乳腺癌的化学治疗(hn)

乳腺癌的化疗

1早期乳腺癌辅助药物治疗2乳腺癌辅助药物治疗NIHConsensusDevelopmentConference:AdjuvantTherapyforBreastCancer1990：乳腺保存治疗可以作为乳腺切除/淋巴结清扫的合理替代辅助化疗/内分泌治疗减少淋巴结（–）病人复发。2000：乳腺癌辅助治疗各类成熟结论：1.乳腺癌辅助内分泌治疗的适应症2.辅助化疗的适应症3.辅助化疗的药物、剂量、和方案4.辅助放疗的适应症3乳腺癌辅助化疗4乳腺癌辅助化疗的适应症NIHConsensusDevelopmentConference20004th

大多数局限期乳癌，只要肿瘤直径>1cm，无论病人有无绝经，淋巴结有无转移，以及激素受体状况，都应该接受辅助化疗。对于肿瘤<1cm，淋巴结阴性病人，是否需要化疗应个体化。5CMF（Milan）最早的化疗方案，改善DFS和OS，通常化疗6个月。含蒽环类较无蒽环类方案显著减少复发（12%）和死亡率（11%）（1995EBCTCG）。NSABP:AC×4vsCMF×6复发率和死亡率无差别含紫杉类方案：AC→Taxol显示减少复发和死亡率，进一步的研究正在进行中(CALGB9344、NSABPB-28、BCIRG001)。6乳腺癌常用辅助化疗方案CMFCTX100mg/m2pod1-14MTX40mg/m2IVd1,d85-FU600mg/m2IVd1,d8q4wOrCTX600mg/m2IVd1MTX40mg/m2IVd15-FU600mg/m2IVd1q3w7乳腺癌常用辅助化疗方案CAFCTX100mg/m2pod1-14ADR30mg/m2IVd1,d85-FU500mg/m2IVd1,d8q4worCTX500mg/m2IVd1ADR50mg/m2IVd15-FU500mg/m2IVd1,d8q3w8乳腺癌常用辅助化疗方案

FEC50FEC100CEF120ADR×4

→CMF×3-4

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

AC:ADR60mg/m2IVd1CTX600mg//m2IVd1q3w

EC:10含紫杉类辅助化疗方案

11CALGB9344trial

对3170例随机对照研究，观察

AC→T方案与AC方案的疗效。中位随访30个月时，FDA于99年10月批准AC→T方案在LN+的乳腺癌辅助治疗。随访69个月时，AC→T仍优于AC方案。但是对ER+患者没有优势。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结果无差别，paclitaxel对无TAM组有作用。AC

→Paclitaxel组有5例AL。15NSABPB28trial中位随访65月结果

ACAC-PHazardRatioN15291531Events4614000.83(P=.008)Death2552430.94(P=.46)5yDFS72%76%5yOS85%85%结论：1Pacli组明显减少复发风险2生存尚未见到差别3对ER+和ER-都减少复发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早期乳腺癌术后剂量密度化疗CALGB9741术后淋巴结阳性乳腺癌辅助化疗随机临床试验dose-dense与传统3周对照序贯与联合对照25届

SanAntonio乳腺癌年会JClinOncol2003Apr15;21(8):1431-919CALGB9741-治疗方案2,005例淋巴结阳性乳腺癌随机分成4组中位年龄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，应用G-CSF（FilgrastimorNeupogen)预防中性粒细胞减少。20CALGB9741Results

medianfollow-upof36months

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

density

改善疗效31%序贯化疗与同时化疗一样有效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乳腺癌辅助

高剂量化疗和干细胞支持治疗—随机对照研究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化疗时间对疗效的影响FEC×6较FEC×3更有效。（法国）CMF×6与CMF×3比较，疗效一样，但是发现对年轻的和雌激素受体阴性的患者疗效更好。辅助化疗与内分泌治疗的顺序Intergroup0100结果：淋巴结阳性、激素受体阳性的绝经后患者TAM在化疗之后应用优于两者同时使用。StGallen8th25NIH2000共识--化疗推荐蒽环类方案，建议CAF和CEF为好。法国研究FEC100优于FEC50，认为存在剂量关系。HD-CT并不优于标准剂量联合方案，在临床研究以外不推荐使用。在CALGB9344

研究里，AC以外加Taxol只对激素受体阴性有作用。26辅助性内分泌治疗27TAM单药5年减少激素受体阳性乳腺癌患者年复发40%，其作用持续到15年，对淋巴结阳性/阴性、年龄>/<50岁疗效相当2000EarlyBreastCancerTrialists'CollaborativeGroup(EBCTCG)meta-analysisTAM服药5年疗效优于1、2年，减少年复发分别为43%,18%,and25%。1995EBCTCGmeta-analysis服药10年与5年相比，疗效不增加，但是毒性增加。NSABPB-14trialNIH200028卵巢去势对绝经前患者15年期间减少复发：Node-negative,8.9%Node-positive,13.4%与CMF疗效相当与化疗合用没有增加疗效NIH200029TheConsensusStatementrecommendsthatallwomenwhosebreastcancersexpresshormonereceptorsshouldreceiveadjuvanthormonaltherapy,regardlessofage,nodestatus,ortumorsize.NIH200030ATAC试验证实Anastrozole对绝经后患者疗效优于TAM.ZEBRA试验证实Zoledex+/-TAM对绝经前患者与6疗程CMF疗效相当。在CMF之后序贯应用Zoledex对淋巴结阴性的患者要比两者单用要好。TAM仍然是激素受体阳性患者术后辅助治疗的主要选择。激素受体阳性仅次于淋巴结转移，成为辅助治疗的重要决定因素。要求有优良质控的实验室激素受体的定量测评。StGallen8th312003年StGallen

早期乳腺癌治疗最新共识第8届瑞士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辅助治疗方向37病例讨论患者女性，28岁，顺产一女后7个月，发现右乳腺肿块38转移性乳腺癌的治疗39复发和stageIV的治疗局限病变：曾经全乳切除者，局部切除（如果可能）+放疗（如果可能），然后考虑全身治疗。曾经区段切除+放疗者，全乳切除后考虑全身治疗。NCCNV1200240复发和stageIV的治疗（续）广泛病变：内分泌治疗ER/PR阳性，仅有骨或软组织病变，无症状内脏转移。过去1年内TAM治疗，改用二线内分泌治疗。过去无或TAM治疗停止>1年。绝经后可用来曲唑或抗雌激素。绝经前用抗雌激素+/-LHRH拮抗剂。NCCNV1200241

广泛病变：内分泌治疗内分泌治疗有效或稳定，继续治疗到疾病进展，改用未曾用过的内分泌药继续治疗。如果连续2个内分泌药物治疗无效或者出现症状性内脏病变，改用化疗。42复发和stageIV的治疗（续）广泛病变：ER/PR阴性或症状性内脏转移，或内分泌治疗失败。1。Her2过表达：herceptin+/-化疗2。无Her2过表达：化疗，如果连续2个方案失败，或ECOGPS>/=3，转支持治疗或者临床试验。43复发和StageIV乳腺癌的化疗一线：蒽环类方案，紫杉类或CMF。二线：一线用过蒽环类或CMF，用紫杉类。一线用过紫杉类，用蒽环类或CMF。其他可选用的药物：Xeloda,NVB,Gemcitabin,Mitoxantron,铂类。NCCNV1200244晚期和转移性乳腺癌

治疗目的和手段

缩小肿瘤，减轻症状，改善生存质量和延长生存时间。手术、放疗、化疗、内分泌治疗和生物治疗。45紫杉类治疗MBC临床研究46紫杉类单药一线治疗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蒽环类+紫杉类与联合化疗一线治疗MBC的随机对照临床研究

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蒽环类+紫杉类与联合化疗随机对照一线治疗MBC的临床研究

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)376.813.80Paclitaxel49两个紫杉类联合蒽环类的比较TAX306

AD%AC%RR6047内脏5942肝脏6243肺5936>/=3器官6041辅助化疗5441TAX307

TACFACRR55%42%P=.00850蒽环类与紫杉类失败后的化疗51

CapecitabineVinorebineGemcitabine

52希罗达单药对泰素难治性MBC(n=135)

n(%)C.I.(%)----------------------------------------------------------OR(CR/PR)272014-28CR320-6SD544032-49PD463426-43(Blum,ASCO1998)-----------------------------------------------------------MS12.8mo,MDR8.1mo,MTTP3.1mo.53希罗达和多西紫杉醇联合化疗511例MBC随机分组1希罗达1250mg/m2bidd1-14多西紫杉醇75mg/m2d1q21d2多西紫杉醇100mg/m2d1q21d所有病人都用过蒽环类，80%内脏转移，2/3接受过2/3线研究药物治疗。

有效率42%vs30%P=.006TTP14.5m11.5mP=.0126单个D更多中粒减少性发热，联合组更多3/4级腹泻、胃炎和HFS.住院和SAE相当。FDA2001.09批准泰素帝/希罗达联合治疗转移性乳腺癌54异长春花硷（Vinorelbine）55Vinorelbine-GemcitabineCombination(1)

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

方案Gem1200mg/m2d1,8NVB30mg/m2d1,8every3weeks疗效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)疗效RR55.5%first-line,40%second-lineSD27%first-line,33%second-line副作用Grade3-4neutropenia8%Grade3anemia5%57健择58Gemcitabine单药治疗MBCN=39(35evaluable)Gem1200/m2d1,8,15,q28d4CR,9PR,37%ORR.MS17.8m,MedianTTP5monthsG3neutropenia30.3%Thrombocytopenia6.3%Nausea/vomiting10.3%.Blacksteinfirst-linemonotherapyinabc59

Gemcitabine单药治疗MBCN=47(41evaluable)Gem1200mg/m2d1,8,15Q28dORR29%(4CR,8PR)中位有效时间8.1monthsG3/4ANC↓28%G3PLT↓6%衰弱是最常见的非造血系统毒性second-orthird-linestudyinMBC--Spielmann60Gemcitabine单药治疗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紫杉类和健择联合Gemcitabine+DocetaxelGemcitabine+PaclitaxelResponserate36%to79%22%to68%TTP4-5months5-8monthsSurvivaltime12-25months~12monthsHematologictoxicitiesManageable;dose/scheduledependent62

蒽环类-健择

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个疗程后年龄<60yr，疗效达到CR,PR,SD者接受HDCT作为巩固治疗。

ORR92%,11CR,ORR96%inHDCTM-PFS21mToxicity(G3/4)neutropenia37%Dosedelaysin34%Dosereductions14%64赫赛汀65Trastuzumab单药治疗难治性MBC

难治性MBC(1