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Smith&Tanagho'sGeneralUrology,18e>

Chapter20.ChemotherapyofUrologicTumors
EricJ.Small,MD

ChemotherapyofUrologicTumors:Introduction
Theuseofchemotherapyinthetreatmentofmalignanttumorsofthegenitourinarysystemservesasa
paradigmforamultidisciplinaryapproachtocancer.Thecarefulintegrationofsurgicalandchemotherapeutic
treatmentshasresultedinimpressiveadvancesinthemanagementofurologiccancer.Bydefinition,surgical
interventionsaredirectedatlocalmanagementofurologictumors,whereaschemotherapyandbiologic
therapyaresystemicinnature.Althoughthereisnoquestionthattherearetimesinthenaturalhistoryofa
genitourinarytumorwhenonlyonetherapeuticmethodisrequired,amultidisciplinaryapproachisalways
calledfor.Thischapterdetailstheimportanceofajointsurgicalmedicalapproachtopatientswithurologic
cancer.Apracticingurologistshouldcollaboratecloselywithamedicaloncologistandshouldfeel
comfortablespeakingwithpatientsabouttheuses,risks,andbenefitsofchemotherapy.

PrinciplesofSystemicTherapy
ClinicalUsesofChemotherapy
Systemictherapyisindicatedinthetreatmentofdisseminatedcancerwheneithercureorpalliationisthegoal.
Inaddition,chemotherapymaybeusedaspartofamultimodalitytreatmentplaninanefforttoimproveboth
localanddistantcontrolofthetumor.Anunderstandingofthegoalsandlimitationsofsystemictherapyin
eachofthesesettingsisessentialforitseffectiveuse.
CurativeIntentofMetastaticDisease
Inconsideringtheroleofpotentiallycurativechemotherapyinpatientswithmetastaticdisease,severalfactors
mustbetakenintoaccount.Thefirstistheresponsivenessofthetumor.Responsivenessisgenerallydefined
bytheobservedpartialorcompleteresponsesthattogetherconstitutetheoverallobjectiveresponserate.The
assessmentofneoplasmswithfrequentbonymetastasessuchasprostatecancer,renalcellcarcinoma,and
transitionalcellcarcinoma(TCC)isdifficult,asapersistentlyabnormalbonescandoesnotnecessarilyimply
residualcancer.Patientsinwhomtheonlysiteofdiseaseisbonegenerallymustbeconsiderednonassessable
byconventionalmeasures,andifavailable,intermediatemarkersofresponse(suchasprostatespecificantigen
[PSA])arerequired.Thetransientworseningappearanceofabonescanwiththerapybutwhichrepresents
healingboneistermedbonescanflare,andcanbeindistinguishablefromtruediseaseprogression.Forthis
reason,assessmentofallparametersincludingsymptomatology,PSAinprostatecancerpatients,CTandMRI
isessential.Forpatientswithmetastaticprostatecancerinwhombonescanflareissuspectedorpossible,
repeatingscansseveralmonthslaterisessential.
Ifcureistheintentwithsystemictherapy,therelevantresponsecriteriontoconsideristhepercentageof
patientsachievingacompleteresponse.Thisnumberislessthan10%inpatientswithmetastaticrenalcell
carcinomaandhormonerefractoryprostatecancer,25%orlessinpatientswithmetastatictransitionalcell
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carcinoma,andupto80%inpatientswithmetastaticgermcellmalignancies.Undersomecircumstances,
however(forexample,inpostchemotherapyresidualmassesinpatientswithgermcellcarcinoma),anapparent
partialresponsecanbeconvertedintoacompleteresponsewithjudiciousresection(seeSectionSystemic
TherapyUsedinConjunctionwithSurgery:AdjuvantandNeoadjuvantTherapy).
Thesecondfeaturetoconsiderintreatingpatientswithpotentiallycurativesystemictherapyistheanticipated
toxicityofsuchtherapy.Ingeneral,higherlevelsoftoxicityareacceptableifacurecanbeachieved,although
caremustbeexercisedtoavoidacureworsethanthedisease.Thisisparticularlytrueinthecaseoffairly
toxictherapiessuchasinterleukin2orbonemarrowtransplantation.Thesetreatmentscanresultinapparent
curesofapproximately10%and30%,respectively,ofpatientswithmetastaticrenalcellcarcinomaor
refractorygermcelltumors(GCTs).Patientsundergoingtheserigoroustherapiesmustbecarefullyselected
andmustbeasfullyinformedaspossibleaboutpotentialtoxicities.
TreatmentofPatientswithIncurableMetastaticCancer
Whenthegoalofsystemictherapyispalliationofsymptomsratherthancure,thetoxicityofthetreatmentto
beofferedmustbebalancedagainstthecancerrelatedsymptomsthepatientisexperiencing,andingeneral,
moretoxictherapiesarenotindicated.Nonetheless,anunderstandingofthepotentialcapabilitiesofsystemic
therapymustbeunderstoodbecauseeveninotherwiseincurablediseasetheremaybearoleforsystemic
therapyifthereisalikelihoodthatthepatient'slifecanbeprolongedwithitsuse.Thisisthecasefordocetaxel
orcabazitaxeltherapyinprostatecancerandcombinationcisplatinumbasedchemotherapyinbladdercancer.
Inaddition,systemicchemotherapycanbeassociatedwithacontrolofpain,andanimprovementinqualityof
life.Thisappearstobethecaseforbothmitoxantroneanddocetaxelinpatientswithmetastatichormone
refractoryprostatecancer.
SystemicTherapyUsedinConjunctionwithSurgery:AdjuvantandNeoadjuvantTherapy
Systemictherapyadministeredafterapatienthasbeenrenderedfreeofdiseasesurgicallyistermedadjuvant
therapy.Severalimportantcriteriamustbemetifadjuvanttherapyistobeusedoutsideofaresearchsetting.
First,anassessmentmustbeundertakenofknownriskfactorspredictiveofrelapseordevelopmentofdistant
metastases.Patientsatlowriskofrelapsegenerallyshouldnotreceiveadjuvanttherapybecausetheyare
unlikelytoderiveabenefitandwillbeunnecessarilyexposedtothetoxicityoftherapy.Second,theproposed
therapymusthavebeenshowntodecreasetherateofrelapseandincreasethediseasefreeinterval(and,itis
hoped,survival)inarandomized,phaseIIItrial.Finally,becausepatientswhoarebeingtreatedwithadjuvant
therapyarefreeofdiseaseandpresumablyasymptomatic,toxicitymustbekeptataminimum.Thisopensthe
waytoatailoredapproachinwhichpatientswithhighriskdisease,asdeterminedbypathologicreviewofthe
surgicalspecimen,aretreatedinordertodecreasetheriskofmicrometastaticdisease.
Bycontrast,neoadjuvanttherapyisadministeredbeforedefinitivesurgicalresection.Here,thepotential
advantagesincludeearlytherapyofmicrometastaticdiseaseandtumordebulkingtoallowamorecomplete
resection.Patientswithknownmetastaticdiseasegenerallydonotexhibithighenoughresponseratesto
systemictherapytowarrantlocalsurgeryfollowingchemotherapy,withtheclearexceptionofpatientswith
GCT.Whetherornotpatientswithmetastaticrenalcellcarcinomawhoexhibitapartialresponsetosystemic
therapymaybenefitfromresectionofresidualmassesisnotknown.Aswithadjuvanttherapy,theproposed
therapymusthavebeendemonstratedtoimpactfavorablyonrateofrelapse,diseasefreeinterval,andsurvival
inarandomizedphaseIIItrial.

ChemotherapeuticAgentsandTheirToxicity
Theusefulnessofantineoplasticagentsliesintheirtherapeuticindexorpreferentialtoxicitytomalignantcells
overnormal,nonmalignantcells.Themechanismofactionofmostchemotherapeuticdrugsisbasedontheir
toxicitytorapidlydividingcells.Thus,ingeneral,malignanciesthathaverelativelyrapidgrowth,suchas
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GCT,arerelativelychemosensitive,whereasslowergrowingneoplasmssuchasrenalcellcarcinomaareless
sensitive.Toxicityfromchemotherapeuticagentsisseenprimarilyinnormal,nonmalignantcellsthatarealso
rapidlydividing,suchashematopoieticcellsinthebonemarrow,gastrointestinalmucosa,andhairfollicles,
andismanifestedincytopenias,mucositis,andalopecia.Othercommontoxicitiesobservedwithagents
frequentlyusedinthetreatmentofgenitourinarymalignanciesincludenephrotoxicity,neurotoxicity,
hemorrhagiccystitis,pulmonaryfibrosis,andcardiotoxicity.Table201summarizesthespectrumofactivity
andprimarytoxicitiesofcommonlyusedchemotherapeuticagents.
Table201.CommonlyUsedChemotherapeuticAgentsinUrologicOncology,andTheirToxicity.
Agent
Activity
Commontoxicities
Bleomycin
Germcelltumors
Fever,chills,pulmonaryfibrosis
Cabazitaxel
Prostatecancer
Myelosupression
Capecitabine
Renalcellcarcinoma
Mucositis,diarrhea,myelosuppression
Carboplatin
Bladdercancer,germcelltumors Myelosuppression
Bladdercancer,germcelltumors, Renalinsufficiency,peripheralneuropathy,auditory
Cisplatin
prostatecancer
toxicity,myelosuppression
Docetaxel
Bladdercancer,germcelltumors,
Myelosuppression,neuropathy
(Taxotere)
prostatecancer
Doxorubicin
Bladdercancer,prostatecancer
Myelosuppression,mucositis,cardiomyopathy
Etoposide(VP
Germcelltumors,prostatecancer Myelosuppression
16)
Gemcitabine
Bladdercancer,renalcell
Myelosuppression
(Gemzar)
carcinoma
Ifosfamide
Germcelltumors
Myelosuppression,neurologic(CNS)toxicity,cystitis
Methotrexate Germcelltumors,bladdercancer Mucositis,myelosuppression,renaltoxicity
Mitoxantrone Prostatecancer
Myelosupression,cardiac
Paclitaxel
Bladdercancer,germcelltumors Myelosuppression,neuropathy
(Taxol)
Bladdercancer,germcelltumors,
Vinblastine
Peripheral,autonomicneuropathymyelosuppression
prostatecancer
Table202.CommonlyUsedChemotherapeuticRegimensinUrologicOncology.
Regimenname,
Indication
Components
ifany
D/P
Docetaxel+Prednisone
Metastaticprostatecancer,castration
resistant,frontline
M/P
Mitoxantrone+Prednisone
Metastaticprostatecancer,castration

Cabazitaxel+Prednisone
resistant,secondline
Bladdercancermetastaticsecondline
ITP
Ifosfamide,Paclitaxel,Cisplatinum
Bleomycin,Etoposide,Cisplatinum,
Germcelltumorsfrontline
BEP
Etoposide,Cisplatinum
VIP
Etoposide,Ifosfamide,Cisplatinum
Germcelltumorssecondline
ITP
Ifosfamide,Paclitaxel,Cisplatinum
Renalcellcarcinoma(rarely)
Gem/cape
Gemcitabine,Capecitabine
Thedevelopmentofchemotherapydrugresistanceremainsanimportantclinicalprobleminthefieldof
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oncology.Malignantcellsdevelopresistanceinavarietyofways,includingtheinductionoftransportpumps,
whichactivelypumpthedrugoutofthecellandthroughincreasedactivityofenzymesnecessarytoinactivate
theparticularchemotherapeuticagent.Althoughthereareseveralexperimentalmethodsofcircumventing
thesemechanismsofdrugresistance,onepracticalapproachtothisproblemistheuseofmultiagent
chemotherapy.Increasedtumorcellkillingisachievedbyexposingneoplasticcellstomultipleagentswith
differentmechanismsofaction.Furthermore,thisapproachallowstheselectionofagentswithnonoverlapping
toxicityprofiles.
Theuseofincreaseddoseintensity(higherdosesofadrugadministeredoverthesametimeperiod)asameans
ofovercomingdrugresistanceremainsexperimentalinurologicmalignancieswithoneclearexception.A
subsetofpatientswithotherwiseincurableGCTappeartobecurablewithhighdosechemotherapyand
autologousbonemarrowtransplantsupport(seethesectionGermCellMalignancies).

UniqueFeaturesofGenitourinaryMalignancies
Thesystemictherapyofurologicmalignanciesoffersuniquechallengestothepractitioner.Renalinsufficiency
duetoobstructiveuropathyfromlocalextensionofthetumororpostsurgicalorpostradiotherapychangesis
notinfrequentandmayalterantineoplasticdrugclearance.Inpatientswithrenalcellcarcinoma,previous
nephrectomymayalsoimpactdrugclearance.Furthermore,thecommonuseofthenephrotoxic
chemotherapeuticagentcisplatininthetreatmentofurologicmalignancies(mostprominently,inbladderand
testicularneoplasms)mayfurtherdiminishrenalfunction.Carefulattentionmustbepaid,therefore,torenal
functionthroughoutthecourseofsystemictherapy,withappropriatedoseadjustmentsmade.Dosing
adjustmentsalsomustbeconsideredinpatientswhohaveundergonecystectomybecauseilealconduitsor
neobladdershavethecapacitytoresorbchemotherapeuticagentsthatareexcretedintheurineinactiveform
(mostnotably,methotrexate).
Frequentlocalextensioninthepelvispresentsadditionaluniqueproblems.Patientswithpreviouspelvic
radiotherapyhavemarkedlydiminishedbonemarrowreserves,whichmaylimittheuseofmyelosuppressive
drugs.Furthermore,localpelvicrelapseshavethepotentialtobesymptomaticandpainful.Particularlyin
patientswhohavealreadyreceivedradiotherapy,systemictherapymaybeimportantforpalliation.

GermCellMalignancies
Overview
TheevolutionoftherapyforGCThasbeendeliberateandthoughtful,andhasresultedincuresof8085%of
menwithGCT,servingasamodelforthetreatmentofcurablecancers.Nonetheless,challengesinthe
managementofGCTremain.Becauseoftheiryoungage,patientswhohavebeencuredareatriskofdelayed,
treatmentinducedtoxicity.Furthermore,an8085%cureratealsoimpliesthat1520%ofpatientswithGCT
willnotbecuredandultimatelywillsuccumbtotheirdisease.Anunderstandingofstagingandrisk
assessmentiscrucialif(1)patientswithgoodriskfeaturesarenottobeovertreatedandexposedtoundue
toxicrisks,and(2)patientswithpoorriskfeaturesaretoreceiveadequate(curative)therapy.
ThemostcommonmultiagentchemotherapyregimenforthetreatmentofGCTisathreedrugcombination
consistingofbleomycin,etoposide,andcisplatin(BEP).Thetreatmentisrepeatedevery21days.Onecycle
consistsofcisplatin20mg/m2IVday15,etoposide100mg/m2IVday15,andbleomycin,30unitsIV,day
2,9,and16.Frequentlythefirst5daysoftreatmentrequirehospitalization.Thedeletionofbleomycinfrom
thisregimenresultsinthepulmonaryembolus(PE)regimen.Thesubstitutionofifosfamideforbleomycin
yieldstheVIPregime(UP16,ifosfamide,platinum).

UseofChemotherapyforPatientswithStageIandIIDisease
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ThestandardofcareforpatientswithstageIGCTremainsorchiectomyfollowedbyretroperitoneal
lymphadenectomyorsurveillancefornonseminomapatients.Inseminomapatients,followingorchiectomy,a
singledoseofcarboplatinhasbeenshowntobeaseffectiveasretroperitonealradiation,andmaybeassociated
withalowerincidenceofsecondarymalignancies,includingcontralateraltesticularneoplasms.Surveillanceis
alsoanappropriateoptionforStageIseminomapatients.
PatientswithstageIInonseminomatousmicroscopicdiseaseidentifiedatlymphadenectomy(stageIIA)or
patientswithlowvolumeclinicalstageIIdisease(stageIIB)whohaveundergoneretroperitoneal
lymphadenectomymaybenefitfromtwocyclesofadjuvantPEorcisplatinetoposidebleomycin(PEB)
chemotherapy.Theuseofadjuvanttherapyresultsina96%longtermdiseasefreesurvival.Whiletherelapse
rateforpatientswhodonotreceiveadjuvanttherapyrangesfrom2040%,thevastmajorityofrelapsing
patientscanalsobecuredwitheitherthreeorfourcyclesofsubsequentchemotherapy,yieldinganidentical
longtermsurvivalrate.Thedecisionaboutadjuvantchemotherapyafterlymphadenectomymustbe
individualized.Patientsathighriskforrelapsemaychoosetoundergotwocyclesofchemotherapyatthat
pointinordertoavoidthepossibilityofthreetofourcyclesinthefuture.

UseofChemotherapyinPatientswithAdvancedDisease
PatientswithadvancedGCTshouldbetreatedwithsystemictherapyaftercompletionoftheirorchiectomy.
ThisgroupincludessomestageIIBnonseminomatoustumorsandallstageIICorhighertumors,both
seminomasandnonseminomas.Avarietyofchemotherapyregimenswillresultinapproximately80%of
patientswithadvancedGCTachievingacompleteresponseand70%achievinglongtermapparentcures
(goodprognosis).Bythesametoken,however,2030%ofpatientshaveapoorprognosisandwillstill
ultimatelydiefromtheirdisease.Studiesofpretreatmentclinicalcharacteristicshavesoughttoidentify
prognosticfeaturesthatcanbeprospectivelyusedtosegregatethisdiversegroupofadvancedGCTpatients
intopoorandgoodprognosticsubsets.
AcommonclassificationsystemhasbeendevelopedbytheInternationalGermCellCancerCollaborative
Group(IGCCC).Inthissystem,goodprognosispatientswithnonseminomatousGCThaveatestisor
retroperitonealprimarytumor,nononpulmonaryvisceralmetastases,andlowserumtumormarkers.
Intermediateprognosispatientsarethesameasgoodprognosispatientsbuthaveintermediateserumtumor
markers.Poorprognosispatientshaveamediastinalprimarytumorornonpulmonaryvisceralmetastases
(liver,bone,brain)orhighlevelsofserumtumormarkers.Fiveyearoverallsurvivalforthegood,
intermediate,andpoorprognosiscategorieswithcurrentregimensis92%,80%,and48%,respectively.By
definition,seminomasareneverinthepoorprognosiscategory.Seminomasaresegregatedintogood
prognosiscases(anyprimarysite,butnononpulmonaryvisceralmetastases),withan86%5yearsurvival,and
intermediateprognosiscases(anyprimarysitebutwiththepresenceofnonpulmonaryvisceralmetastases),
witha72%5yearsurvival.
Becauseitisnotlikelythattheextraordinarilyhighcurerateforgoodprognosispatientscanbeimproved
upon,mosteffortsinthetreatmentofthesepatientshavebeenaimedatoptimizingtreatmentwithlesstoxic
regimensthatwillhaveequalefficacy.Trialsevaluating(1)theeliminationofbleomycin,(2)areductionin
thenumberofchemotherapycyclesadministered,or(3)thesubstitutionofcarboplatinforcisplatinhavebeen
undertaken.
Theoutlookforpoorprognosispatientsisnotasgood,withonlyapproximately3060%ofpatientsachieving
acompleteresponse.Thus,whereasthemajorconcerningoodprognosispatientshasbeenthereductionof
toxicity,themajorobjectiveofclinicalinvestigationinpoorprognosispatientshasbeentoimproveefficacy,
withlessconcernforreducingtoxicity.Clinicaltrialsinpoorprognosispatientshavebyandlargereliedon
oneorbothoftwoapproaches.Thefirsthasbeentoexploitagentsthathavebeendemonstratedtobe
efficaciousinthesalvagesetting,andthesecondhasbeentoevaluatetheroleofdoseescalation.
Currentlyacceptableregimensforgoodprognosispatientsarefairlywelldefinedandincludethreecyclesof
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PEBorfourcyclesofPE.Bycontrast,optimaltherapyforpoorprognosispatientsisnotfullydefined.Four
cyclesofPEBorfourcyclesofVIPareappropriateoptions.Theuseofhighdosechemotherapywith
peripheralstemcelltransplantdoesnotappeartoimproveoutcomesoverconventionalhighrisktherapy.

AdjunctiveSurgeryandSalvageTherapy
Postchemotherapyadjunctivesurgerymustbeintegratedintothetreatmentplanofpatientswithadvanced
GCT.Approximately20%ofpatientswithGCTshaveresidualmassesaftersystemictherapy.Theroleof
adjunctivesurgeryinpatientswithGCTwithpostchemotherapyresidualmasseshasbeenreviewed.Exceptin
rarecircumstances,adjunctivesurgeryisnotindicatedinthepresenceofpersistentlyelevatedserumtumor
markers.Adjunctivesurgeryusuallycanbeundertakensafelywithin12monthsofcompletionof
chemotherapy.Itmustbenoted,however,thatallpatientswhohavereceivedbleomycin,whetherornotthere
isclinicalevidenceofpulmonaryfibrosis,areatriskofdevelopmentofoxygenrelatedpulmonarytoxicity.
Theanesthesiologistmustbemadeawareofthepatient'spreviousexposuretobleomycinandeveryeffort
mustbetakentomaintaintheFiO2aslowaspossiblethroughoutthesurgicalprocedure.Patientswhoare
foundtohaveactivecarcinomaintheirresectedspecimensarefrequentlytreatedwithfurthersalvage
chemotherapy,generallywithadifferentregimen,althoughcompellingevidencesupportingthisprocedureis
stillforthcoming.Patientswhoappeartobenefitfrompostsurgicalchemotherapyarepatientswithincomplete
resections,patientswhoseresectedspecimencontainsmorethan10%viablecancercells,andpatientswho
wereintheIGCCChighriskgrouppriortobeginningfrontlinechemotherapy.
Whileapproximately80%ofpatientswithGCTcancurrentlybecuredwithplatinumbasedtherapy,20%
ultimatelydieoftheirdisease,eitherbecauseacompleteresponseisnotachievedwithinductiontherapyor
becausetheyrelapseafterbecomingdiseasefreewithprimarytherapy.Beforetheinitiationofsalvagetherapy,
thediagnosisofrelapsedorprimary,refractoryGCTmustbeclearlyestablished.Inparticular,falselyelevated
humanchorionicgonadotropinoralphafetoproteinvaluesandfalsepositiveradiographicstudiesofthechest
duetopreviousbleomycinusemustberuledout.Persistentorslowlygrowingmasses,particularlyinthe
absenceofserologicprogression,mayrepresentbenignteratoma.Therapiesbasedonifosfamide,paclitaxel,or
highdosechemotherapywithautologousbonemarrowtransplantprovideasalvagerateofapproximately25%
inpatientswithrelapsedorrefractoryGCT.

TransitionalCellCarcinomaoftheUroepithelium
NonmetastaticDisease
Thedevelopmentofeffectivechemotherapyregimensforthetreatmentofmetastatictransitionalcell
carcinoma(TCC)hasresultedinmorewidespreaduseoftheseregimensincombinationwithothermodesfor
thetreatmentoflocallyadvancedbutnonmetastaticdisease.Inbulkyinoperableinvasivebladdertumors(T3b,
T4,N+),chemotherapyhasbeenusedasameansofcytoreductioninordertomakesurgerypossible.
Chemotherapybeforesurgery,termedneoadjuvanttherapy,hasalsobeenusedinmuscleinvasivecancers
thatareresectable,inanefforttotreatmicrometastaticdiseasebeforecystectomy.Itmustbeborneinmind
thatthepathologiccompleteresponserateinthebladderafterneoadjuvantchemotherapyisprobablyinthe
2040%rangetherefore,definitivesurgicalresectionafterchemotherapyisusuallyrequired.Asurvival
advantagehasbeendemonstratedwithneoadjuvantmethotrexate,vinblastine,doxorubicinandcisplatin
(MVAC)chemotherapy(comparedwithnochemotherapy,andthisisthereforeconsideredthestandardofcare
formuscleinvasivedisease).
AdjuvanttrialsgenerallyhavebeenusedtotreatonlypatientsfoundtohavepathologicT3andT4lesionsafter
radicalcystectomy.Severalsmall,randomizedtrialshaveshownabenefittovariousadjuvantchemotherapy
regimensalargerandomizedmultiinstitutiontrialremainstobedone.
Chemotherapyincombinationwithradiationtherapyhasbeenadvocatedbysomeasabladderpreserving
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approachformuscleinvasivetumors.Patientsareusuallytreatedwithtwocyclesofchemotherapy,followed
byradiationtherapyandconcomitantcisplatinasaradiosensitizer.Iffollowupcystoscopyrevealsnocancer,
consolidativemultiagentsystemicchemotherapyisadministered.Thisapproachappearstobeparticularly
usefulforsmaller,lowerstagetumors.Thepresenceofhydronephrosisorhydroureterisacontradictiontothis
approach,asthesepatientsdolesswellwithabladdersparingapproach.Whilelongerfollowupisrequired,it
appearsthatapproximately3050%ofpatientscanattainlongtermdiseasefreestatuswithafunctional
bladderwiththisapproach.

MetastaticDisease
ThedevelopmentofsuccessfultherapyofmetastaticbladderTCChasbeenbasedontheuseofcisplatin.Until
recently,twocommoncisplatinbasedregimensareinwideuse:(1)cisplatin,methotrexate,andvinblastine
(CMV)and(2)thesamedrugsinaslightlydifferentscheduleanddosealongwithdoxorubicin(Adriamycin),
inaregimenknownasMVAC.Theseregimensresultinoverallresponseratesofapproximately5060%and
completeremissionratesinthe2035%range.Medianoverallsurvivalforpatientswithmetastaticdisease
treatedwiththeseregimensisinthe8to14monthrange.Despiteearlypromise,however,longtermsurvival
afterMVACorCMVremainsinthesingledigits.BothCMVandMVACareintensiveregimens,with
myelosuppressionoccurringcommonly.Theuseofhematopoieticgrowthfactorshasmadeiteasierto
administerfulldosesonschedule,althoughthisimprovementindoseintensitydoesnotappeartotranslateinto
aclinicalbenefit.
ThecombinationofgemcitabineandcisplatinhasbeencomparedtoMVAC,andhasbeenshowntobeless
toxicandequivalentinefficacytoMVAC.Asaconsequence,gemcitabine/cisplatincanbeconsideredthe
standardofcareforthetreatmentofadvancedTCC.However,itshouldbenotedthatthegemcitabine/cisplatin
regimehasbeentestedinarandomizedstudyonlyinpatientswithmetastaticdisease,anditsutilityasan
adjuvantorneoadjuvanthasnotbeentested.Forpatientswithimpairedrenalfunction,agentssuchas
carboplatinandpaclitaxelhavebeenutilized.

RenalCellCarcinoma
Thetreatmentofmetastaticrenalcellcarcinomawithchemotherapyremainslargelyunsatisfactory.The
generallackofactiveagentsandtheexcessivetoxicityofmanyoftheagentsthatexhibitsomeactivityhave
contributedtotheabsenceofadjuvantorneoadjuvanttrials.Trialsthatusedadjuvantinterferonalphafor
patientsconsideredathighriskforrelapseafternephrectomyfailedtoshowanadvantageoftheadjuvant
therapy.Alargeadjuvanttrialofthenoveltyrosinekinaseinhibitors,sorafenibandsunitinib,isunderway.
Metastaticrenalcellcarcinomaisrelativelyresistanttochemotherapy.Thefluoropyrimidinescapecitabinehas
modestactivity,asdoesgemcitabine,withresponseproportionsof1015%reported.Renalcellcarcinomais
oneofveryfewneoplasmsthatclearlyareresponsivetobiologicresponsemodifiers.Theutilityofbiologic
responsemodifiers,antiangiogenicagents,tyrosinekinaseinhibitors,andmammaliantargetofrapamycin
(mTOR)inhibitorsinrenalcellcarcinomaarediscussedelsewhereinChapter20.Theseagentsareusedprior
tousingchemotherapy.

HormoneRefractoryProstateCancer
Thesystemictherapyofpatientswithmetastaticprostatecancerinwhomhormonaltherapyhasfailed
generallyconsistsofsecondaryhormonalmanipulationsfollowedbychemotherapy.Approximately15%of
patientswhohavehadprogressivediseasedespitetherapywithcombinedandrogenblockadewillhaveafall
inPSAwhentheirantiandrogenisdiscontinued.Thismaneuverismandated,therefore,beforeinitiatingother
systemictherapy.Furthermore,secondlinehormonalmaneuverssuchasadrenalandrogendeprivationwith
ketoconazole,estrogens,orsecondaryantiandrogenssuchasnilutamideclearlyhaveactivityand,particularly
inasymptomaticpatients,shouldbeconsidered.Asnotedpreviously,theevaluationofresponsesinpatients
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withbonediseaseonlyischallenging.TheuseofthePSAinthissettinghasbeenfairlyextensivelyevaluated,
anditappearstobeareasonableintermediateendpoint.Thus,adeclineinPSAof3050%appearstobe
predictiveoflongersurvivalforthesepatients.
Mitoxantroneisapprovedincombinationwithprednisoneforthetreatmentofprogressive,symptomatic
hormonerefractoryprostatecancer(HRPC).Twentyninepercentofthosetreatedwiththecombination
experienceddecreasedpain,comparedwith12%receivingprednisonealone.Inaddition,thereweregreater
improvementsinqualityoflifemeasures.Thetoxicityofthetreatmentwasmildinbothgroupsfewerthan
2%ofpatientshadinfectiousepisodes.Mediansurvivalforbothgroupswasapproximately1year.
MitoxantronehasmodestalbeitdefinableactivityinHRPC,althoughitprobablydoesnotsignificantly
prolongsurvival.
Untilrecently,chemotherapyforprostatecancerwasconsideredineffectiveinprolongingsurvival.However,
theresultsoftwophaseIIItrialshaveestablisheddocetaxelbasedchemotherapyasthestandardofcarefor
firstlinetreatmentofmetastaticHRPC.Theevery3weekdocetaxelregimensineachoneofthesetrials
demonstratedamodestbutstatisticallysignificant(2month)survivalbenefitovermitoxantrone/prednisone.
Themediansurvivalwithdocetaxelwas1819months.Thus,every3weekdocetaxel/prednisonehasemerged
astheFDAapproved,firstlineregimenforHRPC.Followingtherapywithdocetaxel,patientswhoremain
candidatesforfurtherchemotherapycanbetreatedwithcabazitaxel,anagentshowntoprolonglifeinthis
groupofpatientscomparedwithmitoxantrone/prednisone.ZolendronicacidorDenosumabareindicatedin
castrationresistantprostatecancer(CRPC)patientswithbonemetastases,aseachreducestheincidenceof
skeletalrelatedevents.
Manypatientswithadvancedprostatecancerhavebonepainorfunctionalimpairmentsthatadverselyaffect
qualityoflife,andprovisionofappropriatepalliativecareisanintegralcomponentoftheirmanagement.In
additiontotheusualanalgesics,glucocorticoidsserveasantiinflammatoryagentsandcanalleviatebonepain.
Forpatientswithwidespreadbonemetastasesandpainnoteasilycontrolledwithanalgesicsorlocalirradiation
strontium89andsamarium153canbeadministeredintravenouslytheyareselectivelyconcentratedinbone
metastasesandalleviatepainin70%ormoreoftreatedpatients.

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