Cancerul de prostata avanseaz de la un hormon-sensibil, androgen-dependente etap, un hormon-refractar, androgen-independent tumorii.Func]iile cale receptorilor androgeni n aceste tumori androgen-independent, n ciuda anti-androgen terapie. Cel mal mulLl paclenLl raspund la Lerapllle sLandard de ablaLle androgenl dar in cele dln urm aproape Lo(l paclen(ll cu recdere cu boala care a fosL numlL boala hormon derefracLar sau androgenlndependenL LforLurlle de a uLlllza anLagonl;Ll al A8 cum ar fl fluLamlda sau blcaluLamld penLru a imbunL(l rspunsurlle la Lerapla prlmara ablaLle androgenl sau penLru a LraLa androgenlndependenL de cancer de prosLaLa au fosL dezamglLoare care a dlmlnuaL enLuzlasmul penLru meLode mal agreslve sau alLernaLlve penLru a bloca func(la de A8 Cu LoaLe acesLea mulLe llnll de dovezl lndlc fapLul c func(la de A8 conLrlbule la supravleLulrea celulelor Lumorale dup ablaLle androgenl ;l la o cre;Lere a cancerulul de prosLaL androgenlndependenL Abstract ,osL cases of advanced carclnoma of Lhe prosLaLe are hormonosenslLlve 1he use of comblned androgen blockade (CA8) seems Lo lmprove survlval and quallLy of llfe buL only when comblned wlLh chemlcal casLraLlon by luLelnlzlnghormonereleaslng hormone analog and wlLhouL Lhe use of sLeroldal anLlandrogens AfLer CA8 furLher hormonal LreaLmenLs remaln efflcaclous such as anLlandrogen wlLhdrawal followed by esLrogens aromaLase lnhlblLors and hormonerefracLory prosLaLe cancer mulLlple cyLoLoxlc agenLs lor palnful bone leslons exLernal beam radloLherapy blphosphonaLes and sLronLlum 89 or samarlum 133 provlde paln rellef 1he use of new meLhods for Lhe evaluaLlon of response and quallLy of llfe wlll allow Lhe rapld ldenLlflcaLlon of effecLlve LreaLmenLs and permlL powered phase lll Lrlals

Introduct|on rosLaLe cancer ls Lhe cause of more Lhan 1 of all deaLhs ln men lLs lncldence ls lncreaslng by 23 per year 1here are Lwo maln reasons for Lhls lncrease 1he flrsL ls lncreased llfe expecLancy and Lhe second ls LhaL prosLaLespeclflc anLlgen (SA) LesLlng has enabled earller and more accuraLe dlagnosls of Lhe dlsease 1he general prognosls for dlagnosed prosLaLe cancer remalns poor wlLh 70 survlval aL 10 years compared Lo Lhe general populaLlon AbouL 30 of cases are dlagnosed aL a locally advanced sLage and abouL 30 have bone meLasLases aL Lhe Llme of dlagnosls 1 ln 1996 ln Lhe unlLed SLaLes 317000 new cases were dlagnosed and 41000 deaLhs reporLed 1hls laLLer flgure represenLs 13 of all uS cancer deaLhs ln lay Lerms Lhls means LhaL one deaLh from prosLaLe cancer occurred every 13 mlnuLes 2 ln 1990 slmllar flgures were recorded ln lrance wlLh 17600 new cases and 9200 deaLhs reporLed (11 of all cancer deaLhs) 3 Powever ln 1999 Lhe 33rd annual compllaLlon of cancer sLaLlsLlcs 4 showed LhaL Lhe lncldence of prosLaLe cancer had decreased slgnlflcanLly wlLh a decllne ln deaLh raLe of 11 slnce 1991 1hese sLaLlsLlcs also reporLed an lncrease of 20 ln 10year survlval beLween 1988 and 1993 SysLemlc LreaLmenLs for prosLaLe cancer lnclude varlous Lypes of hormone Lherapy 8lphosphonaLes or radlonuclldes such as sLronLlum 89 or oLher lsoLopes may be used ln cases where bone leslons are ldenLlfled CLher LreaLmenLs lnclude exLernal radloLherapy and surgery ChemoLherapy has become an addlLlonal opLlon when hormone LreaLmenL falls 3 6 @reatment Cpt|ons for normoneSens|t|ve D|sease Around 73 of meLasLaLlc prosLaLe cancers are hormone senslLlve 1he average Llme for response Lo androgen deprlvaLlon ls abouL 18 monLhs survlval afLer secondllne LreaLmenL varles from 6 Lo 10 monLhs 7 Lar|y @reatment lor sympLomaLlc paLlenLs or for Lhose wlLh progresslve dlsease hormonal LreaLmenL ls consldered compulsory Powever for nonsympLomaLlc hormonesenslLlve paLlenLs Lhls may noL necessarlly be Lhe case Pormonal LreaLmenL has unwanLed slde effecLs parLlcularly of a sexual naLure 1he cosLs of such LreaLmenL may also be conslderable lL ls also lmporLanL Lo remember LhaL hormone LreaLmenL conLlnues Lo remaln effecLlve ln nonsympLomaLlc paLlenLs Powever delaylng LreaLmenL by [usL nlne monLhs lnLroduces Lhe rlsk of splnal cord compresslon ln Lhelr sLudy ctowfotJ and coworkers 8 have shown LhaL 43 of prosLaLe cancer paLlenLs regarded quallLy of llfe as more lmporLanL as opposed Lo 29 who sLaLed a preference for prolonged survlval A Lrlal carrled ouL by ,edlcal 8esearch Councll rosLaLe Cancer Worklng arLy lnvesLlgaLor Croup comparlng early versus delayed LreaLmenL has recenLly been publlshed 9 lor Lhe flrsL Llme Lhe beneflLs of early LreaLmenL have been clearly demonsLraLed ln Lerms of meLasLaLlc progresslon compllcaLlons and deaLhs relaLed Lo cancer Androgen Depr|vat|on Slnce Lhe publlcaLlon of Lhe early works of ln 1941 10 Lhe prlmary LreaLmenL for prosLaLe cancer has been Lo sLop LesLlcular androgen producLlon 1hls can be achleved by casLraLlon uslng esLrogens such as dleLhylsLllbesLrol (uLS) or more recenLly uslng anLlandrogens (AAs) and luLelnlzlnghormonereleaslng hormone (LP8P) agonlsLs (monLhly or every Lhree monLhs) 1hls LreaLmenL decreases Lhe plasma level of LesLosLerone by 93 Androgen deprlvaLlon however ls assoclaLed wlLh numerous posslble slde effecLs 1hese lnclude decreased llbldo lmpoLence hoL flushes anemla halr loss osLeoporosls faLlgue and psychologlcal facLors 1he appearance of Lhese effecLs markedly alLers Lhe paLlenLs quallLy of llfe costrotion CasLraLlon ls elLher carrled ouL surglcally by bllaLeral orchlecLomy or medlcally by LP8P agonlsLs such as LrlpLorellne leuprorellne buserellne and goserellne 1hese LreaLmenLs may someLlmes lnduce a paradoxlcal effecL usually descrlbed as a flareup" 1hls effecL ls more frequenL ln cases lnvolvlng bone leslons and ls due Lo lnlLlal Lemporary lncreases ln levels of LP and LesLosLerone 1hese may lead Lo bone palns LhaL lasL for abouL a week 1hls phenomenon explalns Lhe need for an AA LhaL musL be Laken for Lwo weeks before and afLer medlcal casLraLlon ln order Lo avold Lhls flareup effecL stroqens lor many years Lhese agenLs have been regarded as Lhe gold sLandards ln androgen blockade 1hey lnfluence Lhe plLulLary axls adrenal secreLlon and 3alphareducLase acLlvlLy 1hey have played a very lmporLanL role ln hormonal Lherapy Powever uLS does have lLs drawbacks due Lo lLs cardlovascular LoxlclLy As has been demonsLraLed ln a sLudy of veLerans 11 Lhe beneflLs obLalned from 3 mg/d of uLS appear Lo be counLered by Lhe reporLed slde effecLs 1hese resulLs have led Lo Lhe use of lower doses of uLS even as low as 1 mg/d 1hese low doses have resulLed ln LherapeuLlc beneflLs and reduced rlsk of cardloLoxlclLy ln cerLaln paLlenLs even Lhough lL appears LhaL Lhe Lhreshold dose of 3 mg/d ls necessary Lo obLaln LoLal androgen blockade ln lrance fosfesLrol ls wldely used mosLly by lv admlnlsLraLlon 12 AnoLher esLrogen ls esLramusLlne phosphaLe whlch has Lhe advanLage of havlng boLh a hormonal sLeroldal componenL and a nlLrogen musLard alkylaLlng agenL 1he besL known acLlon of esLramusLlne ls Lhe depolymerlzaLlon of mlcroLubules by lnLeracLlon wlLh Lubulln Powever esLramusLlne has also been demonsLraLed Lo have a cyLoLoxlc acLlon by blndlng Lo Lhe nuclear maLrlx 13 14 @ota| Androgen 8|ockade 1hls concepL developed by ln 1943 ls based on Lhe facL LhaL Lhe prosLaLlc cells are androgen dependenL and Lhls ls parLlcularly so for dlhydroLesLosLerone (uP1) a very acLlve meLabollLe of LesLosLerone 1he producLlon of Lhls meLabollLe ln Lhe prosLaLlc gland means LhaL levels of androgen followlng casLraLlon vary beLween 20 and 40 of normal levels 13 ln facL Lhere are Lwo paLhways Lo brlng abouL Lhe LransformaLlon of LesLosLerone lnLo uP1 Cne rouLe depends on Lhe acLlon of Lhe enzyme 3alphareducLase LhaL Lransforms LesLosLerone lnLo uP1 1he oLher rouLe lnvolves producLlon of dehydroeplandrosLerone by Lhe adrenal glands 1hls ls converLed Lo LesLosLerone and Lhen Lo uP1 ln Lhe prosLaLlc gland 1he dlscovery LhaL mosL meLasLaLlc prosLaLe cancers are sLlmulaLed by androgens led Lo Lhe search for and developmenL of dlfferenL means for Lhelr suppresslon As a resulL of work 10 bllaLeral orchlecLomy was long consldered Lo be Lhe sLandard LreaLmenL ,ore recenLly esLrogens LP8P agonlsLs and AAs have emerged as newer LreaLmenL opLlons ntiondroqens 1he mode of acLlon of Lhe AAs resulLs ln Lhe blockade of Lhe androgen recepLors of Lhe prosLaLe cells 1here are Lwo Lypes of AAs sLeroldal AAs and nonsLeroldal AAs (nSAAs) SLeroldal AAs lnduce a decrease ln plasma levels of LesLosLerone by slowlng Lhe release of plLulLary LP and by parLlal lnhlblLlon of 3alphareducLase SLeroldal AAs lnclude cyproLerone aceLaLe and megesLrol aceLaLe whlch also block Lhe cellular androgen recepLors 1he nSAAs are more lnLeresLlng from a cllnlcal polnL of vlew because Lhey are purely AAs acLlng malnly by lnhlblLlng compeLlLlon wlLh Lhe flxaLlon of uP1 on Lhe androgen recepLors 1hey do noL reduce and may even lncrease Lhe plasma levels of LesLosLerone and Lhls may have an lmpacL on Lhe llbldo of Lhe paLlenLs 1he nSAAs lnclude fluLamlde nlluLamlde and blcaluLamlde 1oto/ ndroqen 8/ockode 1he assoclaLlon of AAs wlLh an LP8P agonlsL such as leuprollde allows LoLal androgen blockade (1A8) aL boLh LesLlcular and adrenal levels 8esulLs of Lhe flrsL randomlzed naLlonal Cancer lnsLlLuLe sLudy LhaL Look place ln 1989 16 were very encouraglng ln Lhls sLudy 603 sLage 2 paLlenLs were randomlzed beLween chemlcal casLraLlon wlLh leuprollde and placebo or AA wlLh fluLamlde 1he resulLs showed an lmprovemenL ln Lhe raLe of progresslon (136 versus 163 monLhs) and a marked lmprovemenL ln global survlval (283 versus 336 monLhs) a galn of 73 monLhs ( 0033) ln Lhe 1A8 group 1hese resulLs reporLed by ctowfotJ and colleagues were laLer conflrmed ln 1993 by a Luropean CrganlsaLlon for 8esearch and 1reaLmenL of Cancer (LC81C) sLudy AL Lhe same Llme ue and coworkers 17 reporLed a slmllar lmprovemenL ln survlval Llme of 73 monLhs ( 002) ln favor of a comblnaLlon of fluLamlde wlLh LP8P agonlsL compared Lo orchlecLomy alone ln 1993 ctowfotJ 18 ln a second sLudy wlLh 1387 u2 paLlenLs LreaLed wlLh orchlecLomy and fluLamlde or placebo dld noL flnd such a clearcuL dlfference ln Lhe decrease of SA or ln progresslonfree survlval (33 versus 30 monLhs) ln Lhe same year a meLaanalysls of 23 Lrlals comparlng casLraLlon alone Lo 1A8 19 found no slgnlflcanL dlfference beLween Lhe Lwo LreaLmenLs (flveyear survlval 228 versus 262 00312) 1he dlfferenL means of achlevlng 1A8 do noL appear Lo be equlvalenL 1he longLerm effecLs of uslng esLrogens and LP8P agonlsLs compared Lo bllaLeral orchlecLomy do noL seem Lo be Lhe same 20 1he Lrlals LhaL show a slgnlflcanL beneflL wlLh 1A8 ln Lerms of survlval are Lhose where casLraLlon ls medlcal and nonsurglcal lL has been shown LhaL esLrogens and Lhe LP8P agonlsLs have a dlrecL cyLoLoxlc effecL on prosLaLe cancer cells 21 ,oreover Lhe assoclaLlon beLween LP8P agonlsLs and AAs seems Lo have an addlLlve lf noL synerglsLlc effecL lndeed lnvesLlgaLlons of recepLors Lo LP8P 20 on lmmorLal llnes of prosLaLe cancer cells (LnCa and ALvA31) have Laken place 8esulLs revealed LhaL Lhe comblnaLlon of LP8P agonlsLs wlLh AAs has greaLer powers of lnhlblLlon Lhan each one of Lhem alone acLlng on androgen senslLlve (LnCa) or reslsLanL llnes (ALvA31) coet and colleagues 22 ln a recenL meLaanalysls used rlgld lncluslon crlLerla LhaL excluded nonrandomlzed sLudles and Lhose sLudles where Lhere ls no nSAA 1hls meLaanalysls lncluded nlne sLudles and esLabllshed Lhe beneflLs of 1A8 ln Lerms of ob[ecLlve response as well as progresslonfree survlval and overall survlval (buL wlLhouL slgnlflcanL sLaLlsLlcal dlfference) ln Lhe conLexL of 1A8 Lhe use of LP8P agonlsLs wlLh nSAAs appears Lo be Lhe beLLer opLlon lluLamlde ls Lhe reference AA A recenL randomlzed sLudy of 813 paLlenLs 13 compared fluLamlde wlLh blcaluLamlde assoclaLed wlLh an LP8P agonlsL 1he resulLs show progresslonfree survlval and an ldenLlcal survlval aL 93 weeks buL wlLh a beLLer Lolerance Lo blcaluLamlde especlally gasLrolnLesLlnal (lower lncldence of dlarrhea) 23 Interm|ttent Androgen 8|ockade Several lnvesLlgaLors 24 have suggesLed LhaL hormone Lherapy be sLopped when normallzaLlon of SA level ls achleved and LhaL hormone Lherapy should be sLarLed agaln ln case of relapse 1he alms are Lo lncrease Lhe quallLy of llfe of Lhese paLlenLs and Lo delay Lhe appearance of hormonal reslsLance 1o [usLlfy Lhls sLraLegy Lhese lnvesLlgaLors conslder LhaL apopLosls ls hormone dependenL and Lhe Lumor can grow even ln Lhe absence of LesLosLerone CerLalnly Lhls ls llnked Lo Lhe selecLlon of hormonereslsLanL clones buL geneLlc alLeraLlons may appear ln Lhls cellularreslsLanL populaLlon 23 26 Androgen (LesLosLerone) producLlon would allow a Lumoral redlfferenLlaLlon and relnduce Lhe capaclLy of prosLaLe cancer cells for apopLosls and so would reLaln hormonal dependence 27 and agaln effecLlveness of androgen blockade 1hls approach would permlL a beLLer quallLy of llfe along wlLh assoclaLed obvlous economlc beneflLs As has already been menLloned LhectowfotJ sLudy 8 has shown LhaL paLlenLs prefer preservaLlon of quallLy of llfe raLher Lhan prolonged survlval (43 for preservaLlon of quallLy of llfe 29 for Lhe prolongaLlon of survlval and 13 for survlval wlLhouL progresslon) Conversely physlclans seem Lo focus on efflcacy of LreaLmenL ,et ln a personal communlcaLlon has reporLed LhaL 23 ouL of 31 paLlenLs LreaLed wlLh lnLermlLLenL androgen blockade who were sexually acLlve before Lhe beglnnlng of Lhe LreaLmenL redlscovered Lhelr sexual acLlvlLy when hormonal Lherapy was sLopped once Lhe deslred response had been achleved revlous SecLlonnexL SecLlon SecondL|ne @reatment AA W|thdrawa| 1he need for secondllne LreaLmenL or Lhe need Lo lnLerrupL AA Lherapy 28 may follow fallure of 1A8 1hls may Lake place afLer an 18monLh response Lo androgen deprlvaLlon 1hree sLudles reporLed by oll 7 lnvolvlng 139 paLlenLs on fluLamlde wlLh progresslve dlsease have lndeed shown LhaL slmple wlLhdrawal of fluLamlde broughL a SA decrease ln abouL 21 of Lhe cases wlLh a medlan response of 33 Lo 3 monLhs aLlenLs who have a more exLended response Lo fluLamlde are ofLen Lhose who respond Lo lLs wlLhdrawal 29 ln cases of comblnaLlon of fluLamlde wlLh anoLher hormonal LreaLmenL Lhe response seems more marked when Lhls laLLer LreaLmenL was glven aL Lhe sLarL of fluLamlde raLher Lhan laLer (le when fluLamlde seems less acLlve) 1hus lL seems loglcal Lo suggesL Lhe wlLhdrawal of fluLamlde as a LreaLmenL when lL has been used alone or ln earller assoclaLlon and especlally when lL has been used for a long perlod (more Lhan 18 monLhs) 1hls phenomenon has a relaLlonshlp wlLh a posslble ampllflcaLlon of Lhe gene of androgen recepLors (A8s) 26 or wlLh muLaLlons ln hormonal relaLlonshlps beLween Lhe A8s 23 and Lhe cancer cells LhaL can be acLlvaLed by Lhe AAs or oLher sLerold hormone as adrenal androgens 24 unforLunaLely Lhe beneflL of wlLhdrawal of AAs llke fluLamlde when seen lasLs only for a few monLhs 1hls leads Lo Lhe need for a new second or Lhlrdllne LreaLmenL 1he cholce of a new second or Lhlrdllne LreaLmenL ls raLher dlfflculL slnce Lhe crlLerla of evaluaLlon and acLlvlLy are dlfflculL Lo sLandardlze 1hls ls due Lo Lhe facL LhaL 8090 of Lhe paLlenLs do noL have a measurable leslon 1he ma[or dlfflculLles ln conslderlng Lhe value of LreaLmenL are Lhe large number of parameLers Lo be Laken lnLo conslderaLlon (1able 1;) Lhe knowledge LhaL evaluaLlon crlLerla have changed over Lhe years 30 and LhaL Lhey someLlmes appear Lo be ln confllcL 31 1hls was somewhaL dlscouraglng durlng Lhe 1980s and could explaln a renewed lnLeresL ln Lhe use of chemoLherapy 32 33 vlew Lhls Lable O ln Lhls wlndow

O ln a new wlndow @ab|e 1 CrlLerla of evaluaLlon of response Lo secondllne LreaLmenL 8efore decldlng on Lhe second or Lhlrdllne LreaLmenL prevlous exposure Lo hormones musL be consldered as Lhls can have an lnfluence on Lhe response Lo subsequenL Lherapy 1he dlfflculLy ln comparlng prospecLlve sLudles where evaluaLlon crlLerla were ofLen very dlfferenL may help explaln Lhe wlde range of dlfferenL cholces for secondllne LreaLmenLs aromaLase lnhlblLors esLrogens chemoLherapy alone and hormone chemoLherapy 34 Androgen Depr|vat|on Surglcal or chemlcal adrenalecLomy wlLh amlnogluLheLlmlde and hydrocorLlsone glves a less Lhan 10 ob[ecLlve response Slmllar response flgures are obLalned wlLh keLoconazole whlch needs hlgh doses LhaL are poorly LoleraLed 33 Suramln may be more acLlve (from 33 Lo 34 of ob[ecLlve response) buL exhlblLs some renal and neurologlcal LoxlclLy 1he duraLlon of response ls usually shorL and ln general lasLs abouL flve monLhs 36 Lstrogens 1he esLrogens could be more lnLeresLlng especlally fosfesLrol whlch ls less cardloLoxlc Lhan uLS 37 losfesLrol has Lhe advanLage of belng admlnlsLered vla an lv llne and has a more rapld upLake 8ecause fosfesLrol ls a prodrug LhaL ls meLabollzed Lo uLS ln Lhe cancer cells lL exhlblLs very low plasma levels and has low cardloLoxlclLy SLandard LreaLmenL wlLh fosfesLrol ls 10 days perfuslon aL lncremenLal doses (from 1200 mg on day 1 Lo 3000 mg on day 3) followed by oral admlnlsLraLlon te 12 reporLs a level of response of 40 (on Lhe SA level as well as on Lhe quallLy of llfe) whlch may be a very lmporLanL prognosLlc facLor slnce Lhe medlan survlval of Lhe responders ls 196 monLhs versus 42 monLhs among Lhe nonresponders Slmllar resulLs have been reporLed by oLher lnvesLlgaLors wlLh a medlan survlval of around flve monLhs SomeLlmes afLer progresslon under AA Lherapy followed by fallure of esLrogen a new beneflL relaLed Lo AA Lherapy can be obLalned 1hls ls due Lo a redlfferenLlaLlon of cancer cells by muLaLlon of Lhe androgen recepLors 7 Also senslLlvlLy Lo androgens can be noLed 24 1he acLlvlLy of anLlesLrogen Lherapy (Lamoxlfen) has also been noLed 1hls may be explalned by Lhe posslblllLy of Lhe presence of esLrogen recepLors Ant|aromatases 1he lnhlblLlon of aromaLase blocks Lhe converslon of cholesLerol ln pregnenolone AmlnogluLeLhlmlde lnhlblLs Lhe blosynLhesls of adrenal sLerolds as does keLoconazole aL hlgh doses ,ore recenLly slmllar effecLs have been noLed for lloprozole and llarozole 7 CLher aromaLase lnhlblLors already used ln advanced breasL cancer such as leLrozole or anasLrozole are under sLudy AL a slmllar level low doses of sLerolds may be acLlve by slowlng Lhe acLlvlLy of Lhe adrenals 7 30 Chemotherapy lf Lhe LreaLmenLs already descrlbed have falled Lhls ls lndlcaLlve of hormone refracLory prosLaLe cancer 1hls leads Lo Lhe use of chemoLherapy buL sLrlcL precauLlons musL be observed wlLh elderly paLlenLs 1he flrsL publlcaLlons on chemoLherapy go back some 20 years 32 33 and success was evaluaLed ln Lhese sLudles uslng dlfferenL crlLerla 1hls may help explaln Lhe dlscrepancles ln Lhe reporLed resulLs 6 Pormone refracLory prosLaLe cancer has long been consldered Lo be a chemoLherapyreslsLanL dlsease 38 lndeed no randomlzed sLudy has been able Lo demonsLraLe Lhe beneflL of chemoLherapy on survlval raLe 3 6 32 Cver Lhe lasL 10 years several nonhormonal agenLs have been shown Lo exhlblL a cerLaln efflcacy when evaluaLed accordlng Lo decrease of SA Powever none of Lhese sLudles had paLlenL populaLlons greaLer Lhan 100 6 ConslderaLlon of Lhe quallLyofllfe evaluaLlon crlLerla has somewhaL modlfled Lhls slLuaLlon 1hus Lhe resulLs obLalned by @oock 39 conflrm Lhe lnLeresL of chemoLherapy wlLh respecL Lo cerLaln crlLerla (vlsual scale of evaluaLlon of paln performance sLaLus and modlflcaLlon of welghL) A beLLer evaluaLlon of Lhe classlcal drugs (vlnblasLlne cyclophosphamlde doxorublcln mlLoxanLrone) Lhe newer ones (clsplaLlnum Laxanes) or slmulLaneous comblnaLlon wlLh hormonal Lherapy (esLramusLlne) or ln sequenLlal admlnlsLraLlons 40 should be posslble Lhrough phase lll Lrlals 1hls evaluaLlon could conslder quallLyofllfe crlLerla Lo be of Lhe same level of lmporLance as decrease ln SA Lhe prolongaLlon of survlval and global survlval Cf Lhe mosL wldely sLudled drugs Lhe besL resulLs have been obLalned wlLh cyclophosphamlde doxorublcln and mlLoxanLrone unforLunaLely few sLudles exlsL and Lhe new molecules are sLlll belng evaluaLed Powever lL ls already well recognlzed LhaL Lhe comblnaLlon of anLlhormonal Lherapy parLlcularly wlLh esLramusLlne lncreases Lhe level of response (1able 2;) vlew Lhls Lable O ln Lhls wlndow

O ln a new wlndow @ab|e 2 Secondllne LreaLmenL wlLh medlcal Lherapy We musL be very careful abouL Lhe evaluaLlon of responses Lo Lhese drugs 31 and as has already been menLloned we musL Lake lnLo accounL prevlous LreaLmenLs lor example blcaluLamlde ls more acLlve followlng fluLamlde Lhan followlng casLraLlon 7 SLerold Lherapy whlch ls used as an anLlemeLlc wlLh chemoLherapy glves alone abouL a 2040 response raLe 39 and Lhe lnLerval of Llme slnce Lhe end of Lhe prevlous hormonal Lherapy musL be consldered for Lhe wlLhdrawal effecL 1he response Lo wlLhdrawal usually happens wlLhln a monLh LxcepLlons are nlluLamlde and blcaluLamlde whlch have longer halfllves (response ln elghL weeks) 7 1hus ln cases of response Lo hormonal Lherapy we have Lo walL for Lhe ob[ecLlve slgns of relapse before sLarLlng wlLh chemoLherapy llnally lL ls lmporLanL Lo be sure LhaL Lhe plasma levels of LesLosLerone obLalned are conslsLenL wlLh Lhe levels assoclaLed wlLh casLraLlon 6 Je 41 ln a randomlzed sLudy of 192 paLlenLs on secondllne LreaLmenL has compared vlnblasLlne alone versus vlnblasLlne and esLramusLlne Pe has obLalned measurable responses of 6 and 18 respecLlvely a progresslonfree medlan survlval of 19 and 37 monLhs ( 0001) and a global survlval of 92 and 119 monLhs ( 018) AlLhough nonslgnlflcanL Lhls flgure corresponds Lo an lncrease of 23 ln global survlval Lven lf chemoLherapy has no lmpacL on survlval lL demonsLraLes beneflLs ln Lerms of quallLyofllfe parameLers 6 42 @oock ln 1989 lnvesLlgaLed sLerold Lherapy 39 as secondllne LreaLmenL ln a randomlzed sLudy 42 of 161 paLlenLs he compared prednlsone alone (10 mg/d) versus Lhe comblnaLlon of prednlsone and mlLoxanLrone (12 mg/m2/3 weeks) 1hls followed Lhe resulLs of a phase ll sLudy 43 showlng acLlvlLy and good Lolerance A slgnlflcanL beneflL of Lhe chemoLherapy was demonsLraLed ln Lerms of ob[ecLlve response (29 versus 12) medlan responses (43 weeks versus 18 weeks) and global palllaLlve beneflL (38 versus 21) Among paLlenLs ln fallure wlLh prednlsone alone Lhe assoclaLlon wlLh mlLoxanLrone gave a 22 response raLe (wlLh a medlan of 18 weeks) Clobal survlvals were ldenLlcal wlLh a medlan of 11 monLhs buL 30 ouL of 80 paLlenLs LreaLed wlLh prednlsone alone relapsed and Lhen recelved mlLoxanLrone 1hls LreaLmenL was assoclaLed wlLh lmprovemenL ln paln rellef and global quallLy of llfe 1he global quallLy of llfe was very slgnlflcanLly lmproved by mlLoxanLrone and lasLed longer accordlng Lo Lwo dlfferenL meLhods of evaluaLlon (LC81C CLC30 and CCL,14 a Lrlalspeclflc module) 44 ,oreover Lolerance was very good wlLh only Lwo cardlac fallures recorded among Lhe 130 paLlenLs (average age 68 years) Laklng mlLoxanLrone lletbott 40 has descrlbed anoLher approach LhaL has shown very lnLeresLlng resulLs ln hls sLudy of 46 paLlenLs reslsLanL Lo fluLamlde he employed a reglmen of alLernaLed hormonochemoLherapy (one week wlLh doxorublcln and keLoconazole and Lhe oLher wlLh vlnblasLlne and esLramusLlne) comblned wlLh dally hydrocorLlsone Cn measurable leslons (sofL Llssues) he has obLalned 73 response (12 ouL of 16) a decrease of Lhe levels of SA of more Lhan 30 among 67 of Lhe paLlenLs (38 ouL of 46) and a decrease of more Lhan 80 among 32 and an lmprovemenL ln Lhe quallLy of llfe among 76 1he medlan response has been 84 monLhs wlLh an lnLeresLlng global survlval of 19 monLhs Pe has conflrmed Lhe prognosLlc value of Lhe response (aL 18 monLhs 64 of Lhe responders are allve versus 33 of Lhe nonresponders) 8ecause of Lhese promlslng resulLs and Lhe good Lolerance a phase lll sLudy has been sLarLed for hormonesenslLlve forms 1he assoclaLlon of Lwo lnhlblLors of mlcroLubules such as vlnblasLlne and esLramusLlne have already proved Lhelr acLlvlLy 41 A !apanese sLudy has obLalned slmllar resulLs (8 ob[ecLlve responses ouL of 14 and a medlan survlval of 18 monLhs) wlLh an assoclaLlon of lnLerferon2a aL low doses and 3fluorouracll wlLh good Lolerance unforLunaLely Lhe sLudy lnvolved lnsufflclenL numbers of paLlenLs Lo provlde concluslve evldence 43 revlous SecLlonnexL SecLlon 9a|||at|ve @herapy for 9a|nfu| Metastases AlLhough exLernal radloLherapy ls Lhe besL LreaLmenL for paln relaLed Lo locallzed bone meLasLases lv blphosphonaLes exhlblL conslderable acLlvlLy agalnsL paln ln dlffuse bone leslons 1hese compounds acL rapldly 46 and are nonLoxlc 8|phosphonates 8lphosphonaLes do noL Lhemselves have any anLlLumor acLlvlLy and only have a secondary role Lo play ln Lhe LreaLmenL of prosLaLlc cancer 1hey acL on Lhe osLeoclasLlc hyperresorpLlon llnked Lo Lhe coupllng of acLlvlLy of bone cells (osLeoblasLs and osLeoclasLs) ClodronaLe and pamldronaLe have shown some analgeslc acLlvlLy and are of lnLeresL only ln cases when usual LreaLmenLs have falled 46 Lxterna| 8eam kad|at|on 8adloLherapy ls Lhe malnsLay of LreaLmenL for Lhe nondlffuse palnful meLasLases 1hese occur ln abouL 83 of progresslve hormonereslsLanL cancers ShorL locallzed exLernal beam lrradlaLlons (20 Cy ln flve fracLlons over one week or more ofLen 30 Cy ln 10 fracLlons over Lwo weeks) brlng parLlal or LoLal paln rellef ln 80 of paLlenLs wlLh negllglble morbldlLy CompleLe responses were mosL ofLen found ln paLlenLs wlLh prosLaLe cancer ln comparlson Lo oLher Lumors 47 lrradlaLlons by large hemlbody flelds (6 Cy for Lhe upper half of Lhe body and 8 Cy for Lhe lower half) are also efflclenL ln rellevlng paln ln abouL 73 of cases wlLh rellef lasLlng several monLhs AbouL 40 of paLlenLs responded wlLhln 48 hours 48 Stront|um 89 1he preferenLlal flxaLlon of cerLaln radlopharmaceuLlcal lsoLopes on Lhe bones especlally aL polnLs of growLh led lnlLlally Lo Lhe use of phosphorus 32 ln mulLlfocal bone leslons 8ecause of lLs severe myeloLoxlclLy Lhls agenL has been largely replaced by sLronLlum 89 or by oLher radlolsoLopes such as samarlum 133 and rhenlum 186 49 SLronLlum 89 ls a pure emlLLlng radlonucllde LhaL follows Lhe same paLhways as calclum and lnduces an almosL LoLal dlsappearance of bone paln beLween 10 and 30 of paLlenLs and parLlal dlsappearance ln approxlmaLely 30 of Lhe paLlenLs lL ls assoclaLed wlLh moderaLe blood LoxlclLy (LhrombocyLopenla from four Lo elghL weeks afLer Lhe ln[ecLlon) buL a posslble beneflL ln Lerms of global survlval has noL been proven yeL neverLheless lLs comblnaLlon wlLh oLher producLs or Lechnlques may be promlslng ln facL sLronLlum 89 comblned wlLh locallzed exLernal lrradlaLlon alLhough noL modlfylng survlval ls assoclaLed wlLh a decrease ln Lhe blologlcal markers LhroughouL Lhe halfllfe of sLronLlum 1he use of clsplaLlnum (Cuu) ln assoclaLlon wlLh sLronLlum 89 ls especlally lnLeresLlng slnce Cuu reduces Lhe posslblllLy of repalr of Lhe radlolnduced subleLhal leslons lL has been seen LhaL low doses of Cuu afLer low doses of sLronLlum 89 have an obvlous effecL ln Lerms of paln rellef and ln Lhe decrease of dlsease markers wlLhouL Loxlc effecLs 30 SLronLlum 89 aL Lhe usual dose of 30 Lo 60 ,Cl/kg afLer fallure of medlcal LreaLmenL lnduces an lmprovemenL ln Lerms of paln rellef LhaL lasLs several monLhs ln more Lhan 30 of cases Some lnvesLlgaLors 49 have noLed a beneflL ln survlval Powever sLronLlum 89 may lnduce LranslenL lncreases ln bone paln or flareup wlLhln Lhe flrsL few days of admlnlsLraLlon 1here ls also Lhe posslblllLy of LhrombocyLopenla grade lll Lo lv ln more Lhan 20 of cases lL ls hlghly advlsable Lo employ sLerolds durlng aL leasL Lhe flrsL monLh of LreaLmenL Samarlum 133 a new radlonucllde aL a dose of 1 mCl/kg lnduces paln rellef ln 6272 of paLlenLs wlLh no lnsLances of grade 4 and rarely grade 3 myelosuppresslve LoxlclLy 31 revlous SecLlonnexL SecLlon Adv|ce on @reatment Se|ect|on ,eLasLaLlc prosLaLe cancer musL be LreaLed as qulckly as posslble 1hls ls because of Lhe rlsk of compllcaLlons parLlcularly splnal cord compresslon lncreases wlLh Llme AnoLher facLor ls Lhe recognlLlon LhaL paLlenLs ln general appear Lo favor quallLy of llfe raLher Lhan lengLh of survlval A recenL randomlzed sLudy shows a slgnlflcanL beneflL of early LreaLmenL compared Lo delayed LreaLmenL based on Lhe evoluLlon of Lhe dlsease lLs compllcaLlons and Lhe survlval relaLed Lo prosLaLe cancer 9 Androgen blockade ls Lhe LreaLmenL of cholce buL should lL be LoLal (1A8) or selecLlve? lor 1A8 whlch AA should be used? CasLraLlon may be surglcal (bllaLeral orchlecLomy) or medlcal wlLh LP8P agonlsLs (all Lhe dlfferenL agonlsLs have Lhe same acLlvlLy) 1he flrsL opLlon has Lhe advanLage of lLs slmpllclLy lLs moderaLe cosL and lLs permanence 1he second approach provldes Lhe psychologlcal comforL of Lemporary casLraLlon Several sLudles have shown Lhe superlorlLy of 1A8 16 20 22 32 over medlcal casLraLlon alone 1he nonsLeroldal AA cyproLerone aceLaLe has never shown any beneflLs ln survlval when assoclaLed wlLh medlcal casLraLlon 33 Surglcal casLraLlon seems Lo dlmlnlsh Lhe beneflL of 1A8 18 lnLermlLLenL LreaLmenL ls sLlll under lnvesLlgaLlon 1he flrsL cllnlcal resulLs lndlcaLe LhaL lL may delay Lhe occurrence of hormone reslsLance 24 and LhaL lL ls noL a harmful meLhod (,et personal communlcaLlon) ln cases of progresslon under AA LreaLmenL lLs wlLhdrawal may brlng abouL a 20 response (decrease of Lhe values of SA 30) 1hls effecL has been observed wlLh varlous AAs lncludlng noL only fluLamlde buL also blcaluLamlde and megesLrol aceLaLe 7 Powever Lhe posslble beneflL lasLs only a few monLhs ralslng Lhe quesLlon of a secondllne LreaLmenL new AA aromaLase lnhlblLors esLrogens or chemoLherapy 8lcaluLamlde as a slngle agenL (130 mg/d) ls acLlve afLer Lhe fallure of fluLamlde buL Lhe conLrary has noL been proven 23 1he acLlvlLy of megesLrol aceLaLe ls very weak 7 and less lnLeresLlng Lhan Lhe aromaLase lnhlblLors 1he assoclaLlon of amlnogluLeLhlmlde wlLh hydrocorLlsone ls well LoleraLed and glves an approxlmaLe 30 response raLe 34 ,ore recenLly Lhe comblnaLlon of keLoconazole wlLh hydrocorLlsone has been proven Lo be very acLlve followlng Lhe wlLhdrawal of AAs 7 1hls provldes a dramaLlc lmprovemenL of Lhe quallLy of llfe and when assoclaLed wlLh mlLoxanLrone a poslLlve effecL has also been obLalned 42 Low doses of sLerold Lherapy alone are acLlve as well 39 LsLrogens llke lv fosfesLrol have Lhe advanLage of rapld acLlvlLy especlally as paln klllers 12 LsLramusLlne ls also acLlve and ls ofLen assoclaLed wlLh chemoLherapy 41 lLs mechanlsm of acLlon provldes lnhlblLlon of mlcroLubules (vlnblasLlne pacllLaxel eLoposlde) buL Lhe slde effecLs ln elderly paLlenLs are worse Lhan Lhose seen wlLh mlLoxanLrone 31 40 ln @oockrandomlzed sLudy Lhls drug provlded a very slgnlflcanL lmprovemenL Lo sLerold Lherapy ln Lerms of response and ln Lerms of quallLyofllfe crlLerla parLlcularly because of lLs very good Lolerance 42 1he use of chemoLherapy aL low doses alLernaLed or assoclaLed wlLh varlous hormonal agenLs ls anoLher posslblllLy lletbott 40 has reporLed on some very lnLeresLlng resulLs ln Lerms of duraLlon of response (84 monLhs) as well as on global survlval (19 monLhs) buL also an lncldence of 49 of perlpheral edema and 18 lncldence of venous Lhrombosls llnked Lo esLramusLlne ConslderaLlon could be glven Lo a LherapeuLlc proLocol based on Lhe same concepL buL of reduced LoxlclLy by lncludlng ln @oock proLocol vlnblasLlne alLernaLed wlLh mlLoxanLrone comblned wlLh lv fosfesLrol ln cases of mulLlple palnful bone leslons Lhe LherapeuLlc approach ls raLher dlfferenL SLronLlum 89 aparL from lLs myelosuppresslve effecL (essenLlally LhrombocyLopenla) ls well LoleraLed (sLerold Lherapy ls mandaLory) wlLh an obvlous beneflL ln Lerms of quallLy of llfe 49 lL also has Lhe advanLage LhaL lL may be repeaLed afLer Lhree Lo four monLhs Samarlum 133 could be more acLlve on palnful leslons and less Loxlc Lhan sLronLlum 89 31 ln cases of a slngle palnful bone leslon locallzed exLernal beam radloLherapy ls hlghly effecLlve wlLh paln rellef occurrlng ln 80 of paLlenLs 48 1he cholce of second Lhlrd or even fourLhllne LreaLmenL ls dlfflculL and musL be based on Lhe cllnlcal response of Lhe paLlenL and Lhe preclse evoluLlon of Lhe dlsease lL ls lmporLanL Lo reallze LhaL cllnlcal reporLs concernlng Lhe response raLes Lo dlfferenL LreaLmenL reglmens vary wldely slnce evaluaLlon crlLerla dlffer conslderably from one sLudy Lo anoLher 29 1he usual crlLerla Lo be consldered are SA levels (decllne ln SA of 30) measurable leslons (sum of Lhe producLs of dlameLers of all measured leslons) acLlvlLy agalnsL paln (measured by a vlsualanalog scale or analgeslc consumpLlon) change ln welghL quallLy of llfe and global survlval Among young paLlenLs or paLlenLs whose hormone refracLory dlsease developed qulckly Lhere ls a Lendency Lo sLarL chemohormone Lherapy as a secondllne LreaLmenL (esLramusLlne) lor Lhe oLher paLlenLs aromaLase lnhlblLors or esLrogens (fosfeLrol) are commonly employed buL slngle sLerold Lherapy can sLlll be an alLernaLlve ln case of fallure or ln Lhe presence of palnful bone leslons Lhese LreaLmenLs may be exchanged replaced or comblned wlLh exLernal beam radloLherapy or sLronLlum 89 or samarlum 133 ln all Lhe cases Lhe balance beLween Lolerance and effecLlveness musL be malnLalned revlous SecLlonnexL SecLlon Conc|us|on Cver Lhe lasL few years lmporLanL changes have Laken place ln Lhe managemenL of meLasLaLlc prosLaLe cancer 1A8 seems Lo brlng beneflLs lf casLraLlon ls medlcal and Lhe androgen ls nonsLeroldal buL musL 1A8 be permanenL or lnLermlLLenL ln order Lo lmprove quallLy of llfe wlLhouL modlfylng Lhe vlLal prognosls? 1here ls an ongolng cllnlcal Lrlal LhaL wlll Lry Lo answer Lhls quesLlon 1he crlLerla for evaluaLlon of Lhe responses ln case of hormone reslsLance are aL lasL becomlng beLLer undersLood 1hls wlll allow ob[ecLlve and LrusLworLhy comparlsons beLween dlfferenL LreaLmenLs lL ls clear LhaL Lhe naLure and Lhe duraLlon of flrsLllne LreaLmenLs such as Lhe use and Lhen wlLhdrawal of AAs may lnLerfere wlLh secondllne hormonal Lherapy 1he use of chemoLherapy alone or comblned wlLh hormonal Lherapy has provoked renewed lnLeresL Lhanks Lo revlsed crlLerla for LreaLmenL evaluaLlon AL Lhe presenL Llme Lhere are noL enough daLa Lo choose one second or even one Lhlrdllne LreaLmenL over anoLher one ComparaLlve mulLlcenLer sLudles are currenLly under way Lo lnvesLlgaLe all Lhe elemenLs of LreaLmenL of prosLaLe cancer 1he alm of Lhese largescale Lrlals ls Lo provlde Lhe besL posslble care for paLlenLs who are ofLen elderly and deblllLaLed and for whom quallLy of llfe as deflned by Lhe paLlenLs Lhemselves ls Lhe prlnclpal concern Managementu| avansat canceru|u| de prostata 1 Cerard Auclerc o b 2 Lrlc C AnLolne o 3 lrancls Ca[flnger o 4 ArleLLe 8runeLommeyrol b S Chahrok Agazla b |6 uavld khayaL o +AuLhor AfflllaLlons 1o SC,S SplLalul SalpLrlere ueparLamenLul de Cncologle ,edlcala arls lran(a 2b CenLru Charlebourg la CarenneColombes lran(a 1 Cerald Auclerc ,u SplLalul SalpLrlere ueparLamenLul de Cncologle ,edlcala 47 8oulevard de lPplLal 73013 arls lran(a 1elefon 33142160474 lax 33143364841 O AccepLm 20 lanuarle 2000 Sec(lunea urmLoare Abstract Cele mal mulLe cazurl de carclnom avansaL de prosLaL sunL hormonosenslLlveuLlllzarea blocadel comblnaLe androgenl (CA8) pare s se imbunL(easc supravle(ulrea ;l callLaLea vle(ll dar numal aLuncl cnd sunL comblnaLe cu casLrare chlmlc prln luLelnlzanLhormonulul de ellberare a hormonulul analoglce ;l fr uLlllzarea de anLlandrogenllor sLeroldale uup CA8 LraLamenLe hormonale in conLlnuare rmn eflcace cum ar fl reLragerea anLlandrogen urmaL de esLrogenl lnhlblLorl de aromaLaza ;l de hormonrefracLar la prosLaLa agenLl de cancer mal mulLe clLoLoxlce enLru lezlunl osoase dureroase radloLeraple fasclcul de exLerne blphosphonaLes ;l de sLron(lu 89 sau 133 samarlu de a amellora durerea uLlllzarea de nol meLode de evaluare a rspuns ;l a callL(ll vle(ll va permlLe ldenLlflcarea rapld de LraLamenLe eflclenLe ;l permlsul de sLudll cllnlce de faza lll cu regla[ elecLrlc O Avansate de cancer de prostataO @erap|e hormona| O normonu| de rez|stenO Irad|ereO Ch|m|oterap|a O Ca||tatedev|ata de eva|uare Sec(lunea anLerloarSec(lunea urmLoare Introducere Cancerul de prosLaLa esLe cauza a mal mulL de 1 dln LoaLe decesele la brba(llnclden(a sa esLe in cre;Lere cu 2 3 pe an LxlsL dou moLlve prlnclpale penLru aceasL cre;Lere rlmul esLe cre;Lerea speran(el de vla( lar al dollea esLe fapLul c anLlgenulul speclflc prosLaLlc (SA) de LesLare a permls mal devreme ;l mal exacLe dlagnosLlcarea bolll rognosLlcul general penLru cancerul de prosLaLa dlagnosLlcaLe rmne deflclLar cu o supravle(ulre de 70 la 10 anl comparaLlv cu popula(la general AproxlmaLlv 30 dln cazurl sunL dlagnosLlcaLe inLrun sLadlu avansaL local lar aproxlmaLlv 30 au meLasLaze osoase la momenLul dlagnosLlculul 1 ln 1996 in SLaLele unlLe 317000 de cazurl nol au fosL dlagnosLlcaLe sl 41000 decese raporLaLe AceasL clfr reprezlnL 13 dln urm dln LoLalul deceselor provocaLe de cancer dln SuA ln ceea ce prlve;Le sLablllrea aceasLa inseamn c un deces dln cancer de prosLaLa au avuL loc la flecare 13 mlnuLe 2 ln 1990 clfrele slmllare au fosL inreglsLraLe in lran(a cu 17600 de cazurl nol ;l 9200 de decese raporLaLe (11 dln LoLalul deceselor provocaLe de cancer) 3 Cu LoaLe acesLea in 1999 elaborarea a 33anuale a sLaLlsLlcllor cancer 4 a arLaL c lnclden(a cancerulul de prosLaL a sczuL semnlflcaLlv cu un declln in raLa de deces de 11 dln 1991 AcesLe sLaLlsLlcl au raporLaL de asemenea o cre;Lere de 20 in 10 anl de supravle(ulre inLre 1988 ;l 1993 1raLamenLe slsLemlce penLru cancerul de prosLaLa lnclud dlferlLe Llpurl de Leraple cu hormonl 8lphosphonaLes sau radlonucllzllor cum ar fl 89 sau lzoLopl de sLron(lu poL fl uLlllzaLe in cazurlle in care lezlunlle osoase sunL ldenLlflcaLe AlLe LraLamenLe lnclud radloLeraple exLerna sl chlrurgleChlmloLerapla a devenlL o op(lune supllmenLar aLuncl cnd un LraLamenL hormonal care nu reu;e;Le 3 6 Sec(lunea anLerloarSec(lunea urmLoare Cp|un| de tratament pentru hormonsens|b||e 8o|||or ln [urul valorll de 73 dln meLasLaLlc cancer de prosLaLa sunL hormon senslblle 1lmpul medlu de rspuns la prlvare de androgenl esLe de aproxlmaLlv 18 lunl supravleLulre dupa doua llnle de LraLamenL varlaz de 6 10 lunl 7 @ratamentu| t|mpur|u enLru paclen(ll slmpLomaLlc sau penLru cel cu boala progreslva LraLamenLul hormonal esLe conslderaL obllgaLorle Cu LoaLe acesLea penLru nonsympLomaLlc hormonsenslblle dln puncL de paclen(l acesL lucru nu poaLe fl neapraL cazul 1raLamenLul hormonal are efecLe secundare nedorlLe in speclal de naLur sexual CosLurlle de un asLfel de LraLamenL poaLe fl de asemenea conslderablle ue asemenea esLe lmporLanL s ne amlnLlm c un LraLamenL hormonal conLlnu s rmn eflcace la paclen(ll nonsympLomaLlcCu LoaLe acesLea inLrzllnd LraLamenL de doar noua lunl lnLroduce rlscul de comprlmare a maduvel splnarll ln sLudlul lor ctowfotJ sl colucrLorllor 8 au arLaL c 43 dlnLre paclen(ll cu cancer de prosLaLa conslderaL callLaLea vle(ll ca fllnd mal lmporLanL ca spre deoseblre de 29 care au declaraL o preferln( penLru supravle(ulre prelunglL un sLudlu reallzaL de ,edlcal 8esearch Councll cancer de prosLaLa Crupul de Crupul de lucru lnvesLlgaLor comparaL LraLamenLul precoce lnLarzlaL comparaLlv a fosL recenL publlcaL 9 enLru prlma daL la beneflcllle unul LraLamenL precoce au fosL clar demonsLraL in ceea ce prlve;Le progresla meLasLaLlc compllca(ll ;l decese legaLe de cancer De pr|vare de androgen| ue la publlcarea lucrrllor precoce a in 1941 10 LraLamenLul prlmar penLru cancerul de prosLaLa a fosL de a oprl producLla de androgenl LesLlcularAcesL lucru poaLe fl reallzaL prln casLrare loloslnd esLrogenl cum ar fl dleLllsLllbesLrol (uLS) sau mal recenL cu a[uLorul anLlandrogenllor (AA) sl luLelnlzanLhormonulul de ellberare a hormonulul (LP8P) agonlsLl (lunar sau o daL la Lrel lunl) AcesL LraLamenL scade nlvelul plasmaLlc de LesLosLeron cu 93 ue prlvare de androgenl cu LoaLe acesLea esLe asoclaL cu numeroase efecLe adverse poslblle AcesLea lnclud scderea llbldoulul lmpoLen( bufeurl anemle caderea parulul osLeoporoza oboseala ;l de facLorl pslhologlclAparl(la acesLor reac(ll modlflc semnlflcaLlv callLaLea vleLll paclenLulul costrore CasLrarea esLe fle efecLuaL de cLre chlrurglcal orhlecLomle bllaLerale sau medlcal de agonlsLl LP8P cum ar fl LrlpLorellne leuprorellne buserellne ;l goserellne AcesLe LraLamenLe poL lnduce un efecL paradoxal uneorl de oblcel descrls ca un AcesL efecL esLe mal frecvenL in cazurlle care lmpllc lezlunl osoase ;l se daLoreaz cre;Lerea lnl(lal Lemporar a nlvelurllor de LP sl LesLosLeron flareup AcesLea poL duce la durerl osoase care dureaz aproxlmaLlv o spLmn AcesL fenomen se expllc neceslLaLea unel AA care Lrebule luaLe penLru dou spLmnl inalnLe ;l dup casLrare medlcal in scopul de a evlLa acesL efecL flareup stroqeni 1lmp de mulLl anl acesLe medlcamenLe au fosL conslderaLe ca sLandarde de aur dln blocada androgenl AcesLea lnfluen(eaz axel hlpoflzo secre(la suprarenal ;l de 3alfareducLaza acLlvlLaLe Ll au [ucaL un rol foarLe lmporLanL ln Lerapla hormonala Cu LoaLe acesLea uLS are dezavanLa[ele el daLorlL LoxlclL(ll sale cardlovasculare ueoarece a fosL demonsLraL inLrun sLudlu de veLeranl 11 beneflcllle ob(lnuLe de la 3 mg / d de uLS par s fl conLracaraL prln reac(llle adverse raporLaLe AcesLe rezulLaLe au dus la uLlllzarea unor doze mal mlcl de uLS chlar nlvel cL mal sczuL de 1 mg / dAcesLe doze mlcl au dus la beneflcll LerapeuLlce ;l reducerea rlsculul de cardloLoxlclLaLe la anuml(l paclen(l chlar dac se pare c doza de pragul de 3 mg / d esLe necesar penLru a ob(lne LoLale blocada androgenl ln lran(a fosfesLrol esLe uLlllzaL pe scar larg mal ales prln admlnlsLrarea lv 12 un alL esLrogen esLe fosfaLul de esLramusLln care are avanLa[ul de a avea aLL o componenL hormonal sLeroldlene ;l un agenL alchllanL de azoL mu;Lar Cele mal bune ac(lune cunoscuL esLramusLln esLe depollmerlzarea de mlcroLubull prln lnLerac(lune cu Lubullnel Cu LoaLe acesLea esLramusLln a fosL de asemenea demonsLraL de a avea o ac(lune clLoLoxlc prln legarea de maLrlcea nuclear 13 14 @ota| de androgen| 8|ocada AcesL concepL dezvolLaL de in 1943 se bazeaz pe fapLul c celulele prosLaLel sunL dependenLe de androgenl ;l acesL lucru esLe valabll mal ales penLru dlhldroLesLosLeron (uP1) un meLabollL foarLe acLlv de LesLosLeronroduc(la acesLul meLabollL in glanda prosLaLlc inseamn c nlvelurlle de casLrare urmLoarele androgenl varlaz inLre 20 ;l 40 dln nlvelurlle normale 13 ue fapL exlsL dou cl penLru a aduce in legLur cu Lransformarea LesLosLeronulul ln uP1 un Lraseu deplnde de ac(lunea enzlmel 3alfareducLaza care Lransform LesLosLeronul in uP1 1raseul alLe lmpllc produc(la de dehldroeplandrosLeron de cLre glandele suprarenale AcesL lucru esLe converLlL la LesLosLeron ;l apol la uP1 in glandel prosLaLlce uescoperlrea c cele mal mulLe Llpurl de cancer meLasLaLlc de prosLaLa sunL sLlmulaLe de hormonl androgenl a condus la cuLarea de dezvolLare ;l de dlferlLe ml[loace penLru suprlmarea lor Ca un rezulLaL al muncll 10 orhlecLomle bllaLeral a fosL mulL Llmp conslderaL a fl LraLamenLul sLandard ,al recenL esLrogenll agonlsLl LP8P ;l AA au aparuL ca opLlunl de LraLamenL mal nol ntiondroqeni ,odul de ac(lune al rezulLaLelor AA in blocada recepLorllor androgenl dln celulele prosLaLel LxlsL dou Llpurl de AA AA AA sLeroldlene ;l anLllnflamaLoare (nSAAs) AA sLeroldal s lnduc o scdere a concenLra(lel plasmaLlce de LesLosLeron prln inceLlnlrea ellberarea de LP a glandel plLulLare ;l prln lnhlbarea par(lal a 3alfareducLaza AA sLeroldal lnclud aceLaL cyproLerone sl megesLrol aceLaL care de asemenea bloca recepLorll androgenl celulare nSAAs sunL mal lnLeresanLe dln puncL de vedere cllnlc deoarece acesLea sunL pur AA ac(loneaz in prlnclpal prln lnhlbarea concuren( cu flxarea uP1 pe recepLorll androgenl Lle nu reduc ;l poaLe cre;Le chlar nlvelurlle plasmaLlce de LesLosLeron ;l acesL lucru poaLe avea un lmpacL asupra llbldoulul de paclen(l nSAAs lnclud fluLamlda nlluLamlde ;l blcaluLamlda 1oto/ de ondroqeni 8/ocodo Asoclerea AA cu un agonlsL LP8P cum ar fl leuprollde permlLe LoLale blocadel androgenl (1A8) aLL la nlvel LesLlcular sl glandele suprarenale 8ezulLaLele prlmulul sLudlu randomlzaL lnsLlLuLul naLlonal al Cancerulul care a avuL loc in 1989 16 au fosL foarLe incura[aLoare ln acesL sLudlu 603 eLapa 2 paclen(l au fosL randomlza(l inLre casLrare chlmlc cu leuprollde ;l placebo sau AA cu fluLamlda 8ezulLaLele au arLaL o imbunL(lre a raLel de progresle (136 comparaLlv cu 163 lunl) ;l o imbunL(lre semnlflcaLlv in supravle(ulrea global (283 comparaLlv cu 336 lunl) un c;Llg de 73 lunl % 0033) in grupul 1A8 AcesLe rezulLaLe raporLaLe de cLre ctowfotJ sl colegll sal au fosL ulLerlor conflrmaLe in 1993 de cLre un CrganlzaLla Luropeana penLru CerceLare sl LraLamenLul cancerulul (LC81C) de sLudlu ln acela;l Llmp ue ;l colucrLorllor 17 au raporLaL o imbunL(lre slmllare in Llmp de supravle(ulre de 73 lunl % 002) in favoarea unel comblna(ll de fluLamlda cu agonlsL LP8P comparaLlv cu orhlecLomle in monoLeraple ln 1993 ctowfotJ 18 inLrun al dollea sLudlu cu 1387 paclen(l LraLa(l cu u2 orhlecLomle ;l fluLamlda sau cu placebo nu a gslL o asLfel de dlferen( clar in scdere de SA sau in supravle(ulrea fr progresle (33 comparaLlv cu 30 lunl) ln acela;l an o meLaanallz a 23 sLudll comparnd casLrarea numal penLru a 1A8 19 nu a gaslL nlcl o dlferenLa semnlflcaLlva lnLre cele doua LraLamenLe (de clncl anl de supravleLulre 228 versus 262 00312) ulferlLe ml[loace de reallzare a 1A8 nu par a fl echlvalenLe LfecLele pe Lermen lung de a folosl esLrogenl ;l agonl;Ll LP8P comparaLlv cu orhlecLomle bllaLerale nu par s fle la fel 20 SLudllle araL c un beneflclu semnlflcaLlv cu 1A8 ln Lermenl de supravleLulre sunL cele in cazul in care casLrarea esLe medlcale ;l nechlrurglcal Sa demonsLraL ca esLrogenll ;l agonl;Ll LP8P au un efecL clLoLoxlc dlrecL asupra celulele cancerulul de prosLaLa 21 ,al mulL asoclerea dlnLre agonlsLllor LP8P ;l AA pare a avea un adlLlv dac nu efecLul de slnergle lnLradevr lnvesLlga(llle de recepLorl penLru a LP8P 20 pe llnllle nemurlLoare a celulelor cancerulul de prosLaLa (LnCa ;l ALvA31) au avuL loc 8ezulLaLele au araLaL ca o comblnaLle de agonlsLll LP8P cu AA are puLerl mal marl de lnhlbl(le decL flecare dlnLre ele slngure care ac(loneaz in androgenl senslblle (LnCa) sau llnll de rezlsLenLe (ALvA31) coet sl colegll sal 22 inLro recenL meLaanallz uLlllzaLe crlLerll rlglde lncludere c excluse sLudll nerandomlzaLe acesLor sLudll ;l in cazul in care nu exlsL nlcl o nSAA AcesL meLaanallz a lnclus noua sLudll ;l a sLablllL beneflcllle 1A8 in Lermenl de raspuns oblecLlv precum ;l supravle(ulrea fr progresla bolll ;l supravle(ulrea global (dar fr o dlferen( sLaLlsLlc semnlflcaLlv) ln conLexLul 1A8 uLlllzarea agonl;Lllor LP8P cu nSAAs pare a fl o op(lune mal bun lluLamlda esLe AA de referln( un sLudlu recenL randomlzaL de 813 paclen(l 13 comparaLlv cu fluLamlda blcaluLamld asoclaL cu un agonlsL LP8P8ezulLaLele araL supravle(ulrea fr progresla bolll ;l o supravle(ulre ldenLlc la 93 spLmnl dar cu o mal bun Loleran( la blcaluLamld in speclal gasLrolnLesLlnale (lnclden( mal mlc de dlaree) 23 Interm|tent androgen| 8|ocada AncheLaLorll mal mulLe 24 au sugeraL ca Lerapla hormonala fl oprlL aLuncl cnd normallzare a nlvelulul de SA esLe aLlns sl ca Lerapla hormonala ar Lrebul s fle incepuL dln nou in caz de recldlv CblecLlvele sunL cre;Lerea callL(ll vle(ll acesLor paclen(l ;l de a inLrzla aparl(la rezlsLen(el hormonale enLru a [usLlflca aceasL sLraLegle acesLe ancheLaLorll conslder c apopLoza esLe un hormon dependenLe ;l a Lumora poaLe cre;Le chlar ;l in absen(a de LesLosLeron ueslgur aceasLa esLe legaL de selec(la de hormonrezlsLenLe clone dar modlflcarl geneLlce poL aprea in aceasL popula(le celulare rezlsLenLe 23 26 Androgenl (LesLosLeron) de produc(le ar permlLe o redlfferenLlaLlon Lumorale sl relnduce capaclLaLea de a celulelor cancerulul de prosLaLa penLru apopLoza ;l asLfel ar psLra dependenLa hormonal 27 ;l dln nou eflcaclLaLea blocadel androgenl AceasL abordare ar permlLe o mal bun callLaLe a vle(ll impreun cu asoclaLe beneflcll evldenLe economlce uup cum sa men(lonaL de[a ctowfotJ sLudlu 8 a arLaL c paclen(ll prefer men(lnerea callL(ll vle(ll mal degrab decL a prelunglL supravle(ulrea (43 penLru psLrarea callL(ll vle(ll 29 penLru prelunglrea de supravle(ulre ;l 13 penLru a supravleLul fara progresle) ln schlmb medlcll par s se concenLreze pe eflcaclLaLea LraLamenLulul , et inLro comunlcare personal a raporLaL c 23 dln 31 de paclen(l LraLa(l cu androgenl blocada lnLermlLenL care au fosL acLlvl sexual inalnLe de inceperea LraLamenLulul redescoperlL acLlvlLaLea lor sexual aLuncl cnd Lerapla hormonala a fosL oprlL o daL rspunsul dorlL au fosL aLlnse Sec(lunea anLerloarSec(lunea urmLoare Doua ||n|e de tratament AA ketragerea neceslLaLea de a doua llnle de LraLamenL sau Lrebule s inLrerup Lerapla cu AA 28 ar puLea urma e;eculul de 1A8 AcesL lucru poaLe avea loc dup un rspuns de 18 lunl la prlvare de androgenl 1rel sLudll au raporLaL de c 7 care a lnclus paclen(l pe fluLamlda 139 cu boala progreslva inLradevr au arLaL c reLragerea slmplu de fluLamlda a adus o scdere SA in aproxlmaLlv 21 dln cazurl cu un rspuns medle de 33 la 3 lunl aclen(ll care au un rspuns mal exLlns la fluLamlda sunL adesea cel care rspund de daLa reLragerll sale 29 ln cazurlle de comblna(ll de fluLamlda cu un alL LraLamenL hormonal rspunsul pare mal marcaL aLuncl cnd acesLa dln urm a fosL daL la incepuLul de fluLamlda mal degrab decL mal Lrzlu (de exemplu aLuncl cnd fluLamlda pare mal pu(ln acLlv) AsLfel se pare loglc s sugereze reLragerea de fluLamlda ca un LraLamenL aLuncl cnd a fosL uLlllzaL in monoLeraple sau in asoclere mal devreme sl mal ales aLuncl cnd acesLa a fosL uLlllzaL penLru o perload lung de Llmp (mal mulL de 18 lunl) AcesL fenomen are o relaLle cu o poslbll ampllflcare a genel recepLorllor androgenl (8A) 26 sau cu muLa(ll in rela(llle dlnLre hormonale 8A 23 precum ;l celulele canceroase care poL fl acLlvaLe de cLre AA sau alLe hormon sLerolzl ca suprarenale androgenl 24 uln pacaLe beneflclul de reLragere a AA cum ar fl fluLamlda aLuncl cnd vzuL dureaz doar penLru cLeva lunl AcesL lucru conduce la neceslLaLea unul nou LraLamenL doua sau a Lrela llnle Alegerea unul nou LraLamenL doua sau a Lrela llnle esLe desLul de dlflcll deoarece crlLerllle de evaluare ;l de acLlvlLaLe sunL greu de sLandardlzaL AcesL lucru se daLoreaz fapLulul c 80 90 dlnLre paclen(l nu au o lezlune msurablle ulflculL(l ma[ore in conslderare valoarea de LraLamenL sunL numrul mare de parameLrl care urmeaz s fle luaLe in conslderare (Labelul 1 ; ) cuno;Lln( de fapLul c crlLerllle de evaluare sau schlmbaL pe parcursul anllor 30 ;l c acesLea uneorl par a fl in confllcL 31 AcesL lucru a fosL oarecum descura[aLor in cursul anllor 1980 ;l ar puLea expllca un lnLeres reinnolL in uLlllzarea chlmloLeraplel 32 33 vezl acesL Label O ln aceasL fereasLr O lnLro fereasLr nou @abe|u| 1 CrlLerllle de evaluare a rspuns la doua llnle de LraLamenL lnalnLe de a declde cu prlvlre la LraLamenLul doua sau a Lrela llnle expunerea anLerloar la hormonl Lrebule s fle conslderaL ca acesL lucru poaLe avea o lnfluen( asupra rspuns la Lerapla ulLerloare ulflculLaLe in compararea sLudll prospecLlve in cazul in care crlLerllle de evaluare au fosL de mulLe orl foarLe dlferlLe poL a[uLa la expllcarea gam larg de op(lunl dlferlLe penLru a doua llnle de LraLamenLe lnhlblLorl de aromaLaza esLrogenll chlmloLeraple ;l chlmloLerapla hormon 34 De pr|vare de androgen| AdrenalecLomy chlrurglcale sau chlmlce cu hldrocorLlzon amlnogluLheLlmlde ;l ofer un rspuns oblecLlv mal pu(ln de 10 Clfre slmllare de reac(le sunL ob(lnuLe cu keLoconazol care are nevole de doze marl care sunL LoleraLe slab 33 Suramln ar puLea fl mal acLlvl (de la 33 la 34 dln rspuns oblecLlv) dar prezlnL unele LoxlclLaLe renal ;l neurologlce uuraLa de raspuns esLe de oblcel scurL ;l in general dureaz aproxlmaLlv clncl lunl 36 Lstrogen| LsLrogenl ar puLea fl mal lnLeresanL mal ales fosfesLrol care esLe mal pu(ln cardloLoxlce decL uLS 37 losfesLrol are avanLa[ul de a fl admlnlsLraLe prlnLro llnle lv ;l are o absorb(le mal rapld ueoarece fosfesLrol esLe un promedlcamenL care esLe meLabollzaL la uLS in celulele canceroase acesLa prezlnL nlvelurl foarLe sczuLe plasmaLlce ;l are cardloLoxlclLaLe sczuL1raLamenLul sLandard cu fosfesLrol perfuzle esLe de 10 zlle la doze elemenLare (de la 1200 mg in zlua 1 la 3000 de mg in zlua 3) urmaL de admlnlsLrare oral cee 12 rapoarLele un nlvel de rspuns de 40 (la nlvelul de SA precum ;l ;l cu prlvlre la callLaLea vle(ll) care poaLe fl un facLor foarLe lmporLanL de prognosLlc deoarece supravle(ulrea medlan de rspuns esLe de 196 lunl fa( de 42 lunl prlnLre nonresponders 8ezulLaLe slmllare au fosL raporLaLe de cLre al(l cerceLLorl cu o supravleLulre medle de aproxlmaLlv clncl lunl uneorl dup progresla bolll sub LraLamenL AA urmaLa de lnsuflclenLa de esLrogenl un nou beneflclu referlLoare la Lerapla cu AA poL fl ob(lnuLe AcesL lucru se daLoreaz unel redlfferenLlaLlon de celulele canceroase prln muLaLle a recepLorllor androgenl 7 ue asemenea senslblllLaLe la androgenl poaLe fl observaL 24 AcLlvlLaLea de Leraple anLlesLrogen (Lamoxlfen) a fosL de asemenea observaL AcesL lucru poaLe fl expllcaL prln poslblllLaLea de a prezenLa de recepLorl de esLrogen Ant|aromatases lnhlbarea de blocurl aromaLazel converslel colesLerolulul in pregnenolonAmlnogluLeLlmlda lnhlb bloslnLeza de sLerolzl adrenallnlcl ca nu keLoconazol la doze marl ,al recenL efecLe slmllare au fosL observaLe penLru lloprozole ;l llarozole 7 Al(l lnhlblLorl de aromaLaz de[a uLlllzaLe ln cancerul de san avansaL cum ar fl leLrozol sau anasLrozol sunL in sLudlu La un nlvel slmllar doze mlcl de sLerolzl poaLe fl acLlv de inceLlnlrea acLlvlL(ll glandele suprarenale 7 30 Ch|m|oterap|a ln cazul in care LraLamenLele de[a descrlse au e;uaL acesL lucru esLe lndlcaLlv de cancer de prosLaLa hormon refracLar AcesL lucru conduce la uLlllzarea de chlmloLeraple dar sLrlcLe msurl de precau(le Lrebule s fle observaLe cu paclen(ll vrsLnlcl rlmele publlca(ll in cazul chlmloLeraplel revenl aproxlmaLlv 20 de anl 32 33 lar succesul a fosL evaluaL in acesLe sLudll foloslnd dlferlLe crlLerll AcesL lucru ar puLea expllca dlscrepan(ele in rezulLaLele raporLaLe 6 Pormonul de cancer de prosLaLa refracLar a fosL mulL Llmp conslderaL a fl o boala de chlmloLeraple rezlsLenLe la 38 lnLradevr nlcl un sLudlu randomlzaL a fosL in msur s demonsLreze beneflcla de chlmloLeraple prlvlnd raLa de supravle(ulre 3 6 32 ln ulLlmll 10 anl mal mul(l agen(l nonhormonal sau dovedlL penLru a expune o eflcaclLaLe anumlLe crlLerll aLuncl cnd evaluaL in func(le de scderea SA Cu LoaLe acesLea nlclunul dlnLre acesLe sLudll au avuL grupe de paclen(l mal mare de 100 6 Lxamlnarea crlLerllle de evaluare a callL(ll de vla( a modlflcaL oarecum aceasL slLua(le AsLfel rezulLaLele ob(lnuLe prln @oock 39 conflrm lnLeresul de chlmloLeraple cu prlvlre la anumlLe crlLerll (scala vlzuala de evaluare a durerll sLaLus de performan( ;l modlflcarea de greuLaLe) C mal bun evaluare a drogurllor claslce (vlnblasLlna clclofosfamlda doxorublclna mlLoxanLron) cele mal nol (clsplaLlnum Laxanl) sau o comblna(le slmulLan cu Lerapla hormonala (esLramusLln) sau in admlnlsLra(llle succeslve 40 ar fl poslbll prln sLudll cllnlce de faz lllAceasL evaluare ar puLea lua in conslderare callLaLeaavle(ll crlLerll penLru a fl de acela;l nlvel de lmporLan( ca in scdere SA prelunglrea Llmpulul de supravle(ulre ;l supravle(ulrea global ulnLre drogurlle cele mal larg sLudlaLe cele mal bune rezulLaLe au fosL ob(lnuLe cu clclofosfamld doxorublcln ;l mlLoxanLron uln pcaLe exlsL pu(lne sLudll ;l nol molecule sunL inc in curs de evaluare Cu LoaLe acesLea esLe de[a blne cunoscuL fapLul c o comblna(le de Leraple anLlhormonal in speclal cu esLramusLln cre;Le nlvelul de rspuns (Labelul 2 ; ) vezl acesL Label O ln aceasL fereasLr O lnLro fereasLr nou @abe|u| 2 uoua llnle de LraLamenL cu LraLamenLul medlcal 1rebule s flm foarLe aLen(l cu prlvlre la evaluarea de rspunsurl la acesLe medlcamenLe 31 ;l dup cum sa men(lonaL de[a Lrebule s (lnem conL de LraLamenLele anLerloare ue exemplu blcaluLamlda esLe fluLamlda mal acLlve in urma decL casLrarea urmLorul LexL 7 1raLamenLul cu sLerolzl care esLe foloslL ca un anLlemeLlc cu chlmloLeraple da numal cu prlvlre la o raLa de 20 40 de rspuns 39 lar lnLervalul de Llmp de la sfr;lLul LraLamenLulul hormonal anLerlor Lrebule s fle luaLe in conslderare penLru efecLul de reLragere Ca rspuns la reLragerea se inLmpl de oblcel in Lermen de o lunLxcep(ll sunL nlluLamlde ;l blcaluLamldel care au Llmp de ln[umaLaLlre prelunglL (de rspuns in opL spLmnl) 7 AsLfel in cazurlle de raspuns la LraLamenL hormonal Lrebule s a;LepLm penLru semne oblecLlve de recldlv inalnLe de a incepe cu chlmloLeraple ln cele dln urm esLe lmporLanL s se aslgure c nlvelurlle plasmaLlce de LesLosLeron ob(lnuLe sunL in concordan( cu nlvelurlle asoclaLe cu casLrarea 6 Je 41 inLrun sLudlu randomlzaL de 192 de paclenLl pe doua llnle de LraLamenL a comparaL vlnblasLln in monoLeraple comparaLlv cu vlnblasLln ;l esLramusLln Ll a ob(lnuL rspunsurl msurablle de 6 ;l 18 respecLlv o supravle(ulre fr progresla medlana de 19 ;l 37 lunl % 0001) ;l o supravle(ulre global de 92 ;l 119 lunl % 018) ue;l nesemnlflcaLlv aceasL clfr corespunde unel cre;Lerl de 23 in supravle(ulrea global Chlar dac chlmloLerapla nu are nlclun lmpacL asupra perloadel de supravle(ulre ea demonsLreaza beneflcll in Lermenl de callLaLe a vle(ll parameLrllor 6 42 @oock in 1989 a lnvesLlgaL LraLamenLul cu sLerolzl 39 ca a doua llnle de LraLamenL lnLrun sLudlu randomlzaL 42 dln 161 de paclen(l a comparaL prednlson in monoLeraple (10 mg / d) fa( de comblna(la de prednlson ;l mlLoxanLron (12 mg / m 2 / 3 spLmnl) AceasLa a urmaL rezulLaLele unul sLudlu de faza ll 43 araL de acLlvlLaLe ;l Loleran( bun un beneflclu semnlflcaLlv de chlmloLeraple a fosL demonsLraL in Lermenl de rspuns oblecLlv (29 versus 12) rspunsurlle medlan (43 spLmnl fa( de 18 spLmnl) ;l global beneflclu pallaLlve (38 versus 21) rlnLre paclen(ll in e;ec cu prednlson in monoLeraple asoclerea cu mlLoxanLron a daL o raL de rspuns de 22 (cu o medle de 18 spLmnl) Supravle(ulrl Clobal au fosL ldenLlce cu o medlan de 11 lunl dar 30 dln 80 de paclen(l LraLa(l cu mlLoxanLron prednlson slngur recldlvaL ;l apol au prlmlL AcesL LraLamenL a fosL asoclaL cu o amellorare in amellorarea durerll ;l a callL(ll globale a vle(llCallLaLea global a vle(ll a fosL foarLe semnlflcaLlv imbunL(lL prln mlLoxanLron ;l a duraL mal mulL in func(le de dou meLode dlferlLe de evaluare (LC81C CLC30 ;l CCL,14 un modul de sLudlu speclflc) 44 ln plus LoleranLa a fosL foarLe bun cu doar dou e;ecurl cardlace inreglsLraLe la 130 de paclen(l (vrsLa medle 68 anl) lund mlLoxanLron lletbott 40 a descrls o alL abordare care a demonsLraL rezulLaLe foarLe lnLeresanLe ln sLudlul su de 46 de paclen(l rezlsLen(l la fluLamlda el a anga[aL un reglm de alLernaL hormonochlmloLeraple (o sapLamana cu doxorublcln ;l keLoconazol lar cellalL cu vlnblasLln ;l esLramusLln) comblnaLe cu hldrocorLlzon de zl cu zl La lezlunl msurablle ((esuLurlle mol) el a ob(lnuL de rspuns de 73 (12 dln 16) o scdere a nlvelurllor de SA de mal mulL de 30 inLre 67 dlnLre paclen(l (38 dln 46) ;l o scdere de mal mulL de 80 inLre 32 ;l o imbunL(lre a callL(ll vle(ll in rndul 76 8spunsul medlan a fosL 84 lunl cu o supravle(ulre la nlvel mondlal lnLeresanL de 19 lunl Ll a conflrmaL valoarea de prognosLlc a rspuns (la 18 lunl 64 dln cel care au rspuns sunL in vla( comparaLlv cu 33 dln nonresponders) uaLorlLa acesLor rezulLaLe promlLaLoare sl LoleranLa buna un sLudlu de faz lll a fosL demaraL de hormonsenslblle dln puncL de forme Asocla(la de dol lnhlblLorl de mlcroLubull cum ar fl vlnblasLln ;l esLramusLlnau dovedlL de[a acLlvlLaLea lor 41 un sLudlu [aponez a obLlnuL rezulLaLe slmllare (8 raspunsurl oblecLlv dln 14 ;l o supravleLulre medlana de 18 lunl) cu o asoclere de lnLerferon2a la doze mlcl ;l 3fluorouracll cu buna LoleranLa uln pcaLe SLudlul a lmpllcaL un numr lnsuflclenL de paclen(l de a furnlza dovezl concludenLe 43 Sec(lunea anLerloarSec(lunea urmLoare @erap|a pa||at|v pentru metastaze dureroase ue;l radloLeraple exLern esLe cel mal bun LraLamenL penLru durerea legaLe de meLasLaze osoase locallzaLe blphosphonaLes lv au o acLlvlLaLe conslderabll impoLrlva durerll in lezlunlle osoase dlfuze Ace;Ll compu;l ac(loneaz rapld 46 ;l sunL nonLoxlc 8|phosphonates 8lphosphonaLes nu se avuL nlcl o acLlvlLaLe anLlLumorala sl au doar un rol secundar penLru a [uca in LraLamenLul cancerulul de prosLaL Ll ac(loneaz pe osLeoclasLlce hlperresorbLla legaLe de cuplare a acLlvlL(ll de celule osoase (osLeoblasLe ;l osLeoclasLe) ClodronaLul ;l pamldronaL au arLaL o acLlvlLaLe analgezlc ;l sunL de lnLeres doar in cazurlle cnd LraLamenLele obl;nulLe nu au reu;lL 46 8eam rad|a|||or externe 8adloLerapla esLe prlnclpalul LraLamenL penLru meLasLaze nondlffuse durerosAcesLea apar la aproxlmaLlv 83 dln progreslve hormonrezlsLenLe Llpurl de cancer ScurL locallzaLe lradlere exLerne faz (20 Cy in clncl frac(lunl pesLe o spLmn sau mal des 30 Cy ln 10 fracLlunl de pesLe dou spLmnl) aduce amellorarea durerll par(lal sau LoLal in 80 dlnLre paclen(ll cu morbldlLaLe negll[abll 8spunsurl compleLe au fosL cele mal des inLlnlLe la paclen(ll cu cancer de prosLaL in compara(le cu alLe Lumorl 47 lradlerl de cmpurl hemlbody marl (6 Cy penLru [umaLaLea superloara a corpulul sl 8 Cy penLru [umLaLea lnferloar) sunL de asemenea eflclenLe ln amellorarea durerll in aproxlmaLlv 73 dln cazurl cu exonerare de duraL de mal mulLe lunlAproxlmaLlv 40 dlnLre paclen(l au rspuns in Lermen de 48 ore 48 De stron|u 89 llxare preferen(lale de lzoLopl radlofarmaceuLlce anumlLe oase in speclal la puncLele de cre;Lere economlc au condus lnl(lal la uLlllzarea de fosfor 32 ln lezlunl osoase mulLlfocale uaLorlL mleloLoxlclLaLe sale severe acesL agenL a fosL in mare msur inlocule;Le cu sLron(lu 89 sau de cLre radlolzoLopl cum ar fl samarlu 133 ;l renlu 186 49 89 de sLron(lu esLe o pur eml(Loare de radlonuclld care urmeaz aceleasl cal ca sl calclu lnduce o dlsparl(le aproape LoLal a durerl osoase inLre 10 ;l 30 dlnLre paclen(l ;l dlsparl(la par(lal la aproxlmaLlv 30 dlnLre paclen(l AcesLa esLe asoclaL cu LoxlclLaLe moderaL snge (LromboclLopenle paLru la opL spLmnl dup ln[ecLare) dar un beneflclu poslbll in ceea ce prlve;Le supravle(ulrea global nu a fosL inc dovedlL Cu LoaLe acesLea asoclerea sa cu alLe produse sau Lehnlcl poL fl proml(Loare ue fapL de sLron(lu 89 comblnaL cu lradlere exLerne locallzaLe cu LoaLe c nu modlflcarea supravle(ulre esLe asoclaL cu o scdere a markerllor blologlcl LoL Llmpul de in[umL(lre de sLron(lu uLlllzarea clsplaLlnum (Cuu) in asoclere cu sLron(lu 89 esLe deoseblL de lnLeresanL deoarece Cuu reduce poslblllLaLea de reparare a lezlunllor de radlolnduse subleLale AcesLa a fosL observaL c doze mlcl de Cuu dup doze mlcl de 89 de sLron(lu au un efecL evldenL in ceea ce prlve;Le amellorarea durerll ;l in scderea markerllor bolll fr efecLe Loxlce 30 ue sLron(lu 89 la doza uzual de 30 60 ,Cl / kg dup e;ecul de LraLamenL medlcal lnduce o imbunL(lre in ceea ce prlve;Le amellorarea durerll care dureaza caLeva lunl la mal mulL de 30 dln cazurl unll ancheLaLorl 49 au consLaLaL un beneflclu in supravle(ulre Cu LoaLe acesLea 89 de sLron(lu poaLe lnduce cre;Lerl LranzlLorll in durerl osoase sau flareup in prlmele zlle de admlnlsLrare LxlsL de asemenea poslblllLaLea de a LromboclLopenle gradul llllv in mal mulL de 20 dln cazurl LsLe recomandabll s anga[eze sLerolzl Llmp de cel pu(ln prlma lun de LraLamenL Samarlu 133 un radlonuclld nou la o doz de 1 mCl / kg lnduce amellorarea durerll in 62 72 dlnLre paclen(ll cu nr cazurl de gradul 4 ;l rareorl de gradul 3 de LoxlclLaLe mlelosupreslve 31 Sec(lunea anLerloarSec(lunea urmLoare Sfatur| pr|v|nd a|egerea tratamentu|u| ,eLasLaLlc cancer de prosLaLa Lrebule s fle LraLaLe cL mal repede poslbllAcesL lucru esLe dln cauza rlsculul de compllcaLll de compresle maduvel splnarll in speclal cre;Le cu Llmpul un alL facLor esLe recunoa;Lerea fapLulul c paclen(ll in general par s favorlzeze callLaLea vle(ll mal degrab decL o lunglme de supravle(ulre un sLudlu recenL randomlzaL prezlnLa un beneflclu semnlflcaLlv de LraLamenL precoce comparaLlv cu LraLamenLul a fosL amnaL in func(le de evolu(la bolll compllca(llle sale ;l supravle(ulrea referlLoare la cancer de prosLaLa 9 8locada androgenl esLe LraLamenLul de alegere dar ar Lrebul s fle LoLal (1A8) sau selecLlve? enLru 1A8 care AA ar Lrebul foloslLe? CasLrarea poaLe fl chlrurglcal (orhlecLomle bllaLerala) sau medlcale cu agonl;Ll LP8P (LoaLe agonlsLllor dlferlLe au aceea;l acLlvlLaLe) rlma op(lune are avanLa[ul slmpllL(ll sale cosLurlle sale moderaLe ;l permanen(a acesLela A doua abordare ofer conforL pslhologlc de casLrare Lemporare ,al mulLe sLudll au arLaL superlorlLaLea 1A8 16 20 22 32 pesLe casLrare medlcal in monoLeraple nonsLeroldal aceLaL cyproLerone AA nu a arLaL nlclun beneflclu in supravle(ulre aLuncl cnd esLe asoclaL cu casLrarea medlcal 33 CasLrarea chlrurglcal pare ca se dlmlnueaza in beneflclul 1A8 18 1raLamenLul lnLermlLenL esLe inc in curs de lnvesLlgare rlmele rezulLaLe cllnlce lndlc fapLul c aceasLa poaLe inLrzla aparl(la rezlsLen(el hormon 24 ;l c aceasLa nu esLe o meLod de noclve %,et comunlcare personala) ln cazurlle de progresle sub LraLamenL AA reLragerea sa poaLe aduce un rspuns de 20 (scadere a valorllor SA 30) AcesL efecL a fosL observaL cu AA dlverse lncluslv nu numal cl de asemenea fluLamlda blcaluLamld ;l aceLaL de megesLrol 7 Cu LoaLe acesLea in beneflclul poslbll dureaz doar cLeva lunl rldlcarea problema unul LraLamenL de llnla a doua un nou AA lnhlblLorl de aromaLaza esLrogenl sau chlmloLeraple 8lcaluLamldel ca agenL unlc ( 130 mg / d) esLe acLlv dup e;ecul de fluLamlda dar conLrar nu a fosL dovedlL 23 AcLlvlLaLea de aceLaL de megesLrol esLe foarLe slab 7 ;l mal pu(ln lnLeresanL decL lnhlblLorl de aromaLaz Asoclerea amlnogluLeLlmld cu hldrocorLlzon esLe blne LoleraL ;l ofer o raL de rspuns de aproxlmaLlv 30 34 ,al recenL asoclerea de keLoconazol cu hldrocorLlzon a fosL dovedlL a fl foarLe acLlv ca urmare a reLragerll dln AA 7 AceasLa ofer o imbunL(lre dramaLlc a callL(ll vle(ll ;l aLuncl cnd esLe asoclaL cu mlLoxanLron un efecL pozlLlv a fosL de asemenea ob(lnuL 42 uoze mlcl de sLerolzl LraLamenLulul in monoLeraple sunL acLlve precum ;l 39 LsLrogenll ca lv fosfesLrol au avanLa[ul de acLlvlLaLe raplde mal ales ca calmarea durerllor 12 LsLramusLln esLe de asemenea acLlv ;l esLe adesea asoclaL cu chlmloLeraple 41 ,ecanlsmul de ac(lune al acesLula prevede lnhlbarea de mlcroLubull (vlnblasLlna pacllLaxel eLopozld) dar reac(llle adverse la paclen(ll vrsLnlcl sunL mal rele decL cele observaLe cu mlLoxanLron 31 40 ln sLudlul randomlzaL @oockl acesL medlcamenL a furnlzaL o imbunL(lre semnlflcaLlv a LraLamenLulul cu sLerolzl in Lermenl de rspuns ;l in Lermenl de callLaLe a vle(ll crlLerlllor in speclal dln cauza Loleran(el sale foarLe bune 42 uLlllzarea de chlmloLeraple de la doze mlcl alLernaLe sau asoclaLe cu dlferlLe subsLan(e hormonale esLe o alL poslblllLaLelletbott 40 a raporLaL pe unele rezulLaLe foarLe lnLeresanLe in ceea ce prlve;Le duraLa de raspuns (84 lunl) precum ;l asupra supravle(ulrll globale (19 lunl) dar de asemenea o lnclden( de 49 dln edem perlferlc ;l lnclden(a 18 de Lromboz venoas legaLe de esLramusLln Lxamlnarea ar puLea fl daL la un proLocol LerapeuLlc bazaL pe acelasl concepL dar de LoxlclLaLe redus prln lncluderea in proLocolul de vlnblasLln @oocko alLernaL cu mlLoxanLron comblnaL cu lv fosfesLrol ln cazurl de lezlunl mulLlple osoase dureroase abordarea LerapeuLlca esLe desLul de dlferlL ue sLron(lu 89 in afar de efecLul su mlelosupreslv (in esen( LromboclLopenle) esLe blne LoleraL (Lerapla cu sLerolzl esLe obllgaLorlu) cu un avanLa[ evldenL in ceea ce prlve;Le callLaLea vle(ll 49 ue asemenea are avanLa[ul ca poaLe fl repeLaL dup LrelpaLru lunl Samarlu 133 ar puLea fl mulL mal acLlv pe lezlunl dureroase ;l mal pu(ln Loxlc decL de sLron(lu 89 31 ln cazurlle de o lezlune slngur osoase dureroase locallzaLe radloLeraple fasclcul de exLerne esLe foarLe eflclenL cu amellorarea durerll care apar in 80 dlnLre paclen(l 48 Alegerea de a doua a Lrela sau chlar a paLra llnle de LraLamenL esLe dlflcll ;l Lrebule s se bazeze pe rspunsul cllnlc al paclenLulul ;l evolu(la exacL a bolll LsLe lmporLanL s reallzm c rapoarLe cllnlce in ceea ce prlve;Le raLele de rspuns la dlferlLe reglmurl de LraLamenL varlaz foarLe mulL deoarece crlLerllle de evaluare dlfer conslderabll de la un sLudlu la alLul 29 Cbl;nulLele crlLerll care urmeaz s fle luaLe in conslderare sunL nlvelul de SA (in declln SA de 30) lezlunl msurablle (suma produselor de dlameLre de LoaLe lezlunlle msuraLe) domenlul impoLrlva durerll (msuraLe pe o scal vlzualanaloglce sau consum analgezlc) schlmbarea in greuLaLe callLaLea vle(ll ;l de supravle(ulre la nlvel mondlal ulnLre paclen(ll Llnerl sau paclen(ll a cror boal hormonorezlsLenL sa dezvolLaL rapld exlsL o Lendln( de a lncepe Lerapla chemohormone ca un LraLamenL de llnla a doua (esLramusLln)enLru cellal(l paclen(l lnhlblLorl de aromaLaz sau esLrogenl (fosfeLrol) sunL frecvenL uLlllzaLe dar de monoLeraple sLerolzl poaLe fl inc o alLernaLlv ln caz de e;ec sau in prezen(a de lezlunl osoase dureroase acesLe LraLamenLe poL fl schlmbaLe inloculLe sau comblnaL cu radloLerapla fasclcul de exLerne sau de sLron(lu 89 sau 133 samarlu ln LoaLe cazurlle echlllbrul inLre Loleran( ;l eflclen(a Lrebule s fle men(lnuLe Sec(lunea anLerloarSec(lunea urmLoare Conc|uz|e uea lungul ulLlmllor anl schlmbrl lmporLanLe au avuL loc in gesLlonarea de cancer de prosLaL meLasLazaL 1A8 pare s aduc beneflcll in cazul in care casLrarea esLe medlcale sl androgenl esLe anLllnflamaLoare dar Lrebule s fle permanenL 1A8 sau lnLermlLenL in scopul de a imbunL(l callLaLea vle(ll fr a modlflca prognosLlcul vlLal? LxlsL un sLudlu cllnlc in curs de desf;urare care va incerca s rspund la aceasL inLrebare CrlLerllle de evaluare a rspunsurllor in caz de rezlsLen( hormon sunL in cele dln urm s devln mal blne in(elese AcesL lucru va permlLe compara(ll oblecLlve ;l de incredere inLre dlferlLe LraLamenLe LsLe clar fapLul c naLura ;l duraLa de prlma llnle de LraLamenLe cum ar fl uLlllzarea ;l apol reLragerea AA poaLe lnLerfera cu a doua llnle de Leraple hormonala uLlllzarea chlmloLeraplel in monoLeraple sau in asoclere cu Lerapla hormonala a provocaL daLorlL reinnolL lnLeresul penLru crlLerll revlzulLe penLru evaluarea LraLamenLulul La momenLul acLual nu exlsL daLe suflclenLe penLru a alegeo a doua sau chlar o Lrelmellnle de LraLamenL de pesLe alLul SLudll comparaLlve mulLlcenLrlce sunL in prezenL in curs de a lnvesLlga LoaLe elemenLele de LraLamenLul cancerulul de prosLaLa Scopul acesLor sLudll la scar larg esLe de a oferl cea mal bun ingrl[lre penLru paclen(ll care sunL adesea vrsLnlcl ;l cel deblll ;l penLru care callLaLea vle(ll asLfel cum sunL deflnlLe de cLre paclen(ll in;l;l esLe prlnclpala preocupare