转移性乳腺癌的内科治疗Squip PPT课件.ppt

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1、 转移性乳腺癌的化疗转移性乳腺癌的化疗中山医科大学肿瘤医院内科中山医科大学肿瘤医院内科 刘冬耕刘冬耕NCCN 2006蒽环类和紫杉类是主要化疗方案蒽环类和紫杉类是主要化疗方案蒽环类单药疗效40%左右。紫杉类单药疗效33%-50%。蒽环类与紫杉类联合疗效优于蒽环类为主的联合化疗。首选的联合治疗方案首选的联合治疗方案 CAF/FAC/FEC/CMFAC/EC Paclitaxel+ADRDocetaxel+XelodaPaclitaxel+Gemcitabine首首选的单药和其他有效的药物选的单药和其他有效的药物蒽环类蒽环类、紫杉类、希罗达、紫杉类、希罗达、NVB和健择。和健择。铂类铂类VP-16

2、(po)、VLB、5-FU(civ)HER2阴性转移性乳腺癌的一线治疗Anthracyclines（？）（？）TaxanesPaclitaxel/AdriamicineXeloda/Taxotere(XT)Paclitaxel/Gemcitabine（GP）XelodaCMFOtherfitter patients with good performance status and rapidly progressing disease or visceral metastases might derive most benefit from more intensive combination

3、swhereas less fit patients or those with more indolent disease might derive more benefit from single-agents.卡培他滨卡培他滨 Capecitabine，Xeloda长春花碱酰胺长春花碱酰胺 Vinorebine吉吉西他滨西他滨 Gemcitabine 铂铂类（类（Cisplatin,Carpoplatin）蒽环类与紫杉类失败后蒽环类与紫杉类失败后的化疗选择的化疗选择XT与与Taxotere对照研究结果对照研究结果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Do

4、ce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 XT T P value Hazard Ratio ORR 42%30%.006 TTP 6.1m 4.2m .0001OS 14.5m 11.5m .013 0.77OShaughnessy J et al.J Clin Oncol 2002;20:281223Capecitabine in Taxane-pretreated Metastatic Breast Cancer1.Blum JL et al.E

5、ur J Cancer 2001;37:S190(Abstract 693)2.Blum JL et al.Cancer 2001;92:1759-1768.3.Reichardt P et al.Ann Oncol.2003;14:1227-1233.4.Fumoleau P et al.Eur J Cancer.2004;40:536-542.StudyNCR+PR,%Disease Control(CR+PR+SD),%Median Response Duration,mosMedianTTP,mosMedian Survival,mosBlum et al.116220637.93.0

6、11.6Blum et al.27426578.33.212.2Reichardt et al.313615627.43.510.1Fumoleau et al.412625545.04.615.2Gemcitabine in Anthracycline/Taxane-Refractory MBC1.Valerio MR et al.Proc Am Soc Clin Oncol.2001.Abstract 1953.2.Rha SY et al.Breast Cancer Res Treat.2005;90:215-221.3.Modi S et al.Clin Breast Cancer.2

7、005;6:55-60.StudyNDose*CR+PR,%Valerio et al.1261000 mg/m223Rha et al.241800 mg/m220Modi et al.321850 mg/m217*Days 1,8,and 15 every 21 days.Vinorelbine in Refractory MBCMultiple phase II studies(ORR,16%-34%)Degardin et al.1(N=100)CR+PR,16%Median duration of response,5 mos(range,3-18)Livingston et al.

8、2(N=40)CR+PR,25%Median TTP,13 weeksMedian survival,33 weeks1.Degardin et al.,Ann Oncol.1994;5:423-426.2.Livingston RB et al.,J Clin Oncol.1997;15:1395-1400.After Anthracyclines and Taxanes:Multiple OptionsCapecitabineVinorelbineGemcitabineIrinotecanVinflunineXRP 9881Ixabepilonenab-paclitaxelAbraxane

9、(ABI-007，楷素)1.Ibrahim NK et al.,J Clin Oncol.2005;23:6019-26.2.Blum JL et al.,Proc Am Soc Clin Oncol.2004.Abstract 543.Albumin-bound paclitaxel,nanoparticle formulationPhase II trial,taxane-refractory MBC(N=106)中国注册研究已经完成II、III期临床FDA已经批准用于MBC治疗每周每周凯素治素治疗紫杉紫杉类耐耐药MBC 两个两个Phase II TrialOShaughnessy JA凯

10、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。紫杉类耐药紫杉类耐药紫杉类耐药紫杉类耐药MBCMBC，n=106n=106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 紫杉类耐药紫杉类耐药紫杉类耐药紫杉类耐药MBCMBC，n=75n=75安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎Vinflunine（长春富宁）After Anthracycline and Taxane Fa

11、ilure in MBCFumoleau et al.,Proc Am Soc Clin Oncol.2004.Abstract 542.Novel semi-synthetic vinca alkaloid Inhibits tubulin assemblyNo stabilizing effect on assembled microtubulesPhase II study(N=60)PR 30.0%,disease control(PR+SD)63.3%PR 36.8%,disease control 57.9%in taxane-refractory(PFI 40 monthsYea

12、rs From RandomizationProgression-Free Survival0.20.40.60.81.0004123THTCHForbes JF,et al.ASCO 2006.Abstract 516.BCIRG 007:First-Line Trastuzumab+Docetaxel Carboplatin HER2+MBCToxicity,n(%)Docetaxel+Trastuzumab(n=131)Docetaxel+Trastuzumab+Carboplatin(n=132)P ValueSensory neuropathy76(57.3)58(44.3).048

13、Motor neuropathy12(9.2)4(3.1).07Myalgia58(44.3)41(31.3).04Desquamatous rash42(32.1)20(15.3).002Nail changes72(55.0)43(32.8).001Grade 3-4 neutropenic infection22(16.8)12(9.2).097Grade 3-4 thrombocytopenia3(2.3)20(15.3).001Nausea70(53.4)96(73.3)NRVomiting37(28.2)58(44.3)NRDifferent toxicity profiles n

14、oted with each treatmentTH:neuropathy,myalgia,rash,nail changes,neutropeniaTCH:thrombocytopenia,nausea,vomitingForbes JF,et al.ASCO 2006.Abstract 516.CerbB2 Over-expressed MBC Herceptin联合化疗的首选方案联合化疗的首选方案 Paclitaxel+/-CarboplatinDocetaxel+/-CarboplatinVinorebineNCCN 2004Tykerb(lapatinib)A Dual Recept

15、or Tyrosine Kinase InhibitorPotent,oral,reversible dual tyrosine kinase inhibitorBinds to ATP site of erbB-1 and erbB-2 receptor kinases,blocking kinase activity and downstream signalingStrategies for ErbB Receptor InhibitionMonoclonal antibodies(MAbs)against erbB receptorsSmall-molecule tyrosine ki

16、nase inhibitors(SMTKIs)Lapatinib:Targeting EGFR and HER2Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2Blocks signaling through EGFR and HER2 homodimers and heterodimersMay also prevent signaling between ErbB1/ErbB2 and other ErbB family membersRusnak DW,et al.Mol Cancer Ther.2001;1:85-9

17、4.Xia W,et al.Oncogene.2002;21:6255-6263.PTENLapatinibP13KpAktRasRafpErkShcGrb2So8Phospholipid cell membraneEGF100151:Lapatinib+Capecitabine in Advanced Breast CancerRefractory,progressive metastatic or locally advanced HER2+breast cancer previously treated with anthracycline,taxane,or trastuzumab(N

18、=528 planned*)Lapatinib 1250 mg daily+Capecitabine 2000 mg/m2 dailyfor Days 1-14,3-week cycles(n=160)Capecitabine 2500 mg/m2 dailyfor Days 1-14,3-week cycles(n=161)Follow-up:until progressionor unacceptabletoxicity*Study enrollment terminated early by IDMC due to superiority of combination arm in pr

19、imary endpoint.Geyer CE,et al.ASCO 2006.Clinical Science Symposium.EGF100151:Lapatinib+Capecitabine in Advanced Breast Cancer(contd)Addition of lapatinib to capecitabine in women with treatment-refractory,advanced metastatic breast cancer associated withLonger time to progression36.9 vs 19.7 wks(P=.

20、00016)Longer progression-free survival36.9 vs 17.9 wks(P=.000045)Fewer progressions or deaths38%vs 48%Response(independent review)Overall:22.5%vs 14.3%(P=.113)Progression-Free Survival(%)Time(Wks)2040608001001020304050CapecitabineLapatinibcapecitabineITT populationGeyer CE,et al.ASCO 2006.Clinical S

21、cience Symposium.EGF100151:Lapatinib+Capecitabine in Advanced Breast Cancer(contd)Gr 3Gr 2SeverityGr 4Gr 1DiarrheaPatients(%)PPESL+CRash and/or Skin Reaction20406080100026131512928201913C AloneL+CC AloneL+CC Alone19116951171000001203Geyer CE,et al.ASCO 2006.Clinical Science Symposium.EGF103009:Lapat

22、inib Monotherapy in Relapsed/Refractory IBC 58 women with relapsed or refractory inflammatory breast cancer given lapatinib 1500 mg/day in phase II studyMedian prior chemotherapy regimens:4.5(range:0-21)Response rates in ErbB2 overexpressers:62%All clinical respondersErbB2(IHC 3+/FISH+)p-ErbB2+Respo

23、nse rates in ErbB1 overexpressers:8.3%Spector NL,et al.ASCO 2006.Abstract 502.Patients(%)62.021.017.08.317.058.00204060ErbB2+(n=24)ErbB1+/ErbB2-(n=12)*Partial responseStable diseaseProgressive disease80100*Status of 17%still pending.单药紫杉醇 vs lapatinib+紫杉醇一线治疗Her2过表达MBCPhase III 首次复发的 转移性乳腺癌有可测量病灶Her

24、2过渡表达（IHC+or FISH+）抗血管生成因子治疗Targeting Dysregulated Pathways With Novel AgentsHER tyrosine kinase inhibitorsApoptosisRas signalingVEGF signalingHER signalingTPApoptotic agentsKinase inhibitorsAnti-HER MAbsTumor-activatedchemotherapyAnti-VEGF MAbs and other moleculesAgents Targeting the VEGF PathwayPo

25、dar and Anderson.Blood.2005;105:1383VEGFR-2VEGFR-1PPPPPPPPEndothelial cellSmall-moleculeVEGFR inhibitors(PTK787,SU11248,ZD6474,BAY 43-9006)Anti-VEGFR antibodies(IMC-1121b)VEGFAnti-VEGF antibodies(bevacizumab)Soluble VEGFRs(VEGF-TRAP)Capecitabine Bevacizumab for MBCSignificantly increased response in

26、 combination arm 19.8%vs 9.1%;19.8%vs 9.1%;P P=.001=.001No significant difference in PFS or OS,combination vs single agent PFS,4.86 vs 4.17 PFS,4.86 vs 4.17 mosmos,HR=0.98;OS 15.1 vs 14.5,HR=0.98;OS 15.1 vs 14.5 mosmosMiller KD et al.J Clin Oncol.2005;23:792-799.Miller KD et al.J Clin Oncol.2005;23:

27、792-799.Capecitabine(n=230)Capecitabine+Bevacizumab(n=232)Patients with MBCPreviously treated with A/TCapecitabine Bevacizumab for MBCMiller KD et al.Miller KD et al.J Clin Oncol.2005;23:792-799.J Clin Oncol.2005;23:792-799.Eligible patients had received anthracycline and taxane treatment1 or 2 prio

28、r chemotherapy regimens for MBC,1 or 2 prior chemotherapy regimens for MBC,ororRelapse within 12 months of completing Relapse within 12 months of completing anthracycline-and taxane-containing adjuvant anthracycline-and taxane-containing adjuvant therapytherapyStudy regimen included bevacizumab 15 m

29、g/kg IV q3w,capecitabine 1250 mg/m2 po BID x 14d q3wBevacizumab的其他研究Miller and colleagues2 比较capecitabine with and without bevacizumabIn 462 patients 一线MBC capecitabine 2500 mg/m2/day 14 d q 21day alone capecitabine 2500 mg/m2/day+bevacizumab 15 mg/kg d1虽然RR在XB组较高（19.8%)vs X alone(9.1%)，但是 PFS(XB 4.

30、86 m vs 4.17 ms X alone)或 OS(XB 15.1 ms vs X 14.5 ms)都没有改善。与Herceptin+Paclitaxel在改善PFS vs OS的疗效十分相似，是以往细胞毒方案所不能比拟的，显示十分重要的前景。有可能成为Her2阴性乳癌的一线治疗。Miller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab 10 mg/kg Days 1,15+Paclitaxe

31、l 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 metastatic sites,adjuvant chemotherapy,andestrogen receptor statusBevacizumab Paclitaxe

32、l 1st linefor Locally Recurrent or Metastatic DiseaseEastern Cooperative Oncology Group(ECOG)2100 trialFirst planned interim analysis of randomized,first-line,phase 3 trialMiller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab

33、Paclitaxel for Locally Recurrent or Metastatic DiseasePFS significantly longer with combination therapy10.97 months vs 6.11 months HR=0.498(95%CI,0.401-0.618),P .001Overall survival significantly higher for patients receiving bevacizumab+paclitaxel vs paclitaxel aloneHR=0.674(95%CI,0.495-0.917),P=.0

34、1Overall response significantly better for patients treated with bevacizumab+paclitaxel28.2%vs 14.2%for paclitaxel alone cohort(P .0001)Grade 3/4 EventBevacizumab+Paclitaxel,%(n=342)Paclitaxel,%(n=330)P ValueHypertension13.30.0001Thromboembolism1.21.2NSBleeding0.90NSProteinuria2.40.0004Neuropathy20.

35、514.2.01Fatigue5.0 2.7NSNeutropenia5.33.0 NSDecreased LVEF0.30.0NSMiller et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.Bevacizumab Paclitaxel for Locally Recurrent or Metastatic DiseaseBevacizumab+paclitaxel regimen associated with more

36、grade 3/4 adverse events vs paclitaxel alone结论Miller and colleagues比较XB vs x 一线MBCRR在XB组较高（19.8%)vs X alone(9.1%)，但是 PFS(XB 4.86 m vs 4.17 ms X alone)或 OS(XB 15.1 ms vs X 14.5 ms)都没有改善。Bevacizumab improves PFS when added to paclitaxel for treatment of locally recurrent or metastatic diseaseImproved

37、overall survival and overall responseIncreased hypertension,proteinuria,neuropathy with bevacizumab与Herceptin+Paclitaxel在改善PFS vs OS的疗效十分相似，是以往细胞毒方案所不能比拟的，显示十分重要的前景。有可能成为Her2阴性乳癌的一线治疗。影响治疗影响治疗MBC选择的因素选择的因素肿瘤的特征：肿瘤负荷，肿瘤部位，进展速度，肿瘤相关并发症，以及肿瘤特殊标志。病人的考虑：患者的年龄，身体条件，患者对治疗方案的主观看法。病史：过去治疗，无病间隔，合并疾病：心、肝、肾功能，糖尿病等。治疗药物和方案的效果和毒性，以及费用。小结细胞毒药物仍然是主要治疗方法.Herceptin 是HER2过表达MBC一线治疗选择。激素受体阳性,同时又适合内分泌治疗,应给予内分泌治疗.根据病人的肿瘤情况和身体状况，选择和制定合理的治疗方案，控制肿瘤同时，尽量避免治疗的不良反应。