上海肿瘤医院王中华晚期乳腺癌治疗讲课.ppt

转移性乳腺癌内科治疗进展,王中华 2012.05.09讲课,Age Distribution,Data from Shanghai Cancer Institute,5-yr disease-free,5-yr recurrence,Gain from adjuvant chemotherapy,70%,30%,70%,10%,20%,Risk reduction: 30%20%, 10/30=33% Absolute benefit: 10% 70% always free 20% always recurred,超过 2/3 的乳腺癌复发为远处转移,远处转移 (61%-75%) 5年生存率 41.3%,对侧乳腺癌 (9%-11%) 5年生存率83.4%,局部复发 (16%-28%) 5年生存率 59.3%,BIG = Breast International Group. Baum et al. Lancet. 2002;359:2131. Thrlimann et al. N Engl J Med. 2005;363:2747.,晚期乳腺癌治疗目的,控制疾病，缓解症状 提高患者的生活质量，延长高质量的生存期,全面评估,内分泌,化疗,乳腺癌的分子分型与内科治疗方法,Luminar A/B ER（+）和/或PR（+）,Her-2 阳性,所有类型MBC 受体三阴性,全身化疗 针对所有类型的晚期乳腺癌,晚期乳腺癌的化疗发展史,1955,1965,1975,1985,1995,2005,2015,Cyclophosphamide 1959,Methotrexate 1971,Doxorubicin 1974,Gemcitabine 2004,Capecitabine 1998,Lapatinib 2006,Accessed on-line at /cder/cancer/druglistframe.htm,Docetaxel 1996,Paclitaxel 1994,Trastuzumab 2000,Approved specifically for first-line use in MBC,Nab paclitaxel 2005,Ixabepilone 2007,Bevacizumab 2008,5-FU 1962,Platinums,晚期乳腺癌化疗适应证,病变发展迅速 内脏转移，如肝、肺广泛转移 无病生存期（DFS）2年 ER和PR阴性 既往内分泌治疗无效,化疗的应用方法,联合 Vs. 单药 （AB Vs. A） ORR TTP OS 或 联合 Vs. 序贯 （AB Vs. AB） TTP、OS未显示有明显优势,联合化疗 VS.单药,优先选择联合化疗 有广泛转移或 有临床症状，需要快速控制病情或 肿瘤进展迅速或 威胁生命的转移或 患者的耐受性较好 优先考虑单药化疗 无重要脏器转移或 无临床症状或 转移部位少,辅助,首选,蒽环,蒽环类联合紫杉类 AT,蒽环类 CAF、CEF AC、EC,未化疗,CMF,复发转移性乳腺癌化疗药物选择原则,多西他赛联合卡培他滨 TX 紫杉醇吉联合吉西他滨 GP,或,蒽环类及紫杉类治疗失败,卡培他滨、长春瑞滨、吉西他滨、铂类、伊沙匹隆 、ABX,First-Line Second-Line Doxorubicin 35-50%1 25-30%1 Epirubicin 52-68% 28% Paclitaxel 29-63%1 19-57% Docetaxel 47-65%1 39-58% Capecitabine 25%1 20-27%1 Gemcitabine 23-37%1 13-41%1 Vinorelbine 40-44%1 17-36%,1Esteva F et al, Oncologist 2001 (6): 133-146,单药治疗MBC有效率,白蛋白结合型紫杉醇 III 期临床试验: 试验设计,Gradishar et al. J Clin Oncol. 2005;23:77947803,MBC,III 期临床试验:注射用紫杉醇（白蛋白结合型）显著延长了患者的至肿瘤进展时间,Gradishar et al. J Clin Oncol. 2005;23:77947803,标准紫杉醇l (n = 224),注射用紫杉醇（白蛋白结合型） (n = 229),中位时间 = 23.0 周 (19.426.1),中位时间 = 16.9 wks (15.120.9),无进展百分比,P = 0.006 风险比 = 0.75,周,0 8 16 24 32 40 48 56 64 72 80 88 96,104,112,120,III 期临床试验: 毒性,Gradishar et al. J Clin Oncol. 2005;23:77947803,Capecitabine 1, 250mg/m2 BID days 114 + Docetaxel 175mg/m2 day 1,Docetaxel 100mg/m2 day 1,3-weekly cycles,n=255,n=256,OShaughnessy et al. J Clin Oncol. 2002;20:2812-2823,SO14999研究： 多西他赛联合希罗达 vs. 多西他赛,R,主要研究终点: TTP,Gemzar 1, 250mg/m2 BID days 1，8 + Paclitaxel 175mg/m2 day 1,Paclitaxel 175mg/m2 day 1,3-weekly cycles,n=529,OShaughnessy et al. J Clin Oncol. 2002;20:2812-2823,JHQG 研究设计 紫杉醇联合吉西他滨 vs. 紫杉醇,R,主要研究终点: TTP,蒽环类和紫杉类均耐药乳腺癌的化疗,希罗达 伊沙匹隆 (Ixabepilone)希罗达 （2B） NVB GEM NVB 希罗达 NVB DDP/CBP GEM DDP/CBP,phase III Spanish Breast Cancer Research Group (GEICAM) trial 疗效： 毒副作用： GEMNVB vs. NVB G3/4 ANC下降 66 vs. 44 （p = 0.0074 ） ANC减少性发热 11 vs. 6 （p = 0.15 ） 非血液学毒性两组无显著差异,蒽环和紫杉类治疗失败 GEMNVB vs. NVB,Lancet Oncology 2007; 8:219-225,gemcitabine 1200 mg/m2 days 1 and 8 vinorelbine 30 mg/m2 days 1 and 8 q21d,vinorelbine 30 mg/m2 days 1 and 8 q21d,PD,252 pts MBC pretreated with anthracyclines and taxanes,Epothilone: Ixabepilone (BMS-247550) Bristol-Myers Squibb, New York, NY,Activity in multiple tumor models Low susceptibility to tumor resistance mechanisms MRP and P-gp efflux pumps () tubuiln overexpression tubuiln mutations Antitumor activity in taxane resistance models,S. cellulosum,Epothilone B,Ixabepilone,59%,36%,23%,22%,35%,12%,41%,Study Design: International, Randomized, Phase III trial, BMS 046,Ixabepilone 40 mg/m2 IV over 3 hrs Day 1, every 3 wks + Capecitabine 1000 mg/m2 orally BID Days 1-14, every 3 wks,Capecitabine 1250 mg/m2 orally BID Days 1-14 every 3 wks,Patients with metastatic or locally advanced breast cancer to anthracyclines PRE/ RESISTANT and taxane RESISTANT,Stratified by visceral metastases previous MBC chemotherapy anthracycline resistance study site,PD,Ixabepilone Plus Capecitabine vs Capecitabine Alone,Ixabepilone Plus Capecitabine vs Capecitabine Alone,Overall response rate* I + C vs C: 35% vs 14% (P .0001) PFS benefit for combination arm* (5.8 vs 4.2 mos) 辅助化疗后快速复发 （5.6 vs. 2.8 mos） 2008 SABCS,*As determined by independent radiologic review,Months,Proportion Progression Free,4,0,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,28,32,36,PFS by Independent Radiologic Review,Capecitabine,Ixabepilone + Capecitabine,HR: 0.75 (95% CI: 0.64-0.88) P = .0003,Vahdat LT, et al. ASCO 2007. Abstract 1006.,Grade 3/4 peripheral neuropathy: 23% for ixabepilone plus capecitabine vs 0% for capecitabine alone 感觉神经 / 累积性 / 可逆性 中位恢复至 G1 or 基线: 6 weeks,More hematologic toxicity observed in ixabepilone arm,Ixabepilone Plus Capecitabine vs Capecitabine Alone,October 22, 2007 FDA Approves Ixempra (ixabepilone, Bristol-Myers Squibb) for Advanced Breast Cancer Patients The U.S. Food and Drug Administration has approved Ixempra (ixabepilone), a new anti-cancer treatment, for use in patients with metastatic or locally advanced breast cancer who have not responded to certain other cancer drugs.,何时停药？治疗越长越好？,效不更方 至病情进展或不可耐受的毒性 选择其中一个药物 用至进展或不可耐受的毒性 更换其他一种化疗药 希罗达，PLD 更换成内分泌治疗 耐受性好，作用机制不同，减少耐药 停止用药（6-8周期后），观察 定期复查，进展再给予处理,三种不同剂量多西他赛治疗MBC,* P 0.05,Paclitaxel (200 mg/m2 ）d2 + Epirubicin (90 mg/m2) d1 or Doxorubicin (50 mg/m2) d1,every 3 weeks 6-8cycles N=459,CR /PR /SD,Paclitaxel 175 mg/m2,no further chemotherapy,every 3 weeks 8cycles,*HR+ HT,Paclitaxel maintenance JCO, 2006,R,Gennari A, et al, JCO,2006,3912-8,N=215 (255),The primary end point : PFS,Gennari A, et al, JCO,2006,3912-8, MANTA1 study,Possible Explanation for MANTA1 study (Paclitaxel maintenance),Use of concurrent endocrine therapy in 60% of hormone receptor-positive patients Control arm patients actual received maintenance hormonal therapy The concurrent of chemo and hormonal may reduce the efficacy Toxicity of paclitaxel Sensory neuropathy grade 2 occurred in 26%, grade 3 in 6% and grade 4 in 2% of the patients in maintenance grade ANC 24%,GEICAM 2001-01 Study Phase III trial,288 pts MBC,2008 ESMO,observation,PLD 40mg/m2 q28d 6,一线,CR / PR / SD,AT （50/75） 6,155 pts,78 pts,77 pts,R,A：ADM T：TXT PLD：脂质体ADM,*Statistically significant; assessed in futility analysis.,Randomized Studies of Chemotherapy Duration in MBC,MBC的化疗,为何用？ 目的 何时用？ 适应症 怎么用？ 方法（联合、单药） 用何药？ 三级选用（蒽环，蒽环耐药， 蒽环及紫杉均耐药） 何时停？ 五种措施,生物靶向治疗 与化疗联合,Targeted therapies for breast cancer,mTOR,Tam,AI,Her-2阳性MBC Herceptin Lapatinib,HER2阳性定义,IHC 3+,CISH +,FISH +,或,或,免疫组织化学法(IHC) 色素原位杂交法(CISH) 荧光原位杂交法(FISH),Hercetpin单药治疗晚期乳腺癌的疗效, HO649g HO551g HO650 （关键试验） （期） （关键试验） _ N (intent-to-treat) 222 46 114 #CR 8 1 7 #PR 26 4 23 有效率 15 11 26 中位缓解期（月） 9.1 6.6 18.8 中位生存期（月） 13 14 24.4 _,Herceptin联合化疗一线治疗Her-2阳性MBC,H: Herceptin, T: TXT, P: PAX, C: CBP, X: Xeloda,曲妥珠单抗联合泰索帝：同时还是序贯使用? HERTAX,Bontenbal et al. ASCO 2008. Abstract 1014.,99 例 HER2 +, 一线 M+ 主要目的: PFS 次要目的: RR & OS,曲妥珠单抗每周 + 泰索帝 100 mg/m,曲妥珠单抗 每周,随机,泰索帝 100 mg/m,序贯,PD,Lapatinib 针对Her-2阳性MBC FDA于2007.3.13批准上市 规格250mg/150#,Lapatinib: Targeting EGFR and HER2,Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 Blocks signaling through EGFR and HER2 homodimers and heterodimers May also prevent signaling between ErbB1/ErbB2 and other ErbB family members,Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94. Xia W, et al. Oncogene. 2002;21:6255-6263.,Geyer CE, et al. ASCO 2006. Clinical Science Symposium.,EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer,到疾病进展时间（ITT Population）,70,20,40,60,80,0,100,10,20,30,40,50,60,0,Time (weeks),Patients Progression Free* (%),EGF100151,Geyer CE, et al. N Engl J Med 2006 ;355(26):2733-2743.,GBG-26：曲妥珠单抗加希罗达 vs. 希罗达，延长TTP近3个月（8.2m vs. 5.6m P0.05) EGF104900：曲妥珠单抗加拉帕替尼 vs. 拉帕替尼，显著延长TTP（2.8m vs. 1.9m P=0.008）,含曲妥珠单抗一线治疗Her-2阳性MBC进展后,von Minckwitz G et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1025. OShaughnessy J et al. J Clin Oncol 2008: 26 (May 20 Suppl); abs 1015.,PCH 或wPCH,贝伐单抗,Paclitaxel Bevacizumab in MBC (E2100),N=715 Locally recurrent or 1st-line MBC,值得关注的是贝伐单抗组有更多感染、 3/4 级的高血压、蛋白尿、头痛、 心脑血管局部缺血,Miller et al. N Engl J Med. 2007;357:2666-2676,Results,Paclitaxel 90 mg/m2 d 1, 8, 15 q4w,Paclitaxel 90 mg/m2 d 1, 8, 15 q4w + bevacizumab 10 mg/kg d1, 15,Yellow text indicates statistically significant values.,R,Docetaxel Bevacizumab in MBC (AVADO),N=705 Locally recurrent or 1st-line MBC Stratification: Region Prior taxane/time to relapse since adjuvant chemo Measurable disease HR status,R,Docetaxel 100mg/m2 + Placebo q3w,Docetaxel + Bevacizumab 7.5mg/kg q3w,Docetaxel + Bevacizumab 15mg/kg q3w,Bevacizumab continued to disease progression; all pts given option to receive bevacizumab with 2nd-line chemo; docetaxel administered for maximum of 9 cycles,Miles et al. ASCO 2008. Late-Breaking Abstract 1011.,Phase III Studies: E2100 and AVADO,*Miller et al. N Eng J Med. 2007; *Miles et al. ASCO 2008 (LBA#1011).,Yellow text indicates statistically significant values.,E2100 and AVADO Safety data,*Miller et al. N Eng J Med. 2007; *Miles et al. ASCO 2008 (LBA#1011). *VTE: no increase in bevacizmab arm in either study.,Ongoing Phase III Trials Evaluating Bevacizumab in First-Line MBC,GEICAM 2006-11,AVEREL,HER2+ Disease Trastuzumab-containing regimens,Hormonal therapy,RIBBON 1,RIBBON 1,RIBBON 1,Capecitabine,AVADO,Single-agent taxane therapy,Anthracycline-based chemotherapy,Bevacizumab,晚期乳腺癌的内分泌治疗 针对Luminal A/B 的 MBC ER（+）PR（+） ER（+）或 PR（+）,内分泌治疗与化学治疗,内分泌 改变肿瘤的内环境来抑制其生长 对正常细胞影响小，副作用小 28周起效，缓解期长 不需要升白、止吐等支持治疗 治疗费用较低,化疗 阻断肿瘤复制来杀死肿瘤细胞 对正常细胞有杀伤，副作用大 12周起效，缓解期短 常需要升白、止吐等支持治疗 治疗费用一般较高,晚期乳腺癌内分泌治疗适应证,患者年龄35岁 无病生存期（DFS) 2年 骨和软组织转移；无症状的内脏转移 ER和或PR阳性,晚期乳腺癌的内分泌治疗,月经状况 治疗药物 绝经前 戈舍瑞林 (Goserelin， zoladex） 亮丙瑞林 (Leuprolide acetate） 绝经后 瑞宁得(Anastrozole ) 来曲唑( Letrozole) 依西美坦 各种年龄 他莫昔芬，孕激素,阿那曲唑的一线疗效优于TAM,Arimidex (anastrozole) versus Tamoxifen for the First-line Treatment of Advanced Breast Cancer in Postmenopausal Women from Trials 0030 and 0027 Known to be Receptor-positive,025试验设计 : 来曲唑 vs. 他莫昔芬 作为晚期一线治疗,Mouridsen et al. J Clin Oncol. 2001;19: 2596.,试验人群: 绝经后; 局部晚期或局部复发或转移的乳腺癌; ER 和/或 PgR阳性或未知,来曲唑的一线疗效优于TAM,非甾体类 AI 失败后的内分泌治疗MBC,芳香化酶抑制剂作用机理: 非甾体 VS 甾体,雄激素,非甾体类（抑制剂） (eg, anastrozole, letrozole),芳香化酶,甾体类（灭活剂） (eg, exemestane),Geisler et al. Clin Cancer Res. 1998;4:2089-93.,EFECT: Evaluation of Treatment Options Following AI Failure,Fulvestrant IM injection loading-dose regimen* (n = 351),Exemestane 25 mg/day orally (n = 342),Postmenopausal women with hormone receptorpositive, progressing/recurring advanced breast cancer after nonsteroidal AI (N = 693),Progression, death, or withdrawal,*Fulvestrant loading-dose regimen comprised 500 mg on Day 0, 250 mg on Days 14 and 28, and 250 mg monthly thereafter.,Gradishar W, et al. SABCS 2006. Abstract 12.,EFECT: Similar TTP in Patients Treated With Fulvestrant or Exemestane,Gradishar W, et al. SABCS 2006. Abstract 12.,Exemestane： 3.7 months Fulvestrant：3.7 months P=.65,绝经后MBC的内分泌治疗,一线,二线,三线,TAM,孕激素,雄激素,AI,TAM,孕激素,辅助,AI,孕激素 ?,氟维司群 ?,TAM ?,1985,2002,新方向 靶向联合内分泌,2008 SABCS,EGF30008：拉帕替尼联合来曲唑 随机期临床,2008 SABCS,PFS,P：拉帕替尼，L:来曲唑 T：TAM,绝经后 ER/PR阳性 MB