1、1.2345内分泌化疗分子生物学治疗6Local Distant relapseNegativePositiveER/PgRHER2NegativePositiveBone/soft tissueVisceral7891011Anthracyclines（？）（？）TaxanesPaclitaxel/AdriamicineXeloda/Taxotere(XT)Paclitaxel/GemcitabineXelodaCMFOther fitter patients with good performance status and rapidly progressing disease or vi
2、sceral metastases might derive most benefit from more intensive combinationswhereas less fit patients or those with more indolent disease might derive more benefit from single-agents.121314作者 方案 N ORR%m-TTF(m)m-OS(m)Paridaens Pacli 200mg/m2 166 25 3.9 15.6Sledge Pacli 200mg/m2 739 33 5.9 22.2 ADR 60
3、mg/m2 34 6.2 20.1 Pacli 150mg/m2 46 8.0 22.4 +ADR 50mg/m2 Bishop Pacli 200mg/m2 107 29 5.3 17.3 CMF(口服)102 35 6.4 13.915Docetaxel16Paclitaxel17181920NR=not reported;ORR=overall response rate;OS=overall survival;TTP=time to tumor progression.21Seidman et al.,J Clin Oncol 1998;16:3353612223standard pa
4、clitaxel (q3w)weekly paclitaxelstandard paclitaxel=trastuzu-mabweekly paclitaxel+trastuzumabR24020406080100泰素每周组泰素每周组泰素三周组泰素三周组联用联用曲妥珠单抗曲妥珠单抗不用不用曲妥珠单抗曲妥珠单抗40%28%35%29%所有病人所有病人(HR=1.61,p=0.017)HER2 阴性阴性病人病人(p=0.34)344373112111百分率百分率25泰素三周组泰素三周组 N=385 事件数事件数=324 中位值中位值=0.44 年年 Chi-square=26.2865泰素每周组泰
5、素每周组 N=350 事件数事件数=221 中位值中位值=0.73 年年 p=0.0008Years From Study EntryProportion Progression-Free01234560.00.20.40.60.81.0Time to Progressionq3wq1wq1wq3w26泰素三周组泰素三周组 N=385 事件数事件数=285 中位值中位值 =1.29 年年 Chi-square=19.1292泰素每周组泰素每周组 N=350 事件数事件数=190 中位值中位值=1.99 年年 p=0.17Years From Study EntryProportion Surv
6、iving01234560.00.20.40.60.81.0Overall Survivalq3wq1wq1wq3w27粒细胞减少粒细胞减少感染感染贫血贫血血小板减少血小板减少15%4%3%2%5%3%5%1%p=0.013泰素三周治疗组泰素三周治疗组泰素每周治疗组泰素每周治疗组3-4级毒性级毒性28感觉神经感觉神经病变病变运动神经运动神经病变病变关节痛关节痛/肌痛肌痛呼吸困难呼吸困难12%4%5%4%23%8%1%7%p=0.001泰素三周治疗组泰素三周治疗组泰素每周治疗组泰素每周治疗组3-4级毒性级毒性29患者患者对对Weekly Paclitaxel耐受耐受性更好，血液毒性更好，血液毒性
7、轻，神经毒性高。性轻，神经毒性高。30凯素是纳米白蛋白紫杉醇,是第一个通过受体介导通道(gp60),使 肿瘤细胞紫杉醇浓度更高。凯素 100 mg/m2/W 3 doses,1 week of rest ORR 15%PFS 12ms 13%1yr SR 38%凯素 125 mg/m2/W 3 doses,1 week of rest 安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎.3132ACCOG BR 0201Opened 2003局部晚期或转移局部晚期或转移性乳腺癌一线或性乳腺癌一线或二线治疗二线治疗N=600泰素泰素 175 mg/m2 over3h q 3 wk泰素泰
8、素 90 mg/m2 over 1 h q wkR33every 3 weeks 8cycleN=550(215)CR/PR/SDRPaclitaxel(175 mg/m2）no further chemotherapyevery 3 weeks 8cycle*HR+HTTable:Results of Maintenance Therapy34352003 ASCO(Abstract 27).R3637Doce 60mg/m26AC/Doce 交替交替6RMBCN=441 AC或Doce组PD后交换到对侧方案治疗,AC/D组PD后继续原方案再次治疗.382005ASCO Updated OS
9、,初始Doce优于初始AC组,P=.04394041Phase III Comparison of Docetaxel and Paclitaxel in Patients With Metastatic Breast Cancer(TAX 311)Ravdin P,Eur J Cancer 2003;1(Suppl 5):s201.Abstract 670 Presented at:ECCO 12 Sep 24.2003.4243Objective Response in Evaluable Population Doce Pacli P valueORR 37.0%25.9%0.02SD
10、42.9%42.9%44结论结论45464748495051 CR+PR (%)ORR+SD (%)Median TTP(months)Median OS(months)Blum(n=162)20 63 3.0 11.6 Blum(n=74)26 57 3.2 12.2 Reichardt(n=136)15 62 3.3 10.4 Fumoleau(n=126)28 63 4.9 15.2 Maung(n=230)19 N/A 4.2 N/A Blum JL et al.Eur J Cancer 2001;37(Suppl.6):S190(Abst 693)Blum JL et al.Canc
11、er 2001;92:175968;Reichardt P et al.Ann Oncol 2003;14:122733Fumoleau P et al.Eur J Cancer 2003.In press;Maung K.Clin Breast Cancer 2003;3:375752Xeloda 1250mg/m2 twice daily,days 114 q3wPaclitaxel 175mg/m2,day 1 q3wTalbot D et al.Br J Cancer 2002;86:136772 Anthracycline-pretreated MBC Xeloda(22)Pacli
12、taxel(19)RR(%)36 2695%C.I.(17-59)(9-51)CR(%)14 0M-duration(m)9.4 9.4M-TTP(m)3.0 3.195%C.I.(1.4-6.6)(2.5-6.5)53Xeloda 1250mg/m2 twice daily,days 114 q3wCMF CTX 600mg/m2 MTX 40mg/m2 5-FU 600mg/m2day 1 q3wFirst-line MBCAge 55 yearsPrior adjuvant or hormonal therapy permitted2:1 randomisationOShaughness
13、y J et al.Ann Oncol 2001;12:124754 Xeloda(64)CMF(32)RR(%)30 1695%C.I.(19-43)(5-33)CR(%)5 0M-TTP(m)4.1 3.095%C.I.(3.2-6.5)(2.4-4.8)MS(m)19.6 17.295%C.I.(17.1-*)(10.5-*)54ASCO 200455Xeloda 1250mg/m2 bid d1-14Taxotere 75mg/m2,day 1 q3wTaxotere 100mg/m2,day 1 q3wPrimary endpoint:TTP(n=255)(n=256)OShaugh
14、nessy J et al.J Clin Oncol 2002;20:281223随随机机分分组组56所有病人用过蒽环类，80%内脏转移，2/3接受过2/3线研究药物治疗。单Doce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发生率相当。FDA 2001.09 批准泰素帝批准泰素帝/希罗达希罗达联合治疗转移性乳腺癌联合治疗转移性乳腺癌OShaughnessy J et al.J Clin Oncol 2002;20:28122357OShaughnessy J et al.J Clin Oncol 2002;20:2812235859601st line2nd+lin
15、e61Spielmann (1994)J.Clin.Oncol.,12,1764R.Hegg Curr Med Res Opin 16(4):225-234,200162636465Taxane 可以是gem的活性代谢产物累积浓度提高，因而有协同作用6667 Interim Overal Survival Report (a global phase III study).68Treat until documented PDAll sites of disease assessed every 8 weeks Paclitaxel 175 mg/m 2(3 hr)Gemcitabine 12
16、50 mg/m2 Paclitaxel 175 mg/m2(3 hr)GT arm(21-day cycle)T arm(21-day cycle)Day 1:Day 1:Gemcitabine 1250 mg/m2Day 8:RANDOMIZEStandard paclitaxel premedications69KS.Albain et al.ASCO 200470KS.Albain et al.ASCO 2004Log rank P=.018 Hazard ratio 0.78(0.63,0.69)Endopoint GT(267)T(262)FDA 2004/571Being test
17、ed in phase III trial72.737475767778n(intent-to-treat)222#Complete responses(CR)8#Partial responses(PR)26Overall response rate15%95%CI11%,21%7980Design and enrolmentNo prior anthracyclinesPrior anthracyclinesPaclitaxel(n=96)Herceptin+paclitaxel(n=92)AC(n=138)Herceptin+AC(n=143)l Metastatic breast ca
18、ncerl HER2 overexpressionl No prior CT for MBCl Measurable diseasel KPS 60%Eligible patients(n=469)81 H+AC(n=143)AC(n=138)H+Paclitaxel(n=92)Paclitaxel(n=96)Complete Response 8%7%7%2%Partial Response 44%36%35%14%Overall Response Rate(CR+PR)52%43%42%16%95%CI(44,61)(34,51)(32,52)(8,23)P-value 0.1038 0.
19、000182AC Stratum00.20.40.60.810510152025MonthsProbabilityPaclitaxel Stratum00.20.40.60.8105101520MonthsProbabilityH+P(n=92)median=6.9 moP (n=96)median=3.0 moH+AC (n=143)median=8.1 moAC (n=138)median=6.1 mop=0.0003p=0.000183CT patients treated withHerceptin after disease24%62%65%progression1.00.80.60
20、.40.200515253545H+CTCTProbability of survival25.4 months(25%)20.3 monthsRR=0.76p=0.025Time(months)84*5-dFUrd is a metabolite of Xeloda;Herceptin plus Xeloda demonstrates additive activity in vivo3DrugCombinationindexp valueInteractionVinorelbine10.340.0001SynergyDocetaxel20.411.370.001SynergyCisplat
21、in20.560.150.001SynergyEpirubicin20.750.10.057AdditionDoxorubicin21.160.180.13AdditionPaclitaxel20.910.230.21Addition5-dFUrd3*1.10.2Not specifiedAddition1Konecny G,et al.Breast Cancer Res Treat 1999;57:114(Abstract 467)2Pegram M,et al.Oncogene 1999;18:2241513Fujimoto-Ouchi K,et al.Cancer Chemother P
22、harmacol 2002;49:21116851Seidman AD,et al.J Clin Oncol 2001;19:25879586Herceptin was administered as a 4mg/kg initial dose followed by 2mg/kg weekly until progressionTrialDocetaxel scheduleRR(%)Kuzar et al.200075mg/m2 q3-weekly7/16(44)Malik et al.200033mg/m2 weekly5/6(83)Uber et al.200135mg/m2 weekl
23、y12/19(63)Esteva et al.200135mg/m2 weekly19/30(63)Medan et al.200135mg/m2 weekly6/12(50)871Burstein H,et al.J Clin Oncol 2001;19:2722302Jahanzeb M,et al.Breast Cancer Res Treat 2001;69:284(Abstract 429)Vinorelbine schedulePatientsRR(%)25mg/m2 weekly1All30/40(75)IHC 3+24/30(80)First line16/19(84)30mg
24、/m2 weekly2All(first line)29/37(78)IHC 3+18/22(82)FISH+10/12(83)88OShaughnessy JA,et al.Breast Cancer Res Treat 2001;69:302(Abstract 523)89Nabholtz J-M,et al.Eur J Cancer 2001;37:S190(Abstract 695)901Bangemann N,et al.Ann Oncol 2000;11:143(Abstract 653P)2Bangemann N,et al.Breast Cancer Res Treat 200
25、0;64:123(Abstract 530)919293Randomized Phase II Trial of Weekly Versus Every 3-week Administration of Paclitaxel,Carboplatin and Trastuzumab in Women with HER2 Positive Metastatic Breast Cancer949596979899100101NCCN 2004102Miller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclo
26、nal Antibody Therapy for Breast Cancer.Bevacizumab 10 mg/kg Days 1,15+Paclitaxel 90 mg/m2 Days 1,8,15(n=365)Paclitaxel 90 mg/m2 Days 1,8,15(n=350)Patients with locally recurrent or metastatic breast cancer,ECOG performance status score 0-1(N=715)Stratified by disease-free interval,number of metastat
27、ic sites,adjuvant chemotherapy,andestrogen receptor status103Miller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.104Miller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.105106107Miller et al.ASCO 2005.Abstract 563.108109110
