Committee
forMedicinalProductsforHumanUse(CHMP)concludedthatthebenefitwasmarginalatbestandtheriskof
peripheralneuropathytobesignificant[45].Alternatedosingschedulesarealsounderactiveinvestigation[46,47].
EtoposideOraletoposide(50mg/m2dailyfor21daysevery28days)isareasonablechoice,especiallyfor
patientswithslowgrowingdiseasewhodesireanoralagent.EtoposidehasshownanORRof30percentin
pretreatedpatients,butmayproducehematologicandgastrointestinaltoxicity[4850].
PlatinumagentsCarboplatinandcisplatinarerarelyusedassingleagentsinmetastaticbreastcancer.
Availabledatasuggesttheresponseratetocisplatinishigheramongchemotherapynaivepatientsratherthanin
womenwhowerepreviouslytreated(ORR42to54percentversuslessthan10percent,respectively)[51].
However,thereisrenewedinterestinusingtheseagentsaspartofacombinationregimen,particularlytotreat
tumorswhereDNAdamagerepairpathwaysareimpaired(suchasinwomenharboringgermlineBRCA1
mutationsandpatientswithtriplenegativebreastcancer).(See'Combinationregimensincorporatingplatinum
salts'below.)
COMBINATIONCHEMOTHERAPYCombinationchemotherapy(ratherthansingleagentsequentialtherapy)
ismostappropriatewhenthehigherchanceofresponseisassessedtobemoreimportantthanthepotentialfor
highertreatmenttoxicity,duetoconcernsaboutimpendingorgandysfunctionfromexistingorrapidlyprogressing
diseaseburden.However,bothcliniciansandpatientsshouldknowtherearenoprospectivedatathatshow
combinationchemotherapyimprovesoverallsurvivalcomparedwithsingleagentsequentialcytotoxic
chemotherapy.
ThiswasshownintheEasternCooperativeGroup(ECOG)1193trialinwhichover700womenwererandomly
assignedtodoxorubicinpluspaclitaxel(AP),doxorubicin,orpaclitaxel.Forthoserandomizedtosingleagent
treatment,theprotocolmandatedcrossovertothealternativeagentatthetimeofdiseaseprogression.Treatment
withAPresultedin:
Ahigheroverallresponserate(ORR)comparedwithdoxorubicinortopaclitaxel(47versus36and34
percent)
Alongermediantimetoprogression(TTP8versus6and6months)
However,therewasnodifferenceinoverallsurvival(OS22versus19and22months)
Althougha2009metaanalysisthatincluded43trials(n=9742women,55percentofwhomweretreatedinthe
firstlinesetting)showedthatcombinationtherapycouldimproveOS[10],thesedataarelimitedbecausetheydid
notevaluatethebenefitsofcombinationchemotherapycomparedwiththesequentialadministrationofagents(eg,
drugAplusBversusdrugAthenB).
Therearefewdatatoinformthebenefitsofcombinationchemotherapyinthesecondorlaterlinesetting.
However,theuseofacombinationinaheavilypretreatedpatientmaybewarranted,particularlyifapatienthasa
significanttumorburden,desiresthebestchanceofaresponse,andiswillingtoacceptthepotentiallysignificant
risksofcombinationtherapy.
Availablecombinationregimensarediscussedbelow.
AnthracyclinecontainingregimensAnthracyclinebasedchemotherapyregimensareassociatedwith
responseratesofupto60percentinpreviouslyuntreatedpatientswithmetastaticbreastcancer[5255],although
theyaremoretoxicthansequentialsingleagenttreatmentornonanthracyclinecontainingcombinations[23,56].
Amongtheavailableregimens,ananthracyclineplustaxanecombinationresultsinahigherresponserate
comparedwithnontaxanecontainingregimens.Thiswasdemonstratedinametaanalysisofpooledindividual
patientdatafromeighttrials(n=3000)thatcomparedanthracyclinecontainingregimens(withoutataxane)with
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anthracyclineplustaxanecombinations[28].Comparedwithnontaxanecontainingtherapy,taxaneplus
anthracyclinetreatmentresultedinasignificantlyhigherORR(57versus46percent)andanimprovementinthe
riskofdiseaseprogression(hazardratio[HR]0.92,95%CI0.850.99).Despitetheseresults,therewasno
differenceinmedianoverallsurvivalbetweenanthracyclineplustaxaneversusanthracyclinecombinationsthatdo
notcontainataxane[28].
Examplesofcommonlyusedanthracyclinebasedcombinationsinclude(see"Treatmentprotocolsforbreast
cancer"):
Doxorubicinpluscyclophosphamide(AC)ORRrangesfrom47to54percent[57,58]
Epirubicinwithcyclophosphamideandfluorouracil(FEC)ORRrangesfrom45to55percent[23,56]
Doxorubicin,docetaxel,pluscyclophosphamide(TAC)ORR77percent[59]
DoxorubicinpluspaclitaxelordocetaxelORRisapproximately40percentforeithercombination[60]
Nonanthracycline,taxanebasedregimensForpatientswhoarenotsuitablecandidatesforanthracyclines,
taxanebasedregimenscanbeadministered.Thechoiceamongthetaxanesisusuallydeterminedbytheprior
treatmenthistory.Giventhelackofcompletecrossresistancebetweenpaclitaxelanddocetaxel,weoftenwill
administerthealternativeagenttotheoneusedintheadjuvantsetting(eg,ifpaclitaxelwasusedadjuvantly,
docetaxelisusedinthemetastaticsetting).Forpatientswhoarechemotherapynaive,thechoicebetweenthem
shouldbebasedonindividualconsiderationsaroundeachoftheirtoxicityprofiles.
GemcitabinepluspaclitaxelordocetaxelGemcitabine(1250mg/m2ondays1and8)pluspaclitaxel(175
mg/m2onday1)resultedinanORRof41percentwhenadministeredasafirstlinetherapyformetastaticbreast
cancer[61].Inaseparatetrial,gemcitabine(1000mg/m2ondays1and8)plusdocetaxel(75mg/m2onday1)
resultedinanORRof43percentinfirstlinetherapy[62].Thesetworegimenshavenotbeencompareddirectly,
butpresumablygemcitabineplusdocetaxelwouldhavehighertoxicity,giventhatbotharemyelotoxicassingle
agents.
CapecitabineplusdocetaxelCapecitabine(1250mg/m2,twicedailyfor14ofevery21days)plus
docetaxel(75mg/m2every21days)(CD)resultedinanORRof42percent[63].Severalstudiesalsosuggestit
improvessurvivaloversingleagentdocetaxelevenwhencapecitabinewasmandatedondiseaseprogression
[63,64].However,limiteddatasuggestthatCDisequivalenttogemcitabineplusdocetaxel(GD)butisthemore
toxiccombination[62].
OtherregimensForpatientswhoarenotcandidatesforanthracyclinesortaxanesandthosewhohave
progresseddespitepriortreatment,thereareseveralavailablealternateoptions.Thesearediscussedbelow.
IxabepilonepluscapecitabineIxabepilone(40mg/m2everythreeweeks)pluscapecitabine(1000mg/m2
twicedailyfor14ofevery21days)resultedinanORRof35percent[65].
Cyclophosphamide,methotrexate,andfluorouracil(CMF)CMFisrarelyadministeredformetastatic
breastcancerbecauseitappearstoproducethesameresponseratewhencomparedwithoralcapecitabine(20
percent)inonetrial[66].However,CMFresultedinashorterOS(median,22versus18monthsHR0.72,95%CI
0.550.94).CMFmaybeindicatedinpatientswhocannottoleratecapecitabineorforpatientsinwhomanoral
regimenisnotfeasibleforwhateverreason.
CombinationregimensincorporatingplatinumsaltsRegimenscombiningplatinumsaltswith
chemotherapiessuchastaxanes,vinorelbine,orgemcitabinehavebeenpostulatedtobespecificallyefficaciousin
tumorswhereDNArepairpathwaysarefaulty,suchasinspecificsubsetsofestrogenreceptor(ER)negative,
progesteronereceptor(PR)negative,andHumanEpidermalGrowthFactorReceptor2(HER2)negativebreast
cancer.(See"Epidemiology,riskfactorsandtheclinicalapproachtoER/PRnegative,HER2negative(Triple
negative)breastcancer",sectionon'Treatmentapproachtotriplenegativebreastcancer'.)
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However,noprospectivetrialshavebeencompletedthatdemonstrateasurvivaladvantagetosuchregimens
comparedwithnonplatinumregimens.Wetypicallyreserveplatinumcontainingcombinationregimensforthose
womenwithgoodperformancestatus,buthighdiseaseburden,whosediseasehasprogressedonotheravailable
chemotherapyagents[67].
HighdosechemotherapyprotocolsHighdosechemotherapywithautologousstemcelltransplantationisnot
anoptionforthestandardtreatmentofmetastaticbreastcancer.A2011systematicreviewthatincludedsix
randomizedtrialsconcludedthathighdosechemotherapydidnotsignificantlyimproveoverallsurvivalandthat
anybenefitfromthistreatmentwasminimal.Therefore,weadviseagainstthesetreatmentsformetastaticbreast
cancer[68].
ADJUNCTIVETHERAPYTheroleofadjunctivetherapy,suchaspainmedicationsandosteoclastinhibitors,
inthetreatmentofpatientswithmetastaticbreastcanceriscoveredseparately.
(See"Cancerpainmanagement:Adjuvantanalgesics(coanalgesics)"and"Cancerpainmanagement:Useof
acetaminophenandnonsteroidalantiinflammatorydrugs"and"Cancerpainmanagementwithopioids:
Optimizinganalgesia"and"Cancerpainmanagement:Generalprinciplesandriskmanagementforpatients
receivingopioids"and"Cancerpainmanagement:Interventionaltherapies".)
(See"Osteoclastinhibitorsforpatientswithbonemetastasesfrombreast,prostate,andothersolidtumors".)
MONITORINGTHERAPYTheongoingevaluationofpatientsduringtherapy(includingtimingofimagingand
theselectionofimagingmodality)shouldbeindividualizedaccordingtopatientandproviderpreferences.Further
discussiononthemonitoringofpatientswithmetastaticbreastcanceriscoveredseparately.(See"Systemic
treatmentformetastaticbreastcancer:Generalprinciples",sectionon'Monitoringtherapy'.)
Carefulassessmentforresponsetotreatmentrequiresserialclinicalexamination,repeatlabevaluation(including
tumormarkers),andradiographicimaging.Althoughthereisnostandardscheduleforevaluationduringtreatment,
areasonableapproachwouldbeasfollows:
Historyandphysicalexampriortothestartofeachtreatmentcycle(ie,dayoneofanew21or28day
treatmentcycle).
Repeatimagingstudies(usingthesameimagingmodalitythroughout)aftercompletionoftwocyclesof
therapy(ie,aftercycletwo,cyclefour,etc).
Serialassayforserumtumormarkers(eg,cancerantigen[CA]153,CA27.29,and/orcarcinoembryonic
antigen[CEA])iftheywereelevatedatbaseline.Ifperformed,wetypicallyreevaluatethematthebeginning
ofeachtreatmentcycle.
DURATIONOFTREATMENTUnlikeintheadjuvantsetting,thereisnopredetermineddurationoftreatment.
Therefore,thedurationofchemotherapyshouldbeindividualizedtakingintoaccountthepatientsgoalsof
treatment,presenceoftreatmenttoxicities,andalternativeoptionsthatmightbeavailable.Ingeneral,patients
shouldcontinuechemotherapytothebestresponse,diseaseprogression,oriftoxicityrequiresdiscontinuationof
treatment.
Forwomenwhorespondtochemotherapy,somedatasuggestthattherearebenefitstocontinuingtreatment
beyondtheirbestresponse(ie,maintenancetherapy):
A2011metaanalysisoffirstlinetreatmentrandomizedtrialsthatincludedalmost2300womencompared
maintenancetreatmentwithtreatmentoveraprespecifiedduration(range,threetoeightcycles)[69].Longer
chemotherapydurationwasassociatedwithimprovementinprogressionfreesurvival(PFShazardratio
[HR]0.64,95%CI0.550.76)andoverallsurvival(OSHR0.91,95%CI0.840.99).
Arandomizedtrialpublishedin2013consistedof324patientswithmetastaticbreastcancer,allofwhom
weretreatedwithpaclitaxelandgemcitabine[70].Patientswhoachieveddiseasecontrol(completeorpartial
response,orstabledisease)totreatment(n=231)wererandomlyassignedtoobservationormaintenance
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chemotherapywiththesameagentsuntildiseaseprogression.
TheadministrationofmaintenancechemotherapyresultedinahigherPFSrateatsixmonthscomparedwith
observation(60versus36percent,respectivelyHR0.73,95%CI0.550.97)andimprovedOS(median,32
versus24monthsHR0.65,95%CI0.420.99).However,continuationofpaclitaxelandgemcitabine
resultedinahigherincidenceofserious(grade3/4)neutropenia(61versus0.9percent)andgrade2/3
neuropathy(0.9verus0percent).
Despitethesefindings,severalissueslimittheuniversalapplicationofthesedatainmetastaticbreast
cancer:
Over70percentofpatientsinthisstudyhadhormonepositivebreastcancerofthesepatients,only
about20percentofthesewomenhadreceivedpriorendocrinetherapyand,forthoseinthecontrolarm,
endocrinetherapywasnotinitiatedafterchemotherapywasdiscontinued.
Themedianageofparticipantswas48,suggestingthatyoungerpatientswerepreferentiallyenrolled.
ThebenefitinPFSwasseenpredominantlyinthesubgroupofwomenwhowereage<50years,had
hormonereceptornegativedisease,hadrespondedtochemotherapy,andhadvisceraldisease.
Whilethesedatasupportmaintenancechemotherapyforwomenwithmetastaticbreastcancer,itshouldnotbe
consideredauniversalapproachtothetreatmentofthesepatients,especiallywhenoneconsidersthebiologic
heterogeneityofbreastcancerandthemultiplewaysthatdiseasecanbetreated.However,fortheyoungpatient
whoisrespondingtotreatment,thesedatasupportthecontinuationofchemotherapybeyondbestresponse,
particularlyifsheacceptstheincreasedrisksoftoxicityassociatedwithcontinuedchemotherapy[71].
DEFINITIONOFTREATMENTFAILUREInourownpractice,wemonitorfortreatmentfailurebytakinginto
accountserialchangesintumormarkers,evidenceofdiseaseprogressionbasedonserialimaging,andthe
clinicalstatusofthepatient.Somecriteriathatweusetodefinetreatmentfailureincludeanyofthefollowing:
Clinicaldeteriorationduringtreatment(ie,increasingdiseaserelatedsymptoms,intolerabletreatment
toxicities,decliningperformancestatus)
Evidenceofnewmetastases
Increasingsizeofpreviouslydocumentedmetastaticlesions
RECISTcriteriaTheprimaryroleofResponseEvaluationCriteriainSolidTumors(RECIST1.1)isto
standardizethereportingofresultsonclinicaltrials(table2)[72].RECISTprimarilyappliestoimagingof
metastaticdisease,anditencompassestwoofthethreereasonsfortreatmentfailure.
AccordingtoRECIST,diseaseprogressiononimagingisdefinedasanyofthefollowing:
A20percentormoreincreaseinthesumofmeasurabletargetlesionscomparedwiththesmallestsum
previouslyrecorded
Theappearanceofanynewlesions
Worseningofexistingnontargetlesions,forexample,bonemetastases
SUMMARYANDRECOMMENDATIONS
Despitethegainsinearlydetection,uptofivepercentofwomendiagnosedwithbreastcancerhave
metastaticdiseaseatthetimeoffirstpresentation.Inaddition,upto30percentofwomenwithearlystage,
nonmetastaticbreastcanceratdiagnosiswilldevelopdistantmetastaticdisease.Althoughmetastatic
breastcancerisunlikelytobecured,meaningfulimprovementsinsurvivalhavebeenseen,coincidentwith
theintroductionofnewersystemictherapies.(See'Introduction'above.)
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Thegoalsoftreatmentofmetastaticbreastcanceraretoprolongsurvivalandimprovequalityoflifeby
reducingcancerrelatedsymptoms.Inordertoachievethesegoalsanindividualizedapproachisneeded
sincenoonestrategycanbeappliedforallwomen.(See'Indications'above.)
Forpatientswithestrogenreceptor(ER),progesteronereceptor(PR),andHumanEpidermalGrowthFactor
Receptor2(HER2)negative(triplenegative)breastcancer,chemotherapyistheonlyoptionfortreatmentof
metastaticbreastcancerbecausetheyarenotcandidatesforendocrineorHER2directedtherapy.(See
'Indications'above.)
Formostpatientswithhormonereceptorpositivedisease,endocrinetherapyisthepreferredtreatmentfor
metastaticbreastcancer.However,wesuggestchemotherapyiftheyaresymptomaticfromtheirdisease
(Grade2C).Thisincludespatientswhoexperiencerapiddiseaseprogressionandthosewithalargetumor
burdeninvolvingvisceralorgans.(See'Indications'above.)
Forpatientsinwhomchemotherapyisrecommended,thechoiceofregimen(ie,singleagentora
combination)andselectionofaspecifictherapydependsonmultiplefactors,includingthetumorburden
(bothintumorvolumeandthepresenceofdiseaserelatedsymptoms),generalhealthstatus,priortreatments
andtoxicities,andpatientpreferences.Thesefactorscanhelpintheformulationofanindividualized
treatmentplaninthefirstorlaterlinesetting.(See'Factorsinfluencingchemotherapychoice'above.)
Forpatientswithalimitedtumorburdenand/orlimitedorminimalcancerrelatedsymptoms,wesuggest
singleagentchemotherapyadministeredsequentiallyratherthancombinationchemotherapy(Grade2B).
(See'Singleagentchemotherapy'above.)
Forselectpatientswithsymptomaticdiseaseduetothelocationofspecificmetastaticlesions(eg,right
upperquadrantpainduetoexpandinglivermetastases,ordyspnearelatedtodiffuselungmetastases)anda
largetumorburden,wesuggestacombinationregimenratherthanasingleagent(Grade2B).Combination
therapyresultsinagreaterlikelihoodofaresponsecomparedwithsingleagenttherapy,whichmaybeofa
sufficientbenefittojustifytherisksoftreatment.(See'Combinationchemotherapy'above.)
Carefulassessmentforresponsetotreatmentrequiresserialclinicalexamination,repeatlabevaluation
(includingtumormarkers),andradiographicimaging.(See'Monitoringtherapy'above.)
Unlikeintheadjuvantsetting,thereisnopredetermineddurationoftreatment.Fortheyoungpatientwhois
respondingtotreatment,wesuggestcontinuationofchemotherapybeyondbestresponse(Grade2B).
However,forpatientswhoexperiencesideeffectstotreatmentorprefernottocontinuetreatmentfor
whateverreason,discontinuationoftreatmentisreasonable.(See'Durationoftreatment'above.)
Somecriteriathatweusetodefinetreatmentfailureincludeanyofthefollowing:clinicaldeteriorationduring
treatment(ie,increasingdiseaserelatedsymptoms,intolerabletreatmenttoxicity,adeclineinperformance
status),appearanceofnewmetastases,andincreasingsizeofpreviouslydocumentedmetastaticlesions.
(See'Definitionoftreatmentfailure'above.)
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