双磷酸盐乳腺癌中的应用研究进展详解演示文稿

双磷酸盐乳腺癌中的应用研究进展详解演示文稿当前1页，总共58页。优选双磷酸盐乳腺癌中的应用研究进展当前2页，总共58页。双膦酸盐在乳腺癌骨转移中的应用当前3页，总共58页。骨转移是常见疾病全球5年的患病人数×1000

1肿瘤患者骨转移发生率％2中位生存时间

月2-5疾病1.FerlayJ,etal.IARCGLOBOCAN2002.CancerIncidence,Mortality,andPrevalenceWorldwide.2.ColemanRE.CancerTreatRev.2001;27:165-176.3.ColemanRE.Cancer.1997;80(suppl):1588-1594.4.ZekriJ,etal.IntJOncol.2001;19:379-382.

5.HussainM,etal.JClinOncol.2001;19:2527-2533.骨髓瘤

18370-956-54乳腺癌4,40665-7519-25前列腺癌

2,36965-7512-53肺癌

1,36230-406-7黑色素瘤

64314-456膀胱癌

1,1104015肾癌

58620-2512当前4页，总共58页。约70%的乳腺癌患者发生骨转移40~50%的患者第1个复发部位症状：骨痛、高钙血症、骨折仅20%发生骨转移的乳腺癌患者存活5年乳腺癌骨转移当前5页，总共58页。骨转移及骨相关事件可带来严重的后果当前6页，总共58页。骨转移如不经治疗，SRE将十分常见SRE=Skeletal-relatedevent;NSCLC=Non-smallcelllungcancer.

*PLACEBOARMFROMZOLEDRONICACIDANDPAMIDRONATETRIALS;ALLPATIENTSRECEIVEDSTANDARDANTINEOPLASTICTHERAPIES.

1.KohnoN,etal.JClinOncol.2005;23:3314-3321;2.SaadF,etal.JNatlCancerInst.2004;96:879-882;

3.BerensonJR,etal.JClinOncol.1998;16:593-602;4.RosenLS,etal.Cancer.2004;100:2613-2621.Placeboarm*50%49%51%46%01020304050

60

70Breast

cancer1

Prostate

cancer2Multiple

myeloma3NSCLCandOST

4PatientswithanSRE,%当前7页，总共58页。Dataarefromplacebo-controlarmsofbisphosphonatetrials.

1.LiptonA,etal.Cancer.2000;88:1082-1090;2.RosenLS,etal.Cancer.2004;100:2613-2621;

3.BerensonJR,etal.JClinOncol.1998;16:593-602;4.SaadF,etal.JNatlCancerInst.2004;96:879-882.2.712.203.701.470.01.02.03.04.0MeanSREs/yearBreastcancer1Lungcancerandothersolidtumors2Multiplemyeloma3Prostatecancer4Patientswithcancer乳腺癌患者每年可能发生多次骨相关事件

当前8页，总共58页。乳腺癌中骨相关事件的发生率LiptonA,etal.Cancer,2000;88:1082-1090;*总SREs中不包含高钙血症乳腺癌骨相关事件（SREs）发生率％当前9页，总共58页。病理性骨折可降低生存病理性骨折与死亡风险增加显著相关1,2

乳腺癌 1.52(1.28,1.81)P<.0001多发骨髓瘤 1.44(1.06,1.95)P=.02前列腺癌 1.29(1.01,1.65)P=.041.HeiY-J,etal.Presentedat:28thAnnualSABCS,2005,Abstract6036.

2.SaadF,etal.Presentedat:ECCO2005.Abstract1265.当前10页，总共58页。两项大型临床试验证实唑来膦酸可有效预防延缓骨相关事件，显著缓解骨痛当前11页，总共58页。唑来膦酸与帕米膦酸随机对照研究设计

（010试验）025月最终分析双盲、双模拟研究，旨在证实：与帕米膦酸二钠相比，唑来膦酸具有非劣效性唑来膦酸8/4mg，1次/3－4周随机化分组唑来膦酸4mg，1次/3－4周n=564n=526帕米膦酸二钠90mg，1次/3－4周三组均每日口服维生素D400IU及钙500mgn=5581,130例IV期乳腺癌患者518例多发性骨髓瘤患者13月核心分析RosenLSetal.CancerJ.2003;98:1735-44当前12页，总共58页。唑来膦酸亚洲乳腺癌骨转移患者临床试验研究设计（1501试验）随机分组唑来膦酸4mg，静脉输注15min，每4周，共12个月n=114安慰剂，静脉输注15min，每4周，共12个月n=114（n=228）多中心、随机、双盲、安慰剂对照研究JClinOncol2005;23:3314-3321当前13页，总共58页。唑来膦酸显著减少骨相关事件发生率CumulativeexpectedSREs,(n)per100patientsMonthssincerandomizationPamidronateZoledronicacid4mgP=.04636912151821250204060100120080BreastcancerCookandLawlessapproach,pooledstratifiedmultipleeventanalysis.

MajorPP,etal.Presentedat:2003ASCOAnnualMeeting.Abstract3062.当前14页，总共58页。唑来膦酸延迟乳腺癌首次骨相关事件的发生ZoledronicacidPamidronateZoledronicacidPamidronate10090807060504030201000120240360480600720463325191093513927201196PatientswithoutSRE,%Timeonstudy,daysSRE=Skeletal-relatedevent.

*MediantimetofirstSREnotreachedineithertreatmentgroup.

CostaL,etal.BreastCancerResTreat.2006;100:S62.Abstract1071.当前15页，总共58页。49.629.80102030405060Placebo(N=113)ZOL4mg(N=114)唑来膦酸显著减低发生SRE的患者比率PercentofpatientsP=.003KohnoN,etal.JClinOncol.2005;23:3314-3321.∆40%当前16页，总共58页。唑来膦酸显著减少骨相关事件发生风险RCC=Renalcellcarcinoma;ZOL=Zoledronicacid;KohnoN,etal.JClinOncol.2005;23:3314-332;

SaadF,etal.JNatlCancerInst.2004;96:879-882;RosenLS,etal.Cancer.2004;100:2613-2621;LiptonA,etal.Cancer.2003;98:962-969.InfavorofZOLInfavorofplaceboRiskreductionPvalue41%.01936%.00231%.00332%.01658%.010ProstateSolidtumorsLungcancerRCC00.81.82RelativeriskofSREBreast当前17页，总共58页。唑来膦酸可显著降低骨相关事件发生风险InfavorofzoledronicacidInfavorofpamidronateRosenLS,etal.Cancer.2003;98:1735-1744.00.81.82Riskratio(zoledronicacid4mgversuspamidronate)Pvalue.025Risk

reduction.79920%Clinicaloutcomewasassessedafter25months.与帕米膦酸相比，唑来膦酸可使骨相关事件发生风险进一步降低20%当前18页，总共58页。唑来膦酸显著降低乳腺癌骨转移患者BPI骨痛评分Meanchangefrombaseline2481216202428323640444852Timeonstudy,weeks************P<.050**BPI=BriefPainInventory.AdaptedwithpermissionfromKohnoN,etal.JClinOncol.2005;23:3314-3321.当前19页，总共58页。唑来膦酸显著改善乳腺癌骨转移患者各种生活质量评分****图中显示的是9次注射后最后一次随访与基线水平相比的总的平均变化。*与基线相比，P<0.05.EORTCQLQ-C30=欧洲研究和治疗癌症组织的患者生活质量问卷30WardleyA,etal.BritishJCancer2005;92:1869-76.当前20页，总共58页。安慰剂对照试验中双膦酸盐治疗乳腺癌的疗效氯屈膦酸（口服）1,600mg (Kristensen) 31% (Paterson) 17%(Tubiana-Hulin) 8%P

值风险降低00.81.82唑来膦酸4mg 41% .001(Kohno2005).59帕米膦酸90mg 23% <.001(Arediastudy18&19).77伊班膦酸6mg 18% .004(Body2003).82伊班膦酸50mg 14% .08(Body2004).2

.03总(95%CI) 21% <.001PavlakisN,etal.CochraneDatabaseSystRev.2005;4:1-38.当前21页，总共58页。唑来膦酸在乳腺癌骨转移的临床试验结论SRE发生显著延迟更少的病人发生SRE

每个病人发生更少的SRE发生SRE的风险减低可显著缓解骨痛与其他双膦酸盐相比，唑来膦酸可更显著降低骨相关事件发生风险当前22页，总共58页。

一、二代双膦酸盐治疗中发生SREs后换用作用更强的药物是否有益？当前23页，总共58页。唑来膦酸换药治疗：II期临床试验目的评估一、二代双膦酸盐（氯屈膦酸、帕米膦酸）治疗期间发生SREs或骨转移病变进展后，换用唑来膦酸是否获益方法收入乳腺癌骨转移患者，经氯屈膦酸、帕米膦酸治疗出现SREs或影像学证实骨转移病变进展唑来膦酸、静脉注射、4mg/月，共3个月随访：第一个月，每周一次；第8周评估换用唑来膦酸对骨痛、生活质量和骨标记物的影响研究开始前1个月和开始后不允许更换化疗或内分泌治疗方案当前24页，总共58页。唑来膦酸换药治疗：II期临床试验结果共有31例患者完成试验第8周时患者疼痛显著减轻(P＜0.001)第8周时，尿NTX水平也出现了下降趋势(P＝0.008)换用唑来膦酸治疗后，疼痛改善和尿NTX的下降呈正相关(Spearman’srhor＝0.27;P＝0.15）当前25页，总共58页。唑来膦酸显著缓解其它双膦酸盐失效的乳腺癌骨痛最差疼痛评分BaselineWeek1Week2Week3Week4Week8±1.96*SE±1.00*SEMean5.55.04.54.03.53.02.52.01.51.0BaselineWeek1Week2Week3Week4Week8±1.96*SE±1.00*SEMean平均疼痛评分ClemonsM,etal.JClinOncol.2006;24:4895-4900.当前26页，总共58页。唑来膦酸换药治疗：II期临床试验结论第一个临床研究证实：氯膦酸或帕米膦酸治疗期间发生SREs或骨转移病变进展后，换用更强的双膦酸盐（唑来膦酸）可获得收益。包括：显著减轻骨痛显著降低骨标记物水平如上述结果如经进一步随机临床试验证实，将对双膦酸盐在乳腺癌骨转移和辅助治疗领域产生重要影响当前27页，总共58页。唑来膦酸何时开始使用，何时停用当前28页，总共58页。早期治疗预防骨相关事件发生非常重要乳腺癌患者发生SRE后，再次发生SRE的机率增加2倍1病理性骨折增加死亡风险2SRE=Skeletal-relatedevent;hazardratioreflectsmultivariatemodeladjustedforpreviousSREsandperformancestatus.

1.KaminskiM,etal.Presentedat:PrimaryTherapyofEarlyBreastCancer9thInternationalConference;January26-29,2005.Abstract107;

2.SaadF,etal.Cancer.2007;110:1860-1867.Hazardratio00.81.82DecreasedmortalityIncreasedmortalityPvalueRisk

increase.00332%1.32Breastcancer当前29页，总共58页。出现骨痛前使用唑来膦酸可使乳腺癌患者获益更多CostaL,etal.BreastCancerResTreat.2006;100:S62.Abstract1071.15%relativereduction;P=.097.当前30页，总共58页。Risk

reductionExtensionphaseonly(months13-25)RelativeriskInfavorofzoledronicacidInfavorofpamidronate00.81.82.026Pvalue0.59141%.0250.79920%25-monthfollow-up唑来膦酸可使乳腺癌患者长期持续获益Inpatientsontheirsecondyearofzoledronicacidtreatment,therelativeriskofexperiencinganSREremainedlowerthanwithpamidronate**AsdeterminedbyAndersen-Gillmultipleeventanalysis.AdaptedfromZhengM,etal.Presentedat:PrimaryTherapyofEarlyBreastCancer9thInternationalConference;

January26-29,2005;Abstract104.当前31页，总共58页。唑来膦酸可显著降低乳腺癌患者再次发生SRE的风险Risk

reductionRelativeriskInfavorofzoledronicacidInfavorofpamidronate00.81.82PvalueAllSREs.0150.71129%.0450.69031%Excludingfirst

SREZoledronicacidreducedtheriskofexperiencingasecondSREbyaboutonethirdcomparedwithpamidronate**AsdeterminedbyAndersen-Gillmultipleeventanalysis.AdaptedfromZhengM,etal.Presentedat:PrimaryTherapyofEarlyBreastCancer9thInternationalConference;

January26-29,2005;Abstract104.当前32页，总共58页。ASCO乳腺癌骨转移治疗指南推荐X线/CT/MRI等影像学检查有骨破坏时开始使用静脉双膦酸盐推荐每3-4周使用静脉唑来膦酸(4mgvia15-minuteinfusion)或帕米膦酸(90mgvia2-hourinfusion)

未推荐口服双膦酸盐双膦酸盐应持续使用直至患者不能耐受或一般状况显著下降HillnerB,etal.JClinOncol.2003;21:4042-4057.当前33页，总共58页。欧洲指南：双膦酸盐在实体肿瘤的应用双膦酸盐作为有效的辅助支持治疗，减少频繁而严重的各种实体瘤骨转移患者的骨并发症预防，减少和延迟肿瘤相关的骨并发症的出现并持续减少后续事件的发生有效治疗肿瘤治疗相关的骨丢失（CTIBL)国际专家委员会根据大量循证证据推荐：乳腺癌骨转移的患者使用含氮双膦酸盐其他实体肿瘤骨转移使用唑来膦酸最好使用静脉注射的药物口服氯屈膦酸仅应用在不能接受正规住院治疗的乳腺癌患者早期癌症患者如果合并CTIBL的高风险，应接受双膦酸盐预防性治疗。目前根据最有效的临床证据，建议使用唑来膦酸M.Aapro，etal.AnnalsofOncology19:420–432,2008当前34页，总共58页。总的来说，双膦酸盐的耐受性良好流感样症状关节痛胃肠道症状（仅出现在口服药物）在接受双膦酸盐治疗期间起始剂量按照肾功能和基线是肌酐清除率来调整后续的治疗推荐帕米膦酸和唑来膦酸，治疗用量根据监测结果调整定期进行牙科检查，评估风险，减少ONJ发生欧洲指南：双膦酸盐在实体肿瘤的应用（续）M.Aapro，etal.AnnalsofOncology19:420–432,2008当前35页，总共58页。双膦酸盐在

乳腺癌治疗相关骨丢失的研究进展当前36页，总共58页。芳香化酶抑制剂治疗伴有快速的骨质流失

StatisticallysignificantlymoreBMDlossonanastrozolethantamoxifen(p<0.0001)Time,yearsEstimated%change(meanand95%CI)Anastrozole420-2-4-6-8-10Baseline12345AnastrozoleTamoxifen420-2-4-6-8-10Baseline12345LumbarspineTotalhipAdaptedfromColemanRE,etal.JClinOncol.2006;24(suppl):5s.Abstract511.Tamoxifen当前37页，总共58页。所有芳香化酶抑制剂治疗均增加骨折风险11.AdaptedfromHadjiP,etal.USOncologicalDisease2007.2007;1:18-21;2.HowellA,etal.Lancet.2005;365:60-62;3.ColemanRE,etal.

LancetOncol.2007;8:119-127;4.ThurlimannB,etal.NEnglJMed.2005;353:2747-2757;5.GossPE,etal.JNatlCancerInst.2005;97:1262-1271.TamoxifenLetrozoleAnastrozolePlaceboFractures,%5.0P<.0001P<.00102468101214P=.003P=.25ExemestaneATAC2(68months)IES3(58months)BIG1-984(26months)MA.175(30months)当前38页，总共58页。正在进行的唑来膦酸预防

芳香化酶抑制剂诱导的骨质丢失(AIBL)研究绝经期前妇女

ABCSG-12(n=404)绝经后妇女 Z-FAST(N=602) ZO-FAST(N=1,066) E-ZO-FAST(N=527)

TotalofnumberofpatientsenrolledN=2,599当前39页，总共58页。ABCSG-12:激素辅助治疗

的绝经前妇女的骨密度（BMD）研究入组时间：1999-20061,800绝经期前患者

测定BMD的亚组：(n=404)StageI&II,<10posnodes,ER+and/orPR+疗程：3年PreoperativeCTallowed骨相关研究于6/03停止入组TamoxifenTamoxifen+Zoledronicacid(4mg)*q6moAnastrozole+

Zoledronicacid(4mg)*q6moAnastrozole3years,BMDR

A

N

D

O

M

I

Z

EBMD=Bonemineraldensity;ER=Estrogenreceptor;PR=Progesteronereceptor;CT=Chemotherapy;XRT=Preoperativeradiotherapy.

*8mgreducedto4mg.

GnantMF,etal.JClinOncol.2007;25:820-828.Surgery(+XRT)Goserelin3.6mg/28daysBaseline

BMD6-monthBMD当前40页，总共58页。ABCSG-12(5年随访结果):

腰椎骨密度的变化情况3660366036603660TamoxifenAnastrozoleTamoxifenAnastrozoleNoZoledronicAcidZoledronicAcidAdaptedfromGnantMFetal.Presentedat:SanAntonioBreastCancerConferenceDec.13-16,2007;Abstract26.-9.0%-4.5%-13.6%-7.8%+1.0%+5.2%-0.1%+3.1%当前41页，总共58页。Z-FAST,1ZO-FAST2,andE-ZO-FAST3

试验设计05years

FinalanalysisLET(2.5mg/day)+延迟*

ZOL4mgq6moLET(2.5mg/day)+早期

ZOL4mgq6moRAND

OMIZED3years1yearER=Estrogenreceptor;PR=Progesteronereceptor;BC=Breastcancer;PMW=Postmenopausalwomen;CT=Chemotherapy;LET=Letrozole;

ZOL=Zoledronicacid.

*延迟唑来膦酸治疗定义为：当基线入组后36个月内出现BMDT-score<–2.0，任何有临床症状的骨折或无临床症状的骨折时，开始唑来膦酸治疗1.Brufsky,etal.Presentedat:30thAnnualSABCS;December13-16,2007;SanAntonio,Texas.Abstract27;

2.DeBoerR,etal.Presentedat:30thAnnualSABCS;December13-16,2007;SanAntonio,Texas.Abstract501;

3.LlombartA,etal.Presentedat:14thECCOConference;September23-27,2007;Barcelona,Spain.Abstract2044.Accrualcompleted: Z-FAST:N=602

ZO-FAST:N=1,066

E-ZO-FAST:N=527 Total:N=2,195入组条件ER+/PR+BC绝经后患者，且

T-score≥–2分层AdjuvantCT

(yesorno)Tscore(>–1orbetween–1and–2)当前42页，总共58页。Z-FAST:唑来膦酸早期治疗

可增加腰椎和髋关节BMD（36个月结果）SEM=Standarderrorofthemean;BMD=Bonemineraldensity;ZOL=Zoledronicacid.

*Pvaluescorrespondtointergroupcomparisons.

†AdaptedfromBrufskyA,etal.Presentedat:29thAnnualSABCS;December14-17,2006;SanAntonio,TX.Abstract5060.

‡Adaptedfrom

BrufskyA,etal.Presentedat:30thAnnualSABCS;December13-16,2007;SanAntonio,TX.Month24†LumbarspineTotalhipMean(SEM)%changeBMD

P<.0001*P<.0001*P<.0001*P<.0001*Month12†Month

24†Month

12†–4%–3%–2%–1%0%1%2%3%4%UpfrontZOL(4mg/6months)DelayedZOL(4mg/6months)Month36‡Month36‡P<.001*P<.001*n=251n=256n=204n=199n=189n=188n=251n=256n=206n=197n=189n=187Δ4.4%Δ5.9%Δ6.7%Δ3.3%Δ4.7%Δ5.2%当前43页，总共58页。ZO-FAST:唑来膦酸早期治疗

增加腰椎和髋关节BMD（24个月结果）BMD=Bonemineraldensity;ZOL=Zoledronicacid.

1.BundredN,etal.Presentedat:5thEBCC;March21-25,2006;Nice,France.Abstract12;2.DeBoerR,etal.Presentedat:30thAnnualSABCS;December13-16,2007.Abstract501.UpfrontZOL(4mg/6months)DelayedZOL(4mg/6months)Lumbarspine–6–4–2024HipP<.0001P<.0001BMD,%changeP<.0001P<.0001Month242Month121Month242Month121–8–6–4–2024PostmenopausalRecentlypostmenopausalLumbarspineHipLumbarspineHipP<.0001P<.0001P<.0001P<.0001BMD,%changeMonth121Month121当前44页，总共58页。E-ZO-FAST:唑来膦酸早期治疗

增加腰椎和髋关节BMD（12个月结果）LumbarspineHipUpfrontZOL

(4mg/6months)DelayedZOL

(4mg/6months)P<.0001P<.0001BMD=Bonemineraldensity;ZOL=Zoledronicacid.LlombartAetal.Presentedat:ECCO14;September23-27,2007Barcelona,Spain.Abstract2044.Δ5.2%Δ3.3%当前45页，总共58页。小结：唑来膦酸预防AIBL与三苯氧胺相比，芳香化酶抑制剂可显著延长乳腺癌患者的无疾病生存时间AIBL在接受芳香化酶抑制剂辅助治疗的乳腺癌患者常见唑来膦酸每年注射2次（4mg/每6个月）可有效预防AIBL：4项试验均获一致结果AI=Aromataseinhibitor;ZOL=Zoledronicacid.当前46页，总共58页。ASCOGuidelinesforTreatingCTIBL

inBreastCancer---2003BMDT-score>-1BMDT-scorebetween-1and-2.5BMDT-score<-2.5提供生活方式的指导补充钙和vitaminDProvidereassurance开始药物治疗

Alendronate(福善美）Risedronate

Zoledronate（择泰）根据病人个体情况考虑药物治疗CTIBL=cancertreatmentinducedbonelossHillneretal.JClinOncol.2003;21:4042当前47页，总共58页。T-score<–2.0Any2ofthefollowingriskfactors:T-score<–1.5Age>65yearsLowBMI(<20kg/m2)FamilyhistoryofhipfracturePersonalhistoryoffragilityfractureafterage50Oralcorticosteroiduseof>6monthsSmoking(currentorhistoryof)T-score≥–2.0,NoriskfactorsMonitorriskstatusandBMDevery

1to2years*Zoledronicacid

(4mg/6months)

calciumandvitaminDsupplementsMonitorBMD

every2yearsCalciumandvitaminDsupplements*≥5%dropinBMDshouldtriggerzoledronicacidtreatment(4mg/6months).UselowestT-scorefrom3sites.HadjiP,etal.Presentedat:SABCS2007.Abstract504.DatafororalbisphosphonatesareemergingEvidencefrom4clinicaltrialsindicatethatzoledronicacidpreventsAI-associatedboneloss开始芳香化酶抑制剂治疗的乳腺癌妇女的推荐当前48页，总共58页。双磷酸盐在乳腺癌探索领域

正在进行的临床研究当前49页，总共58页。骨标志物在乳腺癌骨转移领域

临床研究进展当前50页，总共58页。多数肿瘤骨转移病人基线NTX升高NTXlevels(nmol/mmolcreatinine):Low<50,Moderate50-99,High≥100.

NSCLC=Non-smallcelllungcancer.Colemanetal.JClinOncol.2005;23:4925-4935.当前51页，总共58页。唑来膦酸治疗3个月大多数患者NTX水平正常化BreastcancerNSCLCandOSTsPrimarytumorHRPC8090706050403020100Normalized3-monthNTX(ENgroup)Elevated3-monthNTX(EEgroup)Patients,%NTX=N-telopeptideoftypeIcollagen;HRPC=Hormone-refractoryprostatecancer;NSCLC=Non-smallcelllungcancer;OST=Othersolidtumors.

LiptonA,etal.Presentedat:ECCO2007.Abstract304.当前52页，总共58页。唑来膦酸治疗后NTX正常化与SREs和死亡风险均降低显著相关NTX=N-telopeptideoftypeIcollagen;SRE=Skeletal-relatedevent;BC=Breastcancer;

NS=P>.2;E-E=PatientswhoseNTXlevelsremainedelevatedat3months.

LiptonA,etal.PresentedatESMO2006.Abstract870P.FirstSREBreastcancer0Death490.5050.4730.821Riskreduction,%53.002

Pvalue.00248.0020.51.01.52.0IncreasedriskversusE-EDecreasedriskversusE-E1stFracture/BonesurgeryBonel