雙磷酸鹽乳腺癌中應(yīng)用研究進(jìn)展

雙磷酸鹽乳腺癌中應(yīng)用研究進(jìn)展雙膦酸鹽在乳腺癌骨轉(zhuǎn)移中的應(yīng)用雙膦酸鹽在乳腺癌治療相關(guān)骨丟失的研究進(jìn)展雙磷酸鹽在乳腺癌探索領(lǐng)域正在進(jìn)行中的臨床雙膦酸鹽在乳腺癌骨轉(zhuǎn)移中的應(yīng)用骨轉(zhuǎn)移是常見疾病全球5年的患病人數(shù)×1000

1腫瘤患者骨轉(zhuǎn)移發(fā)生率％2中位生存時(shí)間

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腎癌

58620-2512約70%的乳腺癌患者發(fā)生骨轉(zhuǎn)移40~50%的患者第1個(gè)復(fù)發(fā)部位癥狀：骨痛、高鈣血癥、骨折僅20%發(fā)生骨轉(zhuǎn)移的乳腺癌患者存活5年乳腺癌骨轉(zhuǎn)移骨轉(zhuǎn)移及骨相關(guān)事件可帶來嚴(yán)重的后果骨轉(zhuǎn)移如不經(jīng)治療，SRE將十分常見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,%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發(fā)生多次骨相關(guān)事件

乳腺癌中骨相關(guān)事件的發(fā)生率LiptonA,etal.Cancer,2000;88:1082-1090;*總SREs中不包含高鈣血癥乳腺癌骨相關(guān)事件（SREs）發(fā)生率％病理性骨折可降低生存病理性骨折與死亡風(fēng)險(xiǎn)增加顯著相關(guān)1,2

乳腺癌 1.52(1.28,1.81)P<.0001多發(fā)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.Abstract1265.兩項(xiàng)大型臨床試驗(yàn)證實(shí)唑來膦酸可有效預(yù)防延緩骨相關(guān)事件，顯著緩解骨痛唑來膦酸與帕米膦酸隨機(jī)對(duì)照研究設(shè)計(jì)

（010試驗(yàn)）025月最終分析雙盲、雙模擬研究，旨在證實(shí)：與帕米膦酸二鈉相比，唑來膦酸具有非劣效性唑來膦酸8/4mg，1次/3－4周隨機(jī)化分組唑來膦酸4mg，1次/3－4周n=564n=526帕米膦酸二鈉90mg，1次/3－4周三組均每日口服維生素D400IU及鈣500mgn=5581,130例IV期乳腺癌患者518例多發(fā)性骨髓瘤患者13月核心分析RosenLSetal.CancerJ.2003;98:1735-44唑來膦酸亞洲乳腺癌骨轉(zhuǎn)移患者臨床試驗(yàn)研究設(shè)計(jì)（1501試驗(yàn)）隨機(jī)分組唑來膦酸4mg，靜脈輸注15min，每4周，共12個(gè)月n=114安慰劑，靜脈輸注15min，每4周，共12個(gè)月n=114（n=228）多中心、隨機(jī)、雙盲、安慰劑對(duì)照研究JClinOncol2005;23:3314-3321唑來膦酸顯著減少骨相關(guān)事件發(fā)生率CumulativeexpectedSREs,(n)per100patientsMonthssincerandomizationPamidronateZoledronicacid4mgP=.04636912151821250204060100120080BreastcancerCookandLawlessapproach,pooledstratifiedmultipleeventanalysis.

MajorPP,etal.Presentedat:2003ASCOAnnualMeeting.Abstract3062.唑來膦酸延遲乳腺癌首次骨相關(guān)事件的發(fā)生ZoledronicacidPamidronateZoledronicacidPamidronate10090807060504030201000120240360480600720463325191093513927201196PatientswithoutSRE,%Timeonstudy,daysSRE=Skeletal-relatedevent.

*MediantimetofirstSREnotreachedineithertreatmentgroup.

CostaL,etal.BreastCancerResTreat.2006;100:S62.Abstract1071.49.629.80102030405060Placebo(N=113)ZOL4mg(N=114)唑來膦酸顯著減低發(fā)生SRE的患者比率PercentofpatientsP=.003KohnoN,etal.JClinOncol.2005;23:3314-3321.?40%唑來膦酸顯著減少骨相關(guān)事件發(fā)生風(fēng)險(xiǎn)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唑來膦酸可顯著降低骨相關(guān)事件發(fā)生風(fēng)險(xiǎn)InfavorofzoledronicacidInfavorofpamidronateRosenLS,etal.Cancer.2003;98:1735-1744.00.81.82Riskratio(zoledronicacid4mgversuspamidronate)Pvalue.025Risk

reduction.79920%Clinicaloutcomewasassessedafter25months.與帕米膦酸相比，唑來膦酸可使骨相關(guān)事件發(fā)生風(fēng)險(xiǎn)進(jìn)一步降低20%唑來膦酸顯著降低乳腺癌骨轉(zhuǎn)移患者BPI骨痛評(píng)分Meanchangefrombaseline2481216202428323640444852Timeonstudy,weeks************P<.050**BPI=BriefPainInventory.AdaptedwithpermissionfromKohnoN,etal.JClinOncol.2005;23:3314-3321.唑來膦酸顯著改善乳腺癌骨轉(zhuǎn)移患者各種生活質(zhì)量評(píng)分****圖中顯示的是9次注射后最后一次隨訪與基線水平相比的總的平均變化。*與基線相比，P<0.05.EORTCQLQ-C30=歐洲研究和治療癌癥組織的患者生活質(zhì)量問卷30WardleyA,etal.BritishJCancer2005;92:1869-76.安慰劑對(duì)照試驗(yàn)中雙膦酸鹽治療乳腺癌的療效氯屈膦酸（口服）1,600mg (Kristensen) 31% (Paterson) 17%(Tubiana-Hulin) 8%P

值風(fēng)險(xiǎn)降低00.81.82唑來膦酸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總(95%CI) 21% <.001PavlakisN,etal.CochraneDatabaseSystRev.2005;4:1-38.唑來膦酸在乳腺癌骨轉(zhuǎn)移的臨床試驗(yàn)結(jié)論SRE發(fā)生顯著延遲更少的病人發(fā)生SRE

每個(gè)病人發(fā)生更少的SRE發(fā)生SRE的風(fēng)險(xiǎn)減低可顯著緩解骨痛與其他雙膦酸鹽相比，唑來膦酸可更顯著降低骨相關(guān)事件發(fā)生風(fēng)險(xiǎn)

一、二代雙膦酸鹽治療中發(fā)生SREs后換用作用更強(qiáng)的藥物是否有益？唑來膦酸換藥治療：II期臨床試驗(yàn)?zāi)康脑u(píng)估一、二代雙膦酸鹽（氯屈膦酸、帕米膦酸）治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進(jìn)展后，換用唑來膦酸是否獲益方法收入乳腺癌骨轉(zhuǎn)移患者，經(jīng)氯屈膦酸、帕米膦酸治療出現(xiàn)SREs或影像學(xué)證實(shí)骨轉(zhuǎn)移病變進(jìn)展唑來膦酸、靜脈注射、4mg/月，共3個(gè)月隨訪：第一個(gè)月，每周一次；第8周評(píng)估換用唑來膦酸對(duì)骨痛、生活質(zhì)量和骨標(biāo)記物的影響研究開始前1個(gè)月和開始后不允許更換化療或內(nèi)分泌治療方案唑來膦酸換藥治療：II期臨床試驗(yàn)結(jié)果共有31例患者完成試驗(yàn)第8周時(shí)患者疼痛顯著減輕(P＜0.001)第8周時(shí)，尿NTX水平也出現(xiàn)了下降趨勢(P＝0.008)換用唑來膦酸治療后，疼痛改善和尿NTX的下降呈正相關(guān)(Spearman’srhor＝0.27;P＝0.15）唑來膦酸顯著緩解其它雙膦酸鹽失效的乳腺癌骨痛最差疼痛評(píng)分BaselineWeek1Week2Week3Week4Week8±1.96*SE±1.00*SEMean5.55.04.54.03.53.02.52.01.51.0BaselineWeek1Week2Week3Week4Week8±1.96*SE±1.00*SEMean平均疼痛評(píng)分ClemonsM,etal.JClinOncol.2006;24:4895-4900.唑來膦酸換藥治療：II期臨床試驗(yàn)結(jié)論第一個(gè)臨床研究證實(shí)：氯膦酸或帕米膦酸治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進(jìn)展后，換用更強(qiáng)的雙膦酸鹽（唑來膦酸）可獲得收益。包括：顯著減輕骨痛顯著降低骨標(biāo)記物水平如上述結(jié)果如經(jīng)進(jìn)一步隨機(jī)臨床試驗(yàn)證實(shí)，將對(duì)雙膦酸鹽在乳腺癌骨轉(zhuǎn)移和輔助治療領(lǐng)域產(chǎn)生重要影響唑來膦酸何時(shí)開始使用，何時(shí)停用早期治療預(yù)防骨相關(guān)事件發(fā)生非常重要乳腺癌患者發(fā)生SRE后，再次發(fā)生SRE的機(jī)率增加2倍1病理性骨折增加死亡風(fēng)險(xiǎn)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出現(xiàn)骨痛前使用唑來膦酸可使乳腺癌患者獲益更多CostaL,etal.BreastCancerResTreat.2006;100:S62.Abstract1071.15%relativereduction;P=.097.Risk

reductionExtensionphaseonly(months13-25)RelativeriskInfavorofzoledronicacidInfavorofpamidronate00.81.82.026Pvalue0.59141%.0250.79920%25-monthfollow-up唑來膦酸可使乳腺癌患者長期持續(xù)獲益Inpatientsontheirsecondyearofzoledronicacidtreatment,therelativeriskofexperiencinganSREremainedlowerthanwithpamidronate**AsdeterminedbyAndersen-Gillmultipleeventanalysis.AdaptedfromZhengM,etal.Presentedat:PrimaryTherapyofEarlyBreastCancer9thInternationalConference;

January26-29,2005;Abstract104.唑來膦酸可顯著降低乳腺癌患者再次發(fā)生SRE的風(fēng)險(xiǎn)Risk

reductionRelativeriskInfavorofzoledronicacidInfavorofpamidronate00.81.82PvalueAllSREs.0150.71129%.0450.69031%ExcludingfirstSREZoledronicacidreducedtheriskofexperiencingasecondSREbyaboutonethirdcomparedwithpamidronate**AsdeterminedbyAndersen-Gillmultipleeventanalysis.AdaptedfromZhengM,etal.Presentedat:PrimaryTherapyofEarlyBreastCancer9thInternationalConference;

January26-29,2005;Abstract104.ASCO乳腺癌骨轉(zhuǎn)移治療指南推薦X線/CT/MRI等影像學(xué)檢查有骨破壞時(shí)開始使用靜脈雙膦酸鹽推薦每3-4周使用靜脈唑來膦酸(4mgvia15-minuteinfusion)或帕米膦酸(90mgvia2-hourinfusion)

未推薦口服雙膦酸鹽雙膦酸鹽應(yīng)持續(xù)使用直至患者不能耐受或一般狀況顯著下降HillnerB,etal.JClinOncol.2003;21:4042-4057.歐洲指南：雙膦酸鹽在實(shí)體腫瘤的應(yīng)用雙膦酸鹽作為有效的輔助支持治療，減少頻繁而嚴(yán)重的各種實(shí)體瘤骨轉(zhuǎn)移患者的骨并發(fā)癥預(yù)防，減少和延遲腫瘤相關(guān)的骨并發(fā)癥的出現(xiàn)并持續(xù)減少后續(xù)事件的發(fā)生有效治療腫瘤治療相關(guān)的骨丟失（CTIBL)國際專家委員會(huì)根據(jù)大量循證證據(jù)推薦：乳腺癌骨轉(zhuǎn)移的患者使用含氮雙膦酸鹽其他實(shí)體腫瘤骨轉(zhuǎn)移使用唑來膦酸最好使用靜脈注射的藥物口服氯屈膦酸僅應(yīng)用在不能接受正規(guī)住院治療的乳腺癌患者早期癌癥患者如果合并CTIBL的高風(fēng)險(xiǎn)，應(yīng)接受雙膦酸鹽預(yù)防性治療。目前根據(jù)最有效的臨床證據(jù)，建議使用唑來膦酸M.Aapro，etal.AnnalsofOncology19:420–432,2008總的來說，雙膦酸鹽的耐受性良好流感樣癥狀關(guān)節(jié)痛胃腸道癥狀（僅出現(xiàn)在口服藥物）在接受雙膦酸鹽治療期間起始劑量按照腎功能和基線是肌酐清除率來調(diào)整后續(xù)的治療推薦帕米膦酸和唑來膦酸，治療用量根據(jù)監(jiān)測結(jié)果調(diào)整定期進(jìn)行牙科檢查，評(píng)估風(fēng)險(xiǎn)，減少ONJ發(fā)生歐洲指南：雙膦酸鹽在實(shí)體腫瘤的應(yīng)用（續(xù)）M.Aapro，etal.AnnalsofOncology19:420–432,2008雙膦酸鹽在

乳腺癌治療相關(guān)骨丟失的研究進(jìn)展芳香化酶抑制劑治療伴有快速的骨質(zhì)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所有芳香化酶抑制劑治療均增加骨折風(fēng)險(xiǎn)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)正在進(jìn)行的唑來膦酸預(yù)防

芳香化酶抑制劑誘導(dǎo)的骨質(zhì)丟失(AIBL)研究絕經(jīng)期前婦女

ABCSG-12(n=404)絕經(jīng)后婦女 Z-FAST(N=602) ZO-FAST(N=1,066) E-ZO-FAST(N=527)

TotalofnumberofpatientsenrolledN=2,599ABCSG-12:激素輔助治療

的絕經(jīng)前婦女的骨密度（BMD）研究入組時(shí)間：1999-20061,800絕經(jīng)期前患者

測定BMD的亞組：(n=404)StageI&II,<10posnodes,ER+and/orPR+療程：3年P(guān)reoperativeCTallowed骨相關(guān)研究于6/03停止入組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-monthBMDABCSG-12(5年隨訪結(jié)果):

腰椎骨密度的變化情況3660366036603660TamoxifenAnastrozoleTamoxifenAnastrozoleNoZoledronicAcidZoledronicAcidAdaptedfromGnantMFetal.Presentedat:SanAntonioBreastCancerConferenceDec.13-16,2007;Abstract26.-9.0%-4.5%-13.6%-7.8%+1.0%+5.2%-0.1%+3.1%Z-FAST,1ZO-FAST2,andE-ZO-FAST3

試驗(yàn)設(shè)計(jì)05years

FinalanalysisLET(2.5mg/day)+延遲*

ZOL4mgq6moLET(2.5mg/day)+早期

ZOL4mgq6moRAND

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

ZOL=Zoledronicacid.

*延遲唑來膦酸治療定義為：當(dāng)基線入組后36個(gè)月內(nèi)出現(xiàn)BMDT-score<–2.0，任何有臨床癥狀的骨折或無臨床癥狀的骨折時(shí)，開始唑來膦酸治療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入組條件ER+/PR+BC絕經(jīng)后患者，且

T-score≥–2分層AdjuvantCT

(yesorno)Tscore(>–1orbetween–1and–2)Z-FAST:唑來膦酸早期治療

可增加腰椎和髖關(guān)節(jié)BMD（36個(gè)月結(jié)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%ZO-FAST:唑來膦酸早期治療

增加腰椎和髖關(guān)節(jié)BMD（24個(gè)月結(jié)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,%changeMonth121Month121E-ZO-FAST:唑來膦酸早期治療

增加腰椎和髖關(guān)節(jié)BMD（12個(gè)月結(jié)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%小結(jié)：唑來膦酸預(yù)防AIBL與三苯氧胺相比，芳香化酶抑制劑可顯著延長乳腺癌患者的無疾病生存時(shí)間AIBL在接受芳香化酶抑制劑輔助治療的乳腺癌患者常見唑來膦酸每年注射2次（4mg/每6個(gè)月）可有效預(yù)防AIBL：4項(xiàng)試驗(yàn)均獲一致結(jié)果AI=Aromataseinhibitor;ZOL=Zoledronicacid.ASCOGuidelinesforTreatingCTIBL

inBreastCancer---2003BMDT-score>-1BMDT-scorebetween-1and-2.5BMDT-score<-2.5提供生活方式的指導(dǎo)補(bǔ)充鈣和vitaminDProvidereassurance開始藥物治療

Alendronate(福善美）RisedronateZoledronate（擇泰）根據(jù)病人個(gè)體情況考慮藥物治療CTIBL=cancertreatmentinducedbonelossHillneretal.JClinOncol.2003;21:4042T-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開始芳香化酶抑制劑治療的乳腺癌婦女的推薦雙磷酸鹽在乳腺癌探索領(lǐng)域

正在進(jìn)行的臨床研究骨標(biāo)志物在乳腺癌骨轉(zhuǎn)移領(lǐng)域

臨床研究進(jìn)展多數(shù)腫瘤骨轉(zhuǎn)移病人基線NTX升高NTXlevels(nmol/mmolcreatinine):Low<50,Moderate50-99,High≥100.

NSCLC=Non-smallcelllungcancer.Colemanetal.JClinOncol.2005;23:4925-4935.唑來膦酸治療3個(gè)月大多數(shù)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.唑來膦酸治療后NTX正?；cSREs和死亡風(fēng)險(xiǎn)均降低顯著相關(guān)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/BonesurgeryBonelesionprogression0.517–NS唑來膦酸可延長NTX正常化乳腺癌患者生存E-NE-E1008060402003691215182124Proportiondeceased,%patientsTimeonstudy,months(startingatmonth3)NTX=N-telopeptideoftypeIcollagen;E-E=PatientswhoseNTXlevelsremainedelevatedat3months;E-N=PatientswhoseNTXlevelsnormalizedat3monthsfromelevatedbaselinelevels.

LiptonA,etal.PresentedatESMO2006.Abstract870P.BreastcancerP=.0017唑來膦酸治療后NTX正?；M可獲與基線NTX正常組相似生存NTX=N-telopeptideoftypeIcollagen;E-E=PersistentlyelevatedNTX;E-N=ElevatedbaselineNTXthatnormalizedat3months;N-N=NormalNTXatbaselineand3months.

LiptonA,etal.PresentedatSABCS2005.Abstract3015.60801004020003691215182124N-N(132atrisk,49events)E-N(160atrisk,79events)E-E(36atrisk,27events)Timesincerandomization,monthsPatientswhodied,%小結(jié)唑來膦酸治療3個(gè)月使大多數(shù)NTX升高的乳腺癌患者NTX水平下降至正常，同時(shí)在這些患者中：顯著降低首次SRE的發(fā)生風(fēng)險(xiǎn)顯著降低死亡風(fēng)險(xiǎn)下一步應(yīng)進(jìn)行前瞻性、隨機(jī)臨床試驗(yàn)以進(jìn)一步證實(shí)上述結(jié)果NTX=N-telopeptideoftypeIcollagen;BC=Breastcancer;HRPC=Hormone-refractoryprostatecancer;

NSCLC=Non-smallcelllungcancer;OST=Othersolidtumors.雙磷酸鹽在乳腺癌預(yù)防骨轉(zhuǎn)移領(lǐng)域

正在進(jìn)行的臨床研究

唑來膦酸預(yù)防乳腺癌骨轉(zhuǎn)移：AZURE試驗(yàn)主要終點(diǎn):無病生存期

次要重點(diǎn)