簡(jiǎn)介:轉(zhuǎn)移性乳腺癌內(nèi)科治療進(jìn)展,王中華20120509講課,AGEDISTRIBUTION,DATAFROMSHANGHAICANCERINSTITUTE,,,,,,5YRDISEASEFREE,5YRRECURRENCE,,GAINFROMADJUVANTCHEMOTHERAPY,70,30,70,10,20,RISKREDUCTION30?20,10/3033ABSOLUTEBENEFIT1070ALWAYSFREE20ALWAYSRECURRED,,,,超過(guò)2/3的乳腺癌復(fù)發(fā)為遠(yuǎn)處轉(zhuǎn)移,遠(yuǎn)處轉(zhuǎn)移61755年生存率413,對(duì)側(cè)乳腺癌9115年生存率834,局部復(fù)發(fā)16285年生存率593,,,,BIGBREASTINTERNATIONALGROUPBAUMETALLANCET20023592131THüRLIMANNETALNENGLJMED20053632747,晚期乳腺癌治療目的,控制疾病,緩解癥狀提高患者的生活質(zhì)量,延長(zhǎng)高質(zhì)量的生存期,,全面評(píng)估,,內(nèi)分泌,化療,乳腺癌的分子分型與內(nèi)科治療方法,LUMINARA/BER()和/或PR(),HER2陽(yáng)性,所有類型MBC受體三陰性,全身化療針對(duì)所有類型的晚期乳腺癌,晚期乳腺癌的化療發(fā)展史,,,,,,,,,1955,1965,1975,1985,1995,2005,2015,,,CYCLOPHOSPHAMIDE1959,METHOTREXATE1971,DOXORUBICIN1974,GEMCITABINE2004,CAPECITABINE1998,LAPATINIB2006,ACCESSEDONLINEATHTTP//WWWFDAGOV/CDER/CANCER/DRUGLISTFRAMEHTM,,,,,,,,,DOCETAXEL1996,,,PACLITAXEL1994,,TRASTUZUMAB2000,,APPROVEDSPECIFICALLYFORFIRSTLINEUSEINMBC,,,NABPACLITAXEL2005,,,IXABEPILONE2007,BEVACIZUMAB2008,5FU1962,,,,,,PLATINUMS,,,晚期乳腺癌化療適應(yīng)證,病變發(fā)展迅速內(nèi)臟轉(zhuǎn)移,如肝、肺廣泛轉(zhuǎn)移無(wú)病生存期(DFS)<2年ER和PR陰性既往內(nèi)分泌治療無(wú)效,化療的應(yīng)用方法,聯(lián)合VS單藥(A+BVSA)ORR↑TTP↑OS↑或聯(lián)合VS序貫(A+BVSA→B)TTP、OS未顯示有明顯優(yōu)勢(shì),聯(lián)合化療VS單藥,優(yōu)先選擇聯(lián)合化療①有廣泛轉(zhuǎn)移或②有臨床癥狀,需要快速控制病情或③腫瘤進(jìn)展迅速或④威脅生命的轉(zhuǎn)移或⑤患者的耐受性較好優(yōu)先考慮單藥化療①無(wú)重要臟器轉(zhuǎn)移或②無(wú)臨床癥狀或③轉(zhuǎn)移部位少,,輔助,,首選,,蒽環(huán),蒽環(huán)類聯(lián)合紫杉類AT,蒽環(huán)類CAF、CEFAC、EC,未化療,,,CMF,復(fù)發(fā)轉(zhuǎn)移性乳腺癌化療藥物選擇原則,多西他賽聯(lián)合卡培他濱TX紫杉醇吉聯(lián)合吉西他濱GP,,或,,蒽環(huán)類及紫杉類治療失敗,卡培他濱、長(zhǎng)春瑞濱、吉西他濱、鉑類、伊沙匹隆、ABX,,,,FIRSTLINESECONDLINEDOXORUBICIN3550125301EPIRUBICIN526828PACLITAXEL296311957DOCETAXEL476513958CAPECITABINE25120271GEMCITABINE2337113411VINORELBINE404411736,1ESTEVAFETAL,ONCOLOGIST20016133146,單藥治療MBC有效率,白蛋白結(jié)合型紫杉醇III期臨床試驗(yàn)試驗(yàn)設(shè)計(jì),GRADISHARETALJCLINONCOL2005237794–7803,MBC,,III期臨床試驗(yàn)注射用紫杉醇(白蛋白結(jié)合型)顯著延長(zhǎng)了患者的至腫瘤進(jìn)展時(shí)間,GRADISHARETALJCLINONCOL2005237794–7803,標(biāo)準(zhǔn)紫杉醇LN224,注射用紫杉醇(白蛋白結(jié)合型)N229,中位時(shí)間230周194–261,中位時(shí)間169WKS151–209,無(wú)進(jìn)展百分比,,,,,,,,,,,,,,,,,,,,P0006風(fēng)險(xiǎn)比075,,周,081624324048566472808896,104,112,120,III期臨床試驗(yàn)毒性,GRADISHARETALJCLINONCOL2005237794–7803,CAPECITABINE1,250MG/M2BIDDAYS1–14DOCETAXEL175MG/M2DAY1,DOCETAXEL100MG/M2DAY1,3WEEKLYCYCLES,N255,N256,O’SHAUGHNESSYETALJCLINONCOL20022028122823,SO14999研究多西他賽聯(lián)合希羅達(dá)VS多西他賽,,R,,主要研究終點(diǎn)TTP,,GEMZAR1,250MG/M2BIDDAYS1,8PACLITAXEL175MG/M2DAY1,PACLITAXEL175MG/M2DAY1,3WEEKLYCYCLES,N529,O’SHAUGHNESSYETALJCLINONCOL20022028122823,JHQG研究設(shè)計(jì)紫杉醇聯(lián)合吉西他濱VS紫杉醇,,R,,主要研究終點(diǎn)TTP,,蒽環(huán)類和紫杉類均耐藥乳腺癌的化療,希羅達(dá)伊沙匹隆IXABEPILONE+希羅達(dá)(2B)NVB+GEMNVB±希羅達(dá)NVB±DDP/CBPGEM±DDP/CBP,PHASEIIISPANISHBREASTCANCERRESEARCHGROUPGEICAMTRIAL療效毒副作用GEM+NVBVSNVBG3/4ANC下降66%VS44%(P00074)ANC減少性發(fā)熱11%VS6%(P015)非血液學(xué)毒性兩組無(wú)顯著差異,蒽環(huán)和紫杉類治療失敗GEM+NVBVSNVB,LANCETONCOLOGY20078219225,,,GEMCITABINE1200MG/M2DAYS1AND8VINORELBINE30MG/M2DAYS1AND8Q21D,VINORELBINE30MG/M2DAYS1AND8Q21D,,PD,252PTSMBCPRETREATEDWITHANTHRACYCLINESANDTAXANES,,,,EPOTHILONEIXABEPILONEBMS247550BRISTOLMYERSSQUIBB,NEWYORK,NY,ACTIVITYINMULTIPLETUMORMODELSLOWSUSCEPTIBILITYTOTUMORRESISTANCEMECHANISMSMRPANDPGPEFFLUXPUMPS?ⅢTUBUILNOVEREXPRESSION?TUBUILNMUTATIONSANTITUMORACTIVITYINTAXANERESISTANCEMODELS,SCELLULOSUM,EPOTHILONEB,IXABEPILONE,,,,59,36,23,,22,35,12,41,STUDYDESIGNINTERNATIONAL,RANDOMIZED,PHASEIIITRIAL,BMS046,IXABEPILONE40MG/M2IVOVER3HRSDAY1,EVERY3WKSCAPECITABINE1000MG/M2ORALLYBIDDAYS114,EVERY3WKS,CAPECITABINE1250MG/M2ORALLYBIDDAYS114EVERY3WKS,PATIENTSWITHMETASTATICORLOCALLYADVANCEDBREASTCANCERTOANTHRACYCLINESPRE/RESISTANTANDTAXANERESISTANT,,,STRATIFIEDBYVISCERALMETASTASESPREVIOUSMBCCHEMOTHERAPYANTHRACYCLINERESISTANCESTUDYSITE,,PD,IXABEPILONEPLUSCAPECITABINEVSCAPECITABINEALONE,,,IXABEPILONEPLUSCAPECITABINEVSCAPECITABINEALONE,OVERALLRESPONSERATEICVSC35VS14P0001PFSBENEFITFORCOMBINATIONARM58VS42MOS輔助化療后快速?gòu)?fù)發(fā)(56VS28MOS)2008SABCS,ASDETERMINEDBYINDEPENDENTRADIOLOGICREVIEW,MONTHS,PROPORTIONPROGRESSIONFREE,4,0,8,12,16,20,24,00,02,04,06,08,10,,,,,,,28,32,36,PFSBYINDEPENDENTRADIOLOGICREVIEW,,,,,CAPECITABINE,IXABEPILONECAPECITABINE,HR07595CI064088P0003,,VAHDATLT,ETALASCO2007ABSTRACT1006,GRADE3/4PERIPHERALNEUROPATHY23FORIXABEPILONEPLUSCAPECITABINEVS0FORCAPECITABINEALONE感覺(jué)神經(jīng)/累積性/可逆性中位恢復(fù)至G1OR基線6WEEKS,MOREHEMATOLOGICTOXICITYOBSERVEDINIXABEPILONEARM,,IXABEPILONEPLUSCAPECITABINEVSCAPECITABINEALONE,OCTOBER22,2007FDAAPPROVESIXEMPRAIXABEPILONE,BRISTOLMYERSSQUIBBFORADVANCEDBREASTCANCERPATIENTSTHEUSFOODANDDRUGADMINISTRATIONHASAPPROVEDIXEMPRAIXABEPILONE,ANEWANTICANCERTREATMENT,FORUSEINPATIENTSWITHMETASTATICORLOCALLYADVANCEDBREASTCANCERWHOHAVENOTRESPONDEDTOCERTAINOTHERCANCERDRUGS,何時(shí)停藥治療越長(zhǎng)越好,效不更方至病情進(jìn)展或不可耐受的毒性選擇其中一個(gè)藥物用至進(jìn)展或不可耐受的毒性更換其他一種化療藥希羅達(dá),PLD更換成內(nèi)分泌治療耐受性好,作用機(jī)制不同,減少耐藥停止用藥(68周期后),觀察定期復(fù)查,進(jìn)展再給予處理,三種不同劑量多西他賽治療MBC,,P005,,,,PACLITAXEL200MG/M2)D2EPIRUBICIN90MG/M2D1ORDOXORUBICIN50MG/M2D1,EVERY3WEEKS68CYCLESN459,CR/PR/SD,PACLITAXEL175MG/M2,NOFURTHERCHEMOTHERAPY,EVERY3WEEKS8CYCLES,HRHT,PACLITAXELMAINTENANCEJCO,2006,R,,,GENNARIA,ETAL,JCO,2006,39128,N215255,THEPRIMARYENDPOINTPFS,GENNARIA,ETAL,JCO,2006,39128,,MANTA1STUDY,,POSSIBLEEXPLANATIONFORMANTA1STUDYPACLITAXELMAINTENANCE,USEOFCONCURRENTENDOCRINETHERAPYIN60OFHORMONERECEPTORPOSITIVEPATIENTSCONTROLARMPATIENTSACTUALRECEIVEDMAINTENANCEHORMONALTHERAPYTHECONCURRENTOFCHEMOANDHORMONALMAYREDUCETHEEFFICACYTOXICITYOFPACLITAXELSENSORYNEUROPATHYGRADE2OCCURREDIN26,GRADE3IN6ANDGRADE4IN2OFTHEPATIENTSINMAINTENANCEGRADE?ANC↓24,GEICAM200101STUDYPHASEIIITRIAL,288PTSMBC,,,2008ESMO,OBSERVATION,PLD40MG/M2Q28D6,,,一線,,,CR/PR/SD,AT(50/75)6,155PTS,78PTS,77PTS,R,AADMTTXTPLD脂質(zhì)體ADM,,STATISTICALLYSIGNIFICANT?ASSESSEDINFUTILITYANALYSIS,RANDOMIZEDSTUDIESOFCHEMOTHERAPYDURATIONINMBC,,MBC的化療,為何用目的何時(shí)用適應(yīng)癥怎么用方法(聯(lián)合、單藥)用何藥三級(jí)選用(蒽環(huán),蒽環(huán)耐藥,蒽環(huán)及紫杉均耐藥)何時(shí)停五種措施,生物靶向治療-與化療聯(lián)合,TARGETEDTHERAPIESFORBREASTCANCER,MTOR,TAM,AI,HER2陽(yáng)性MBC-HERCEPTIN-LAPATINIB,HER2陽(yáng)性定義,IHC3,CISH,FISH,或,或,免疫組織化學(xué)法IHC色素原位雜交法CISH熒光原位雜交法FISH,HERCETPIN單藥治療晚期乳腺癌的療效,HO649GHO551GHO650(關(guān)鍵試驗(yàn))(Ⅱ期)(關(guān)鍵試驗(yàn))_____________________________________________NINTENTTOTREAT22246114CR817PR26423有效率15%11%26%中位緩解期(月)9166188中位生存期(月)1314244______________________________________________,HERCEPTIN聯(lián)合化療一線治療HER2陽(yáng)性MBC,,,HHERCEPTIN,TTXT,PPAX,CCBP,XXELODA,,,曲妥珠單抗聯(lián)合泰索帝同時(shí)還是序貫使用HERTAX,BONTENBALETALASCO2008ABSTRACT1014,99例HER2,一線M主要目的PFS次要目的RR18594XIAW,ETALONCOGENE20022162556263,GEYERCE,ETALASCO2006CLINICALSCIENCESYMPOSIUM,EGF100151LAPATINIBCAPECITABINEINADVANCEDBREASTCANCER,到疾病進(jìn)展時(shí)間(ITTPOPULATION),70,20,40,60,80,0,100,,,,,,,,,10,20,30,40,50,60,,,,,,,,,,0,,,,,,TIMEWEEKS,,PATIENTSPROGRESSIONFREE,EGF100151,GEYERCE,ETALNENGLJMED20063552627332743,GBG26曲妥珠單抗加希羅達(dá)VS希羅達(dá),延長(zhǎng)TTP近3個(gè)月(82MVS56MP005EGF104900曲妥珠單抗加拉帕替尼VS拉帕替尼,顯著延長(zhǎng)TTP(28MVS19MP0008),含曲妥珠單抗一線治療HER2陽(yáng)性MBC進(jìn)展后,VONMINCKWITZGETALJCLINONCOL200826MAY20SUPPLABS1025O’SHAUGHNESSYJETALJCLINONCOL200826MAY20SUPPLABS1015,,,,PCH或WPCH,貝伐單抗,PACLITAXEL±BEVACIZUMABINMBCE2100,N715LOCALLYRECURRENTOR1STLINEMBC,值得關(guān)注的是貝伐單抗組有更多感染、3/4級(jí)的高血壓、蛋白尿、頭痛、心腦血管局部缺血,MILLERETALNENGLJMED200735726662676,RESULTS,,PACLITAXEL90MG/M2D1,8,15Q4W,,PACLITAXEL90MG/M2D1,8,15Q4WBEVACIZUMAB10MG/KGD1,15,YELLOWTEXTINDICATESSTATISTICALLYSIGNIFICANTVALUES,,,R,DOCETAXEL±BEVACIZUMABINMBCAVADO,N705LOCALLYRECURRENTOR1STLINEMBCSTRATIFICATIONREGIONPRIORTAXANE/TIMETORELAPSESINCEADJUVANTCHEMOMEASURABLEDISEASEHRSTATUS,,,R,DOCETAXEL100MG/M2PLACEBOQ3W,DOCETAXELBEVACIZUMAB75MG/KGQ3W,DOCETAXELBEVACIZUMAB15MG/KGQ3W,BEVACIZUMABCONTINUEDTODISEASEPROGRESSIONALLPTSGIVENOPTIONTORECEIVEBEVACIZUMABWITH2NDLINECHEMODOCETAXELADMINISTEREDFORMAXIMUMOF9CYCLES,MILESETALASCO2008LATEBREAKINGABSTRACT1011,PHASEIIISTUDIESE2100ANDAVADO,MILLERETALNENGJMED2007MILESETALASCO2008LBA1011,YELLOWTEXTINDICATESSTATISTICALLYSIGNIFICANTVALUES,,E2100ANDAVADOSAFETYDATA,MILLERETALNENGJMED2007MILESETALASCO2008LBA1011VTENOINCREASEINBEVACIZMABARMINEITHERSTUDY,,,,,,,,,,,ONGOINGPHASEIIITRIALSEVALUATINGBEVACIZUMABINFIRSTLINEMBC,GEICAM200611,AVEREL,HER2DISEASETRASTUZUMABCONTAININGREGIMENS,HORMONALTHERAPY,,RIBBON1,RIBBON1,RIBBON1,CAPECITABINE,,AVADO,SINGLEAGENTTAXANETHERAPY,ANTHRACYCLINEBASEDCHEMOTHERAPY,BEVACIZUMAB,晚期乳腺癌的內(nèi)分泌治療針對(duì)LUMINALA/B的MBCER()PR()ER()或PR(),內(nèi)分泌治療與化學(xué)治療,內(nèi)分泌改變腫瘤的內(nèi)環(huán)境來(lái)抑制其生長(zhǎng)對(duì)正常細(xì)胞影響小,副作用小2~8周起效,緩解期長(zhǎng)不需要升白、止吐等支持治療治療費(fèi)用較低,化療阻斷腫瘤復(fù)制來(lái)殺死腫瘤細(xì)胞對(duì)正常細(xì)胞有殺傷,副作用大1~2周起效,緩解期短常需要升白、止吐等支持治療治療費(fèi)用一般較高,晚期乳腺癌內(nèi)分泌治療適應(yīng)證,患者年齡>35歲無(wú)病生存期(DFS>2年骨和軟組織轉(zhuǎn)移;無(wú)癥狀的內(nèi)臟轉(zhuǎn)移ER和/或PR陽(yáng)性,晚期乳腺癌的內(nèi)分泌治療,月經(jīng)狀況治療藥物絕經(jīng)前戈舍瑞林GOSERELIN,ZOLADEX)亮丙瑞林LEUPROLIDEACETATE)絕經(jīng)后瑞寧得ANASTROZOLE來(lái)曲唑LETROZOLE依西美坦各種年齡他莫昔芬,孕激素,阿那曲唑的一線療效優(yōu)于TAM,‘ARIMIDEX’ANASTROZOLEVERSUSTAMOXIFENFORTHEFIRSTLINETREATMENTOFADVANCEDBREASTCANCERINPOSTMENOPAUSALWOMENFROMTRIALS0030AND0027KNOWNTOBERECEPTORPOSITIVE,025試驗(yàn)設(shè)計(jì)來(lái)曲唑VS他莫昔芬作為晚期一線治療,MOURIDSENETALJCLINONCOL2001192596,試驗(yàn)人群絕經(jīng)后局部晚期或局部復(fù)發(fā)或轉(zhuǎn)移的乳腺癌ER和/或PGR陽(yáng)性或未知,來(lái)曲唑的一線療效優(yōu)于TAM,非甾體類AI失敗后的內(nèi)分泌治療MBC,芳香化酶抑制劑作用機(jī)理非甾體VS甾體,,,,雄激素,非甾體類(抑制劑)EG,ANASTROZOLE,LETROZOLE,芳香化酶,甾體類(滅活劑)EG,EXEMESTANE,,,,,,,,,,,,,GEISLERETALCLINCANCERRES19984208993,EFECTEVALUATIONOFTREATMENTOPTIONSFOLLOWINGAIFAILURE,FULVESTRANTIMINJECTIONLOADINGDOSEREGIMENN351,EXEMESTANE25MG/DAYORALLYN342,POSTMENOPAUSALWOMENWITHHORMONERECEPTOR–POSITIVE,PROGRESSING/RECURRINGADVANCEDBREASTCANCERAFTERNONSTEROIDALAIN693,PROGRESSION,DEATH,ORWITHDRAWAL,FULVESTRANTLOADINGDOSEREGIMENCOMPRISED500MGONDAY0,250MGONDAYS14AND28,AND250MGMONTHLYTHEREAFTER,,GRADISHARW,ETALSABCS2006ABSTRACT12,EFECTSIMILARTTPINPATIENTSTREATEDWITHFULVESTRANTOREXEMESTANE,GRADISHARW,ETALSABCS2006ABSTRACT12,EXEMESTANE37MONTHSFULVESTRANT37MONTHSP65,絕經(jīng)后MBC的內(nèi)分泌治療,一線,二線,三線,TAM,孕激素,雄激素,AI,TAM,孕激素,,輔助,AI,孕激素,氟維司群,TAM,,,,,,,1985,2002,,新方向靶向聯(lián)合內(nèi)分泌,2008SABCS,,EGF30008拉帕替尼聯(lián)合來(lái)曲唑隨機(jī)Ⅲ期臨床,2008SABCS,PFS,,,,,P拉帕替尼,L來(lái)曲唑TTAM,絕經(jīng)后ER/PR陽(yáng)性MBC一線,受體三陰性乳腺癌,TRIPLENEGATIVEBCANDPARPINHIBITION,BRCA1BRCA2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
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