乳腺癌的化學(xué)治療(hn)

乳腺癌的化療

1早期乳腺癌輔助藥物治療2乳腺癌輔助藥物治療NIHConsensusDevelopmentConference:AdjuvantTherapyforBreastCancer1990：乳腺保存治療可以作為乳腺切除/淋巴結(jié)清掃的合理替代輔助化療/內(nèi)分泌治療減少淋巴結(jié)（–）病人復(fù)發(fā)。2000：乳腺癌輔助治療各類成熟結(jié)論：1.乳腺癌輔助內(nèi)分泌治療的適應(yīng)癥2.輔助化療的適應(yīng)癥3.輔助化療的藥物、劑量、和方案4.輔助放療的適應(yīng)癥3乳腺癌輔助化療4乳腺癌輔助化療的適應(yīng)癥NIHConsensusDevelopmentConference20004th

大多數(shù)局限期乳癌，只要腫瘤直徑>1cm，無(wú)論病人有無(wú)絕經(jīng)，淋巴結(jié)有無(wú)轉(zhuǎn)移，以及激素受體狀況，都應(yīng)該接受輔助化療。對(duì)于腫瘤<1cm，淋巴結(jié)陰性病人，是否需要化療應(yīng)個(gè)體化。5CMF（Milan）最早的化療方案，改善DFS和OS，通常化療6個(gè)月。含蒽環(huán)類較無(wú)蒽環(huán)類方案顯著減少?gòu)?fù)發(fā)（12%）和死亡率（11%）（1995EBCTCG）。NSABP:AC×4vsCMF×6復(fù)發(fā)率和死亡率無(wú)差別含紫杉類方案：AC→Taxol顯示減少?gòu)?fù)發(fā)和死亡率，進(jìn)一步的研究正在進(jìn)行中(CALGB9344、NSABPB-28、BCIRG001)。6乳腺癌常用輔助化療方案CMFCTX100mg/m2pod1-14MTX40mg/m2IVd1,d85-FU600mg/m2IVd1,d8q4wOrCTX600mg/m2IVd1MTX40mg/m2IVd15-FU600mg/m2IVd1q3w7乳腺癌常用輔助化療方案CAFCTX100mg/m2pod1-14ADR30mg/m2IVd1,d85-FU500mg/m2IVd1,d8q4worCTX500mg/m2IVd1ADR50mg/m2IVd15-FU500mg/m2IVd1,d8q3w8乳腺癌常用輔助化療方案

FEC50FEC100CEF120ADR×4

→CMF×3-4

9CEF(NCIC-CTG方案)CTX70mg/m2pod1-14EPI60mg/m2d1,d85-FU500mg/m2d1,d8Ciprofloxacin500mgBidq3w

AC:ADR60mg/m2IVd1CTX600mg//m2IVd1q3w

EC:10含紫杉類輔助化療方案

11CALGB9344trial

對(duì)3170例隨機(jī)對(duì)照研究，觀察

AC→T方案與AC方案的療效。中位隨訪30個(gè)月時(shí)，F(xiàn)DA于99年10月批準(zhǔn)AC→T方案在LN+的乳腺癌輔助治療。隨訪69個(gè)月時(shí)，AC→T仍優(yōu)于AC方案。但是對(duì)ER+患者沒有優(yōu)勢(shì)。RegimenGroup1AC×4(ADR60/75/90mg/m2)Group2AC×4→Paclitaxel175mg/m2×4(q3w)ER(+)TAMfor5yrs121314

NSABPB28trial:LN+Regimen:group1AC×4→Paclitaxel225mg/m2×4(q3w)group2AC×4onlybothgroup:TAM>50yallTAM<50yER+和或PR++/-TAM結(jié)果無(wú)差別，paclitaxel對(duì)無(wú)TAM組有作用。AC

→Paclitaxel組有5例AL。15NSABPB28trial中位隨訪65月結(jié)果

ACAC-PHazardRatioN15291531Events4614000.83(P=.008)Death2552430.94(P=.46)5yDFS72%76%5yOS85%85%結(jié)論：1Pacli組明顯減少?gòu)?fù)發(fā)風(fēng)險(xiǎn)2生存尚未見到差別3對(duì)ER+和ER-都減少?gòu)?fù)發(fā)39thASCO16DocetaxelinOperableBreastCancer:ResultsFromtheBCIRG001Trial

Nabholtzandcolleagues

fromtheBreastCancerInternationalResearchGroup(BCIRG)--interimanalysis

1491ptswithnode-positivebreastcanceramedianageof49years,

FAC×6(500,50,and500mg/m2,q3w)Docetaxel,ADR,andCTX(TAC)(75,50,and500mg/m2,q3w).firsttrialtheuseofdocetaxelintheadjuvantsettinginwhichresultshavebeenreported.17

ResultsoftheBCIRG-001TrialTACFACHazardRatio*No.ofpatients745746No.ofrecurrences1191700.50;P=.0002No.ofdeaths57760.71;P=.049Febrileneutropenia242Grade3-4infection,%2.81.3No.ofsepticdeaths00Chronicheartfailure,%1.20.12003年18早期乳腺癌術(shù)后劑量密度化療CALGB9741術(shù)后淋巴結(jié)陽(yáng)性乳腺癌輔助化療隨機(jī)臨床試驗(yàn)dose-dense與傳統(tǒng)3周對(duì)照序貫與聯(lián)合對(duì)照25屆

SanAntonio乳腺癌年會(huì)JClinOncol2003Apr15;21(8):1431-919CALGB9741-治療方案2,005例淋巴結(jié)陽(yáng)性乳腺癌隨機(jī)分成4組中位年齡50,ER+67%.方案Grupe1:ADR×3-CTX×3-Taxol×3Q3wGrupe2:ADR×3-CTX×3-Taxol×3Q2wGrupe3:ACfollowedbyTQ3wGrupe3:ACfollowedbyTQ2w病人接受dose-dense方案者，應(yīng)用G-CSF（FilgrastimorNeupogen)預(yù)防中性粒細(xì)胞減少。20CALGB9741Results

medianfollow-upof36months

dose-denseconvenriskratio4yDFS82%75%0.74P=.0104yOS0.69P=.013315patientshadexperiencedrelapseordied,comparedwith515expectedtreatmentfailures.Dose

density

改善療效31%序貫化療與同時(shí)化療一樣有效21ComparisonofBreastCancerTrialsEvaluatingTaxanes

C9344B28C9741

BCIRG001N3170306020051491Mfollow-up69m65m36m33mTaxanePaclitaxelPaclitaxePaclitaxelDocetaxelComparisonACvs

AC-->Pevery3weeksACvs

AC-->Pevery3weeksAC-->PorA-->P-->C

every3weeks

vs

AC-->PorA-->P-->C

every2weeksDACvsFACevery3weeksSuperiorArmAC-->PAC-->PAC-->PorA-->P-->Cevery2weeksDACDFSHazardRatio0.83

(P=.0098)0.83

(P=0.008)0.74

(P=.01)0.68

(P=.0002)DeathHazardRatio0.82

(P=.0098)NS0.69

(P=.013)0.76

(P=.04939thASCO22乳腺癌輔助

高劑量化療和干細(xì)胞支持治療—隨機(jī)對(duì)照研究StudySelectionPtsMFTResultsCALGB-1edtrial>/=10N+7855.1yrsNodifferItaliantrial>/=4N+3824.3yrNodifferJapanesetrial>/=10N+974yrsNodifferPEGASE01>/=10N+3143.3yrsincreasedDFS(17%vs55%)37thASCO23ResultsofTrialsEvaluatingHigh-DoseChemotherapyinBreastCancer

GroupNSettingTreatmentArmsResultsECOG540StageII-III

>/=10+nodesCAFx6

CAFx6-->HDC/SCTNosignificantdifferenceinDFSorOSDutch885StageII-III

>/=4+nodesFECx5

FECx4-->HDC/SCT*TrendtowardimprovedDFSforHDC/SCT;notinOSIBCSG344StageII-III

>/=5+nodesHighdoseEC+SCT

EC/AC-->CMFNosignificantdifference;trendtowardimprovedDFSforhigh-doseECUK281StageII-III

>/=4+nodesFECx6

FECx3-->HDC/SCTNosignificantdifferenceinDFSandOSIBDIS110MetastaticATx4-->CMFx4

ATx3-->tandemHDC/SCTSignificantlyimprovedEFSandOS39thASCO24化療時(shí)間對(duì)療效的影響FEC×6較FEC×3更有效。（法國(guó)）CMF×6與CMF×3比較，療效一樣，但是發(fā)現(xiàn)對(duì)年輕的和雌激素受體陰性的患者療效更好。輔助化療與內(nèi)分泌治療的順序Intergroup0100結(jié)果：淋巴結(jié)陽(yáng)性、激素受體陽(yáng)性的絕經(jīng)后患者TAM在化療之后應(yīng)用優(yōu)于兩者同時(shí)使用。StGallen8th25NIH2000共識(shí)--化療推薦蒽環(huán)類方案，建議CAF和CEF為好。法國(guó)研究FEC100優(yōu)于FEC50，認(rèn)為存在劑量關(guān)系。HD-CT并不優(yōu)于標(biāo)準(zhǔn)劑量聯(lián)合方案，在臨床研究以外不推薦使用。在CALGB9344

研究里，AC以外加Taxol只對(duì)激素受體陰性有作用。26輔助性內(nèi)分泌治療27TAM單藥5年減少激素受體陽(yáng)性乳腺癌患者年復(fù)發(fā)40%，其作用持續(xù)到15年，對(duì)淋巴結(jié)陽(yáng)性/陰性、年齡>/<50歲療效相當(dāng)2000EarlyBreastCancerTrialists'CollaborativeGroup(EBCTCG)meta-analysisTAM服藥5年療效優(yōu)于1、2年，減少年復(fù)發(fā)分別為43%,18%,and25%。1995EBCTCGmeta-analysis服藥10年與5年相比，療效不增加，但是毒性增加。NSABPB-14trialNIH200028卵巢去勢(shì)對(duì)絕經(jīng)前患者15年期間減少?gòu)?fù)發(fā)：Node-negative,8.9%Node-positive,13.4%與CMF療效相當(dāng)與化療合用沒有增加療效NIH200029TheConsensusStatementrecommendsthatallwomenwhosebreastcancersexpresshormonereceptorsshouldreceiveadjuvanthormonaltherapy,regardlessofage,nodestatus,ortumorsize.NIH200030ATAC試驗(yàn)證實(shí)Anastrozole對(duì)絕經(jīng)后患者療效優(yōu)于TAM.ZEBRA試驗(yàn)證實(shí)Zoledex+/-TAM對(duì)絕經(jīng)前患者與6療程CMF療效相當(dāng)。在CMF之后序貫應(yīng)用Zoledex對(duì)淋巴結(jié)陰性的患者要比兩者單用要好。TAM仍然是激素受體陽(yáng)性患者術(shù)后輔助治療的主要選擇。激素受體陽(yáng)性僅次于淋巴結(jié)轉(zhuǎn)移，成為輔助治療的重要決定因素。要求有優(yōu)良質(zhì)控的實(shí)驗(yàn)室激素受體的定量測(cè)評(píng)。StGallen8th312003年StGallen

早期乳腺癌治療最新共識(shí)第8屆瑞士32

DefinitionandRiskCategoriesforPatientsWithNode-NegativeBreastCancer

RiskCategoryEndocrineEndocrineResponsiveNonresponsiveMinimalRiskERand/orPRexpressed,Notapplicableplusallofthefollowingfeatures:Tumor</=2cmGrade1Age>/=35yearsAverageRiskERand/orPRexpressed,ERandPRabsent

plusatleastoneofthefollowingfeatures:Tumor>2cmGrades2-3Age<35yearsER,estrogenreceptor;PR,progesteronereceptor.GoldhirschA,etal.JClinOncol.2003;21:33357-3365.ReprintedwithpermissionfromtheAmericanSocietyofClinicalOncology.33

AdjuvantSystemicTreatmentforPatientsWithOperableBreastCancer（1）RiskGroupNode-negativedisease,minimalriskEndocrine-ResponsiveDiseasePremenopausal：TamoxifenornonePostmenopausal：TamoxifenornoneEndocrine-NonresponsiveDiseasePremenopausal：NotapplicablePostmenopausal：Notapplicable34AdjuvantSystemicTreatmentforPatientsWithOperableBreastCancer（2）RiskGroupNode-negativedisease,averagerisk

Endocrine-ResponsiveDiseasePremenopausal：GnRHanalogue(orOA)+tamoxifen[±chemotherapy]or

Chemotherapyfollowedbytamoxifen[±GnRHanalogue(orOA)]or

Tamoxifenor

GnRHanalogue(orOA)Postmenopausal：ChemotherapyfollowedbytamoxifenEndocrine-NonresponsiveDiseasePremenopausal：ChemotherapyPostmenopausal：Chemotherapy35AdjuvantSystemicTreatmentforPatientsWithOperableBreastCancer（3）RiskGroupNode-positivediseaseEndocrine-ResponsiveDiseasePremenopausal：Chemotherapyfollowedbytamoxifen[±GnRHanalogue(orOA)]or

GnRHanalogue(orOA)+tamoxifen[±chemotherapy]Postmenopausal：ChemotherapyfollowedbytamoxifenorTamoxifenEndocrine-NonresponsiveDiseasePremenopausal：ChemotherapyPostmenopausal：Chemotherapy

GnRH,gonadotropinreleasinghormone;OA,ovarianablation.GoldhirschA,etal.JClinOncol.2003;21:3357-3365.ReprintedwithpermissionfromtheAmericanSocietyofClinicalOncology.36輔助治療方向37病例討論患者女性，28歲，順產(chǎn)一女后7個(gè)月，發(fā)現(xiàn)右乳腺腫塊38轉(zhuǎn)移性乳腺癌的治療39復(fù)發(fā)和stageIV的治療局限病變：曾經(jīng)全乳切除者，局部切除（如果可能）+放療（如果可能），然后考慮全身治療。曾經(jīng)區(qū)段切除+放療者，全乳切除后考慮全身治療。NCCNV1200240復(fù)發(fā)和stageIV的治療（續(xù)）廣泛病變：內(nèi)分泌治療ER/PR陽(yáng)性，僅有骨或軟組織病變，無(wú)癥狀內(nèi)臟轉(zhuǎn)移。過去1年內(nèi)TAM治療，改用二線內(nèi)分泌治療。過去無(wú)或TAM治療停止>1年。絕經(jīng)后可用來(lái)曲唑或抗雌激素。絕經(jīng)前用抗雌激素+/-LHRH拮抗劑。NCCNV1200241

廣泛病變：內(nèi)分泌治療內(nèi)分泌治療有效或穩(wěn)定，繼續(xù)治療到疾病進(jìn)展，改用未曾用過的內(nèi)分泌藥繼續(xù)治療。如果連續(xù)2個(gè)內(nèi)分泌藥物治療無(wú)效或者出現(xiàn)癥狀性內(nèi)臟病變，改用化療。42復(fù)發(fā)和stageIV的治療（續(xù)）廣泛病變：ER/PR陰性或癥狀性內(nèi)臟轉(zhuǎn)移，或內(nèi)分泌治療失敗。1。Her2過表達(dá)：herceptin+/-化療2。無(wú)Her2過表達(dá)：化療，如果連續(xù)2個(gè)方案失敗，或ECOGPS>/=3，轉(zhuǎn)支持治療或者臨床試驗(yàn)。43復(fù)發(fā)和StageIV乳腺癌的化療一線：蒽環(huán)類方案，紫杉類或CMF。二線：一線用過蒽環(huán)類或CMF，用紫杉類。一線用過紫杉類，用蒽環(huán)類或CMF。其他可選用的藥物：Xeloda,NVB,Gemcitabin,Mitoxantron,鉑類。NCCNV1200244晚期和轉(zhuǎn)移性乳腺癌

治療目的和手段

縮小腫瘤，減輕癥狀，改善生存質(zhì)量和延長(zhǎng)生存時(shí)間。手術(shù)、放療、化療、內(nèi)分泌治療和生物治療。45紫杉類治療MBC臨床研究46紫杉類單藥一線治療MBC作者方案NORR%m-TTF(m)m-OS(m)ChanDoce100mg/m28250615ADR75mg/m270364.814作者方案NORR%m-TTF(m)m-OS(m)ParidaensPacli200mg/m2166253.915.6SledgePacli200mg/m2739335.922.2ADR60mg/m2346.220.1Pacli150mg/m2468.022.4+ADR50mg/m2BishopPacli200mg/m2107295.317.3CMF(口服)102356.413.947蒽環(huán)類+紫杉類與聯(lián)合化療一線治療MBC的隨機(jī)對(duì)照臨床研究

作者方案NORR%m-TTF(m)m-OS(m)CHF%BonneterreE75+D7565637.8NR1F500+E75+C50067345.9NR0NabholtzA50+D75215608.621.62.8A60+C600214477.419.33.8NabholtzD75+A50+C50023855NANA2F500+A50+C50023742NANA0.4Docetaxel48蒽環(huán)類+紫杉類與聯(lián)合化療隨機(jī)對(duì)照一線治療MBC的臨床研究

作者方案NORR%m-TTF(m)m-OS(m)CHF%BiganzoliA60+P175138585.9NR3A60+C600137546.0NR0JassemA50+P220134688.323<2F500+A50+C500133556.218.3<1LuckE60+P175204469.016.81.4E60+C600197407.420.30CarmichaelE75+P200705406.513.7<1E75+C600(total)376.813.80Paclitaxel49兩個(gè)紫杉類聯(lián)合蒽環(huán)類的比較TAX306

AD%AC%RR6047內(nèi)臟5942肝臟6243肺5936>/=3器官6041輔助化療5441TAX307

TACFACRR55%42%P=.00850蒽環(huán)類與紫杉類失敗后的化療51

CapecitabineVinorebineGemcitabine

52希羅達(dá)單藥對(duì)泰素難治性MBC(n=135)

n(%)C.I.(%)----------------------------------------------------------OR(CR/PR)272014-28CR320-6SD544032-49PD463426-43(Blum,ASCO1998)-----------------------------------------------------------MS12.8mo,MDR8.1mo,MTTP3.1mo.53希羅達(dá)和多西紫杉醇聯(lián)合化療511例MBC隨機(jī)分組1希羅達(dá)1250mg/m2bidd1-14多西紫杉醇75mg/m2d1q21d2多西紫杉醇100mg/m2d1q21d所有病人都用過蒽環(huán)類，80%內(nèi)臟轉(zhuǎn)移，2/3接受過2/3線研究藥物治療。

有效率42%vs30%P=.006TTP14.5m11.5mP=.0126單個(gè)D更多中粒減少性發(fā)熱，聯(lián)合組更多3/4級(jí)腹瀉、胃炎和HFS.住院和SAE相當(dāng)。FDA2001.09批準(zhǔn)泰素帝/希羅達(dá)聯(lián)合治療轉(zhuǎn)移性乳腺癌54異長(zhǎng)春花鹼（Vinorelbine）55Vinorelbine-GemcitabineCombination(1)

Previousadjuvantanthracycline(n=10)first-orsecond-line(n=15)

方案Gem1200mg/m2d1,8NVB30mg/m2d1,8every3weeks療效RR44%SD12%副作用G3/4neutropenia50%pts56Vinorelbine-GemcitabineCombinations(2)First-line(n=45);second-line(n=15)方案Gemn1000mg/m2days1,5,and21NVB30mg/m2days1and21,q5w(G-CSF)療效RR55.5%first-line,40%second-lineSD27%first-line,33%second-line副作用Grade3-4neutropenia8%Grade3anemia5%57健擇58Gemcitabine單藥治療MBCN=39(35evaluable)Gem1200/m2d1,8,15,q28d4CR,9PR,37%ORR.MS17.8m,MedianTTP5monthsG3neutropenia30.3%Thrombocytopenia6.3%Nausea/vomiting10.3%.Blacksteinfirst-linemonotherapyinabc59

Gemcitabine單藥治療MBCN=47(41evaluable)Gem1200mg/m2d1,8,15Q28dORR29%(4CR,8PR)中位有效時(shí)間8.1monthsG3/4ANC↓28%G3PLT↓6%衰弱是最常見的非造血系統(tǒng)毒性second-orthird-linestudyinMBC--Spielmann60Gemcitabine單藥治療MBCCarmichealN=44(40evaluable)Gem800mg/m2d1,8,15,q28d3CR,7PR,

25%ORR.MS11.5m,MDR13.5mBrodowiczN=25Gem1250/m2d1,8,15,q28d1CR,3PR,

34%ORR,

GersonN=19Gem1250/m2d1,8,15,q28d2CR,6PR,7SD,

42%ORR,MS10.4m61紫杉類和健擇聯(lián)合Gemcitabine+DocetaxelGemcitabine+PaclitaxelResponserate36%to79%22%to68%TTP4-5months5-8monthsSurvivaltime12-25months~12monthsHematologictoxicitiesManageable;dose/scheduledependent62

蒽環(huán)類-健擇

NeoadjuvantIIIB,N=39Gem1200mg/m2d1,8ADR60mg/m2d1q21dORR95%,7CRFirstlineMBC,n=42Gem800-1000mg/m2d1,8,15ADR25mg/m2d1,8,15q28dORR55%,3CRM-TTP11.5mMST27m63Epi-Gem-Taxol-Combinations（TEG）FirstlineforMBC,n=36Epirubicin90mg/m2d1paclitaxel175mg/m2d1Gem1000mg/m2d1,4q21d6個(gè)療程后年齡<60yr，療效達(dá)到CR,PR,SD者接受HDCT作為鞏固治療。

ORR92%,11CR,ORR96%inHDCTM-PFS21mToxicity(G3/4)neutropenia37%Dosedelaysin34%Dosereductions14%64赫賽汀65Trastuzumab單藥治療難治性MBC

難治性MBC(1