早期乳腺癌术后辅助化疗ppt课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,早期乳腺癌术后辅助化疗,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2013,早期乳腺癌与化疗,2013早期乳腺癌与化疗,目 录,乳腺癌,TNM,分期与分子分型,2013 NCCN,术后辅助化疗更新及相关理论,乳腺癌化疗药物发展史及其毒副反应,乳腺癌治疗流程图,早期乳腺癌术后辅助化疗,目 录乳腺癌TNM分期与分子分型2013 NCCN 术,2,乳腺癌疾病分类（根据,NCCN,指南）,非浸润性癌乳腺癌,1,. 小叶原位癌,2,. 导管原位癌,3.,伴导管原位癌的,Pages,病,浸润癌乳腺癌,1,浸润小叶癌,2,浸润导管癌,特殊型：,分叶状肿瘤；,Pagets,病；炎性乳腺癌,NCCN Clinical Practice Guidelines in Oncology,TM,乳腺癌临床实践指南（中国版）,2011,年 第一版（源自英文版,V.2.2011,）,早期乳腺癌术后辅助化疗,乳腺癌疾病分类（根据NCCN指南）非浸润性癌乳腺癌早期乳腺,3,ER+,和,/,或,PR+,ER-/PR-,L,uminal B,：,-55%,ER+,和,/,或,PR+ & HER2+,ER+,和,/,或,PR+ &,HER2- & Ki6714%,化疗,靶向药物,内分泌治疗,预后较好,HER2,过表达,：,-15%,ER-/PR- & HER2+,主张化疗,+,靶向药物联合,预后较差,HER2+,Luminal A,：,15%,ER+,和,/,或,PR+ & HER2- & Ki6714%,没有高危因素倡导直接内分泌治疗,对化疗的敏感性低，但预后好,三阴性,：,15%,ER-/PR- & HER2-,对化疗敏感性高，容易达到,pCR,但预后差，容易复发,HER2-,乳腺癌分子分型,Katrina R. et al.Descriptive Analysis of Estrogen Receptor (ER)-Negative, Progesterone Receptor (PR)-Negative,and HER2-Negative Invasive Breast Cancer, the Socalled Triple-Negative Phenotype.A Population-Based Study From the California Cancer Registry.CANCER May 1, 2007 / Volume 109 / Number 9.1721-8,早期乳腺癌术后辅助化疗,ER+ 和/或 PR+ER-/PR-Luminal B：-5,4,目 录,乳腺癌,TNM,分期与分子分型,2013 NCCN,术后辅助化疗更新及相关理论,乳腺癌化疗药物发展史及其毒副反应,乳腺癌治疗流程图,早期乳腺癌术后辅助化疗,目 录乳腺癌TNM分期与分子分型2013 NCCN 术,5,早期乳腺癌的常用治疗手段,辅助治疗,新辅助,内分泌,靶向,手术,化疗,放疗,辅助化疗,被定义为在手术后给予系统的细胞毒化疗以,杀死或抑制临床无法检测的微转移。,S. Aebi ,et al.Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011 Sep;22 Suppl 6:vi12-24.,HER2+,ER+,或,PR+,有放疗指证,有化疗指证,早期乳腺癌术后辅助化疗,早期乳腺癌的常用治疗手段辅助治疗新辅助内分泌 靶向手术化疗放,6,治疗决策树,手术,可手术乳腺癌（,I-III,期）,局部晚期病人,：,IIIA,(,除,T3,N1,M0,),IIIB-IIIC,I-IIIA,(,仅,T3,N1,M0,),选择仅含蒽环类方案,选择仅含紫杉类方案,选择同时含紫杉类和蒽环类方案*,根据分期（肿瘤大小和淋巴结转移）、分子分型、年龄等情况评估复发风险（,2007,年,St. Gallen,制定的复发风险等级划分权威性和影响力很大）,低危患者,IIB,以下,淋巴结阴性,中,高危人群,IIB,以上,淋巴结阳性,（,3,个转移）,年轻,（,1CM,、有高危因素,需完成剩余疗程,疾病诊断,疾病治疗,类别选择,原位癌,浸润性癌中分期很早,(I,期,),没有高危因素,(,没有淋巴转移、年龄,70,岁,),的,Luminal A,不需要术后辅助化疗,早期乳腺癌术后辅助化疗,治疗决策树手术可手术乳腺癌（I-III期）局部晚期病人：II,7,目 录,乳腺癌,TNM,分期与分子分型,2013 NCCN,术后辅助化疗更新及相关理论,乳腺癌化疗药物发展史及其毒副反应,乳腺癌治疗流程图,早期乳腺癌术后辅助化疗,目 录乳腺癌TNM分期与分子分型2013 NCCN 术,8,1970,s,1980,s,1990,s,2000,s,乳腺癌化疗药物的进展,非蒽环类的联合化疗,CMF,蒽环类联合化疗,A,C, F,A,C,A/E, CMF, F,E,C, C,E,F,紫杉类 (,Paclitaxel/Docetaxel,),序贯:,A, P ,C,or,AC, P(T),联合:,T,C, T,AC,靶向药物,与化疗策略结合,AC ,PH(TH),T,C,H,早期乳腺癌术后辅助化疗,1970s1980s1990s2000s乳腺癌化疗药物的进展,9,CMF方案,无化疗,1970,4.2% 获益,蒽环类方案,1980,4.3% 获益,紫杉类方案,2000,5.1% 获益,辅助化疗在过去,40年对患者总生存的改善情况,化疗 + 曲妥珠单抗,6% 获益,2006,化疗持续地改善了早期乳腺癌的预后,在早期乳腺癌的治疗中扮演了非常重要的角色,Peto R.EBCTCG Meta-analysis 2005-2006. SABCS 2007,早期乳腺癌术后辅助化疗,CMF方案无化疗19704.2% 获益蒽环类方案19804.,10,目 录,乳腺癌,TNM,分期与分子分型,2013 NCCN,术后辅助化疗更新及相关理论,乳腺癌化疗药物发展史及其毒副反应,乳腺癌治疗流程图,早期乳腺癌术后辅助化疗,目 录乳腺癌TNM分期与分子分型2013 NCCN 术,11,2012,版乳腺癌,NCCN,指南,2013,版乳腺癌,NCCN,指南,全身治疗,对于激素受体阳性、,HER-2,阳性的乳腺癌患者,辅助内分泌治疗辅助化疗曲妥珠单抗,辅助内分泌治疗或辅助化疗曲妥珠单抗序贯内分泌治疗,激素受体阳性、,HER-2,阴性的乳腺癌患者,“辅助内分泌治疗”及“辅助化疗”为 “,2B,类推荐”,“辅助内分泌治疗”及“辅助化疗”为 “,2A,类推荐”,术前辅助化疗,-,增加“如术前未完成全部化疗，术后应完成全部化疗；如雌激素和,/,或孕激素受体阳性，需加用内分泌治疗（首先进行化疗，随后进行内分泌治疗）,辅助化疗,TAC,方案为优选方案,TAC,方案为其他方案,AC,（多柔比星,/,环磷酰胺）紫杉醇周疗,剂量密集,AC,（多柔比星,/,环磷酰胺）紫杉醇周疗,-,增加“,FAC,T,（氟尿嘧啶,/,多柔比星,/,环磷酰胺紫杉醇周疗）方案,2013,版乳腺癌,NCCN,指南更新要点,早期乳腺癌术后辅助化疗,2012版乳腺癌NCCN指南2013版乳腺癌NCCN指南全身,12,2013,版乳腺癌,NCCN,指南更新要点,全身治疗,激素受体阳性、,HER-2,阴性的乳腺癌患者的全身辅助治疗,对于肿瘤直径,0.5cm,的低,高复发评分的患者，“辅助内分泌治疗”及“辅助化疗”均由“,2B,类推荐”改为“,2A,类推荐,”,激素受体阳性、,HER-2,阳性的乳腺癌患者的全身辅助治疗,对于肿瘤直径,0.5cm,或可行微创手术切除且,pN1mi,的患者，治疗由,2012,版指南中的“辅助内分泌治疗辅助化疗曲妥珠单抗”改为,2013,版指南的“辅助内分泌治疗或辅助化疗曲妥珠单抗序贯内分泌治疗 ”,早期乳腺癌术后辅助化疗,2013版乳腺癌NCCN指南更新要点全身治疗激素受体阳性、,13,2013,版乳腺癌,NCCN,指南更新要点,术前辅助化疗,浸润性乳腺癌的“术前辅助化疗”部分,与,2012,版指南相比，,2013,版指南“术前化疗”中的“辅助治疗”部分增加一点：“如术前未完成全部化疗，术后应完成全部化疗；如雌激素和,/,或孕激素受体阳性，需加用内分泌治疗（首先进行化疗，随后进行内分泌治疗）,”,早期乳腺癌术后辅助化疗,2013版乳腺癌NCCN指南更新要点术前辅助化疗浸润性乳腺,14,2013,版乳腺癌,NCCN,指南更新要点,辅助化疗,浸润性乳腺癌的“辅助化疗”部分,将“,TAC,（多西他赛,/,多柔比星,/,环磷酰胺）”方案由,2012,版指南的“优选方案”改为,2013,版指南的“其他方案”,优选方案中将,2012,版指南的“,AC,（多柔比星,/,环磷酰胺）紫杉醇周疗”改为,2013,版指南的“剂量密集,AC,（多柔比星,/,环磷酰胺）紫杉醇周疗”,2013,版指南中增加“,FAC,T,（氟尿嘧啶,/,多柔比星,/,环磷酰胺紫杉醇周疗）方案,早期乳腺癌术后辅助化疗,2013版乳腺癌NCCN指南更新要点辅助化疗浸润性乳腺癌的,15,同样的药物组合,如何达到最大效能,?,序贯,vs.,联合，哪种给药方式更好？,剂量密集,vs.,传统,3,周，哪种给药方案更优？,早期乳腺癌术后辅助化疗,同样的药物组合,如何达到最大效能?早期乳腺癌术后辅助化疗,16,BCIRG001,多西他赛,75 mg/m,2,多柔比星,50 mg/m,2,环磷酰胺,500 mg/m,2,5-,氟尿嘧啶,500 mg/m,2,多柔比星,50 mg/m,2,环磷酰胺,500 mg/m,2,仅在出现一次粒缺性发热或感染事件后使用环丙沙星预防和治疗,F,A,C,T,A,C,R,每周期化疗前,1,天给予地塞米松, 8 mg bid,连续,3,天,预先给予环丙沙星,500mg bid,每周期的第,5-14,天,每,3,周,6,个周期,淋巴结阳性,乳腺癌患者,N=1480,1997.6-1999.6,N Engl J Med. 2005 Jun2;352(22):2302-13,主要终点：无病生存期,(DFS),次级终点：总生存期,(OS),、毒性,治疗中出现粒缺性发热或感染，立即给予,G-CSF,（来格斯亭,150ug/m,2,.,天，或菲格斯亭,5ug/kg.,天），,并在之后的每个周期的第,4,11,天预防使用,激素受体阳性患者在化疗结束后使用他莫昔芬治疗,5,年,早期乳腺癌术后辅助化疗,BCIRG001多西他赛75 mg/m2 5-氟尿嘧啶,17,TAC: 76%,FAC: 69%,DFS at a Median 10-year Follow-up (ITT),Number at Risk,TAC,745,737,710,678,659,639,617,596,583,562,551,541,530,519,508,491,478,463,444,418,387,FAC,746,730,699,659,618,584,558,541,523,510,499,484,471,453,437,429,414,392,378,351,333,Disease-free survival probability,0.00,0.20,0.40,0.60,0.80,1.00,Disease-free survival time (months),0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,102,108,114,120,HR=0.7295%CI: 0.590.88Log-rank P=0.001,HR=0.8095%CI: 0.680.93Log-rank P=0.0043,BCIRG 001 ,结果,Lancet Oncol. 2013;14: 72-80,早期乳腺癌术后辅助化疗,TAC: 76%FAC: 69%DFS at a Media,18,OS at a Median 10-year Follow-up (ITT),429 deaths:,188 TAC; 241 FAC,Number at Risk,TAC,745,742,732,718,704,693,677,661,650,645,635,622,612,603,594,584,571,563,547,524,495,FAC,746,740,731,724,704,684,657,642,625,608,591,581,573,557,546,532,517,501,482,460,443,Overall survival probability,0.00,0.20,0.40,0.60,0.80,1.00,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,102,108,114,120,TAC: 87%,FAC: 81%,HR=0.7095%CI: 0.530.91Log-rank P=0.008,HR=0.7495%CI: 0.610.90Log-rank P=0.002,Survival time (months),BCIRG 001 ,结果,Lancet Oncol. 2013;14: 72-80,早期乳腺癌术后辅助化疗,OS at a Median 10-year Follow-,19,BCIRG001,三年随访结果：对于,4,个淋巴结阳性的乳腺癌患者，,TAC,方案不能提供显著更优的,DFS,获益,无病生存期,(,月,),无病生存率,(%),Martin M,et L.SABCS 2003(abs 43).,N Engl J Med. 2005 Jun2;352(22):2302-13,早期乳腺癌术后辅助化疗,BCIRG001三年随访结果：对于 4个淋巴结阳性的乳腺癌,20,BCIRG001,亚组分析,3,年,DFS,：,TAC,方案对,HER2+/,三阴性,/Luminal A,型，无治疗优势,三阴性,HER2+,Luminal B,Luminal A,Hugh J, et al. J Clin Oncol 2009;27:1168-1176,早期乳腺癌术后辅助化疗,BCIRG001亚组分析 3年DFS：TAC方案对HER2+,21,BCIRG 001,研究十年随访结果,&,亚组分析报告：,DFS,Mackey R, Martin M, Pienkowski T, et al. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.,Lancet Oncol 2013; 14: 7280.,早期乳腺癌术后辅助化疗,BCIRG 001研究十年随访结果&亚组分析报告：DFSMa,22,BCIRG 001,研究十年随访结果,&,亚组分析报告：,OS,早期乳腺癌术后辅助化疗,BCIRG 001研究十年随访结果&亚组分析报告：OS早期乳,23,BCIRG 001,：,TAC,方案血液学毒性发生率显著更高,毒性,TAC,组,(n=744),FAC,组,(n=736),P,值,P,值,所有患者,3,级及以上毒性,所有患者,3,级及以上毒性,所有患者,3,级及以上毒性,贫血,所有患者,91.5,4.3,71.7,1.6,0.001,0.003,需输血治疗患者,4.6,-,1.5,-,0.001,-,血小板减少,39.4,2.0,27.7,1.2,0.001,0.23,中性粒细胞减少性发热,本研究定义*,24.7,-,2.5,-,0.001,-,NCI,CTC(2.0,版,),定义*,28.8,-,4.4,-,0.001,-,中性粒细胞减少性感染,本研究定义,#,12.1,-,6.3,-,0.001,-,NCI,CTC(2.0,版,),定义,#,20.4,-,10.8,-,20%,58(17%),41(15%),0.632,0.660,LVEF,低于正常下限,41(12%),27(10%),0.492,0.520,Martin M, Pienkowski T, Mackey J,et al. Adjuvant Docetaxel for Node-Positive Breast Cancer. N Engl J Med 2005;352:2302-13.,Mackey R, Martin M, Pienkowski T, et al. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.,Lancet Oncol 2013; 14: 7280.,早期乳腺癌术后辅助化疗,BCIRG 001研究十年随访结果：TAC方案增加远期慢性心,25,BCIRG001,结论,TAC,方案对比,FAC,方案有更好的生存获益，但,对,4,个以上淋巴结阳性的高危患者，,DFS,和,OS,均无治疗优势,（无统计学差异），,对三阴性、,HER2+,、,Luminal A,型患者，其,OS,均无治疗优势,（无统计学差异）,TAC,方案化疗毒性反应严重，尤以,血液学毒性,为甚，,增加患者感染和死亡的风险，同时增加治疗成本,十年随访结果显示，,TAC,方案增加远期慢性心衰的发生率,，可能由于多西他赛易引起体液潴留，加重心脏负担有关,仅供内部使用,早期乳腺癌术后辅助化疗,BCIRG001结论TAC 方案对比FAC方案有更好的生存获,26,AC-T,TAC,治疗指数疗效,/,毒副反应,早期乳腺癌术后辅助化疗,AC-TTAC治疗指数疗效/毒副反应早期乳腺癌术后辅助化疗,27,BCIRG005,：多西他赛序贯化疗,vs.,联合化疗,可手术切除、淋巴结阳性的,HER2,阴性乳腺癌患者,（,N=3298,）,R,TAC,辅助化疗,多柔比星,50 mg/m,2,环磷酰胺,500 mg/m,2,每,3,周,6,个周期,多西他赛,75 mg/m,2,（,n=1649,）,ACT,辅助化疗,多柔比星,60 mg/m,2,环磷酰胺,600 mg/m,2,多西他赛,100 mg/m,2,每,3,周,4,个周期,（,n=1649,）,每,3,周,4,个周期,分层：中心； 腋窝淋巴结数目（,13 vs. 4,）；激素受体状态（,ER,和,/,或,PR,阳性,vs.,阴性）。,主要终点：,DFS,；,次要终点：,OS,、安全性,Eiermann W, Pienkowski T, Crown J,Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.,J Clin Oncol. 2011 Oct 10;29(29):3877-84.,早期乳腺癌术后辅助化疗,BCIRG005：多西他赛序贯化疗 vs. 联合化疗可手术切,28,BCIRG005,：序贯方案与联合方案的,DFS,获益相当,无病生存期,(,月,),无病生存率,Eiermann W, Pienkowski T, Crown J,Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.,J Clin Oncol. 2011 Oct 10;29(29):3877-84.,早期乳腺癌术后辅助化疗,BCIRG005：序贯方案与联合方案的DFS获益相当无病生存,29,BCIRG005,：序贯方案与联合方案的,OS,获益相当,总生存率,总生存期,(,月,),Eiermann W, Pienkowski T, Crown J,Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.,J Clin Oncol. 2011 Oct 10;29(29):3877-84.,早期乳腺癌术后辅助化疗,BCIRG005：序贯方案与联合方案的OS获益相当总生存率总,30,BCIRG005,：序贯方案与联合方案相比,中性粒细胞减少性发热等血液学毒性发生率更低,7.7,17.4,2.0,2.9,1.3,2.5,P0.0001,P=0.07,P=0.01,AC T,TAC,发生率,(%),Eiermann W, Pienkowski T, Crown J,Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.,J Clin Oncol. 2011 Oct 10;29(29):3877-84.,早期乳腺癌术后辅助化疗,BCIRG005：序贯方案与联合方案相比,中性粒细胞减少性发,31,AC-T,TAC,治疗指数疗效,/,毒副反应,序贯方案的,治疗指数,优于联合方案,早期乳腺癌术后辅助化疗,AC-TTAC治疗指数疗效/毒副反应序贯方案的治疗指数优于,32,同样的药物组合,如何达到最大效能,?,剂量密集,vs.,传统,3,周，哪种给药方案更优？,早期乳腺癌术后辅助化疗,同样的药物组合,如何达到最大效能?早期乳腺癌术后辅助化疗,33,Norton-simon,剂量密集学说：与“正常”给药周期相比，剂量密集化疗能杀死更多的肿瘤细胞,1,10,2,10,4,10,6,10,8,10,10,10,12,1,0,7,6,5,4,3,2,时间,(,月,),肿瘤细胞数,剂量密集假说：通过缩短传统化疗间隔时间，给药的时间更频繁，而给药的剂量不变，以达到更大程度的细胞杀伤作用。,利用这种方法有两个好处：,由于缩短化疗间隔时间，这样在化疗间歇期可使更少的肿瘤细胞重新进入再生长，也可减少对化疗药耐药的恶性细胞的出现。,通过缩短给药间隔时间，可以使肿瘤细胞更频繁地曝露在细胞毒药物中，使细胞内的生长信号受到更大程度的影响，促进细胞凋亡和抗血管生成，从而达到最大程度的细胞杀伤作用。,陈强,杨建伟,.,剂量密集疗法及其在乳腺癌治疗中的应用,.,药品评价,. 2005; 2(4):251-254.,Monica Fornier and Larry Norton. Dose-dense adjuvant chemotherapy for primary breast cancer. Breast Cancer Research .2005;7():64-69.,早期乳腺癌术后辅助化疗,Norton-simon剂量密集学说：与“正常”给药周期相比,34,INT C9741/CALGB 9741,：研究设计,Citron ML, Berry DA, Cirrincione. C, et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439,淋巴结阳性的,原发性乳腺癌患者,（,N=2005,）,R,方案,I,：,A q3w 4P q3w 4C q3w 4,多柔比星,60mg/m,2,紫杉醇,175 mg/m,2,环磷酰胺,600mg/m,2,剂量密集化疗组加用非格司亭,5ug/kg,，,d3d10,。,主要终点：,DFS,次要终点：,OS,方案,II,：,A q2w 4P q2w 4C q2w 4,方案,III,：,AC q3w 4P q3w 4,方案,IV,：,AC q2w 4P q2w 4,早期乳腺癌术后辅助化疗,INT C9741/CALGB 9741：研究设计Citro,35,INT C9741/CALGB 9741,：紫杉醇剂量密集化疗方案,较常规,3,周方案显著降低复发风险达,26%,Citron ML, Berry DA, Cirrincione. C, et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439,0,0.2,0.4,0.6,0.8,1,0,1,2,3,4,无病生存期,(,年,),无病生存率,q 2 wks,（,n=988,）,q 3 wks,（,n=985,）,RR,：,0.74; P=0.010,中位随访,36,个月,紫杉醇剂量密集方案的获益不受肿瘤大小、累及的淋巴结数量、患者的激素受体以及绝经状态影响,早期乳腺癌术后辅助化疗,INT C9741/CALGB 9741：紫杉醇剂量密集化疗,36,INT C9741/CALGB 9741,：紫杉醇剂量密集化疗方案,较常规,3,周方案显著降低死亡风险达,31%,Citron ML, Berry DA, Cirrincione. C, et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439,q 2 wks,（,n=988,）,q 3 wks,（,n=985,）,RR,：,0.69; P =0.013,0,0.2,0.4,0.6,0.8,1,0,1,2,3,4,总生存期,(,年,),总生存率,中位随访,36,个月,紫杉醇剂量密集方案的获益不受肿瘤大小、累及的淋巴结数量、患者的激素受体以及绝经状态影响,早期乳腺癌术后辅助化疗,INT C9741/CALGB 9741：紫杉醇剂量密集化疗,37,INT C9741/CALGB 9741,：,G-CSF,支持下，紫杉醇剂量密集方案的严重中性粒细胞减少发生率更低,Citron ML, Berry DA, Cirrincione. C, et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439,6%,33%,发生率,(%),4,级中性粒细胞减少,P0.0001,早期乳腺癌术后辅助化疗,INT C9741/CALGB 9741：G-CSF支持下，,38,紫杉醇密集和,TAC,方案哪个更好呢？,早期乳腺癌术后辅助化疗,紫杉醇密集和TAC方案哪个更好呢？早期乳腺癌术后辅助化疗,39,NSABP B-38,：研究设计,可手术的腋窝淋巴结阳性乳腺癌患者,（,N=4894),R,DD ACP,辅助化疗,多柔比星,60mg/m,2,环磷酰胺,600mg/m,2,紫杉醇,175 mg/m,2,每,2,周,4,（,n=1634,）,每,2,周,4,DD ACPG,辅助化疗,多柔比星,60mg/m,2,环磷酰胺,600mg/m,2,紫杉醇,175 mg/m,2,吉西他滨,2000 mg/m,2,（,n=1630,）,每,2,周,4,每,2,周,4,TAC,辅助化疗,多西他赛,75mg/m,2,多柔比星,50mg/m,2,每,3,周,6,环磷酰胺,500mg/m,2,（,n=1630,）,Swain SM, Tang G, Geyer CE, et al. NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dose-dense (DD) ACpaclitaxel (P) plus gemcitabine (G) with DD ACP and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. J Clin Oncol 30, 2012 (suppl; abstr LBA1000).,主要终点：,DFS,；,次要终点：,OS,、毒性,早期乳腺癌术后辅助化疗,NSABP B-38：研究设计可手术的腋窝淋巴结阳性乳腺癌患,40,TITLE,早期乳腺癌术后辅助化疗,TITLE早期乳腺癌术后辅助化疗,41,TITLE,早期乳腺癌术后辅助化疗,TITLE早期乳腺癌术后辅助化疗,42,NSABP B-38,：,TAC,方案的中性粒细胞减少性,发热等严重毒性和治疗相关性死亡发生率更高,发生率,(%),0.8%,0.3%,0.4%,P=0.2,发生率,(%),9%,4%,4%,8%,2%,2%,P0.001,P0.001,TAC,方案的,3/4,级中性粒细胞减少性发热、腹泻发生率显著更高,TAC,方案的治疗相关性死亡发生率有更高的趋势,Swain SM, Tang G, Geyer CE, et al. NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dose-dense (DD) ACpaclitaxel (P) plus gemcitabine (G) with DD ACP and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. J Clin Oncol 30, 2012 (suppl; abstr LBA1000).,TAC,ddAC P,AC PG,TAC,ddAC P,AC PG,早期乳腺癌术后辅助化疗,NSABP B-38：TAC方案的中性粒细胞减少性发热等严,43,ddAC-ddP,TAC,治疗指数疗效,/,毒副反应,紫杉醇剂量密集方案的,治疗指数,优于,TAC,方案,早期乳腺癌术后辅助化疗,ddAC-ddPTAC治疗指数疗效/毒副反应 紫杉醇剂,44,常规,3,周间隙,缩为,1,周,早期乳腺癌术后辅助化疗,常规3周间隙早期乳腺癌术后辅助化疗,45,ECOG1199,：研究设计,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,接受手术后的,腋窝淋巴结阳性或高危的腋窝淋巴结阴性的,乳腺癌患者,(n=4950),AC,方案,多柔比星 ：,60mg/m,2,环磷酰胺 ：,600mg/m,2,q3w 4,紫杉醇,175 mg/m,2,i.v 3h q3w 4,紫杉醇,80 mg/m,2,i.v 1h qw 12,多西他赛,100 mg/m,2,i.v 1h q3w 4,多西他赛,35 mg/m,2,i.v 1h ; qw 12,R,主要终点：,DFS,早期乳腺癌术后辅助化疗,ECOG1199：研究设计Sparano JA, Wang,46,ECOG1199,：紫杉醇单周方案的,DFS,获益更优,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,无病生存率,(%),无病生存期,(,月,),多西他赛每周方案,多西他赛每,3,周方案,紫杉醇每周方案,紫杉醇每,3,周方案,5,年无病生存率,早期乳腺癌术后辅助化疗,ECOG1199：紫杉醇单周方案的DFS获益更优Sparan,47,ECOG1199,：紫杉醇单周方案较,3,周方案,显著降低复发风险达,27%,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,早期乳腺癌术后辅助化疗,ECOG1199：紫杉醇单周方案较3周方案显著降低复发风险,48,ECOG1199,：紫杉醇单周方案的,OS,获益更优,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,总生存率,(%),总生存期,(,月,),5,年总生存率,多西他赛每周方案,多西他赛每,3,周方案,紫杉醇每周方案,紫杉醇每,3,周方案,早期乳腺癌术后辅助化疗,ECOG1199：紫杉醇单周方案的OS获益更优Sparano,49,ECOG1199,：紫杉醇单周方案较,3,周方案,显著降低死亡风险达,32%,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,早期乳腺癌术后辅助化疗,ECOG1199：紫杉醇单周方案较3周方案显著降低死亡风险,50,ECOG1199,：紫杉类,4,组方案中，,紫杉醇单周方案的严重毒性发生率最低,Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med. 2008;358(16):1663-71.,早期乳腺癌术后辅助化疗,ECOG1199：紫杉类4组方案中，紫杉醇单周方案的严重毒,51,紫杉醇单周方案,vs.,多西他赛,/,卡培他滨联合方案用于可手术乳腺癌患者的,III,期研究,Kelly CM, Green MC, Broglio K,et al. Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable,Breast Cancer. J Clin Oncol .2012;30:1-7.,可手术的,IIII,期乳腺癌患者,（,N=603,）,R,1:1,分层：辅助化疗,vs.,新辅助化疗,wP,紫杉醇,80mg/m,2,每周,12,周,（,n=302,）,XT,多西他赛,75 mg/m,2,D1,卡培他滨,1500 mg/m,2,D114,每,3,周,4,个周期,（,n=301,）,FEC,氟尿嘧啶,500 mg/m,2,表柔比星,100 mg/m,2,环磷酰胺,500 mg/m,2,每,3,周,4,个周期,主要终点：,RFS,；,次要终点：,OS,、,pCR,率、新辅助化疗后行,保乳手术的患者比例,早期乳腺癌术后辅助化疗,紫杉醇单周方案 vs.多西他赛/卡培他滨联合方案用于可手术乳,52,与多西他赛每,3,周方案相比，,紫杉醇单周方案的,RFS,获益具有更优的趋势,无复发生存期,(,月,),无复发生存率,wPFEC,XT FEC,RFS,率：,90.7%(95%CI 86.4%93.7%),RFS,率：,87.5%(95%CI 82.7%91.1%),中位随访,50,个月,Kelly CM, Green MC, Broglio K,et al. Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable,Breast Cancer. J Clin Oncol .2012;30:1-7.,早期乳腺癌术后辅助化疗,与多西他赛每3周方案相比，紫杉醇单周方案的RFS获益具有更,53,与多西他赛每,3,周方案相比，,紫杉醇单周方案的,OS,获益具有更优的趋势,总生存期,(,月,),总生存率,wPFEC,XT FEC,中位随访,50,个月,OS,率：,95.0%(95%CI 91.3%97.2%),OS,率：,92.2%(95%CI 88.0%95.0%),Kelly CM, Green MC, Broglio K,et al. Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable,Breast Cancer. J Clin Oncol .2012;30:1-7.,早期乳腺癌术后辅助化疗,与多西他赛每3周方案相比，紫杉醇单周方案的OS获益具有更优,54,与多西他赛每,3,周方案相比，,紫杉醇单周方案的,2-3,级毒性发生率显著更低,2-3,级血液学毒性,发生率,(%),6.8,0.7,4.4,0,XT FEC,wPFEC,P0.001,P0.001,2-3,级非血液学毒性,发生率,(%),P0.001,P0.001,P0.001,P0.001,48.8,23.2,42.0,10.4,78.5,56.6,43.2,2.0,XT FEC,wPFEC,Kelly CM, Green MC, Broglio K,et al. Phase III Trial Evaluating Weekly Paclitaxel Versus Docetaxel in Combination With Capecitabine in Operable,Breast Cancer. J Clin Oncol .2012;30:1-7.,早期乳腺癌术后辅助化疗,与多西他赛每3周方案相比，紫杉醇单周方案的2-3级毒性发生,55,2012,版指南,vs.2013,版指南,乳腺癌的辅助化疗方案中，,乳腺癌,NCCN2013,版指南仍,1,类推荐剂量密集,AC,紫杉醇,(,单周或双周,),两种方案作为乳腺癌辅助化疗的优选方案；,TAC,方案从,2012,版,NCCN,指南推荐的优选方案降至,2013,版,NCCN,指南中的其他可选方案。,乳腺癌,NCCN2012,版指南,不含曲妥珠单抗的优选辅助化疗方案：,TAC(,多西他赛,/,多柔比星,/,环磷酰胺,),AC ,紫杉醇剂量密集双周方案,AC ,紫杉醇每周方案,TC (,多西他赛,/,环磷酰胺,),乳腺癌,NCCN2013,版指南,不含曲妥珠单抗的优选辅助化疗方案：,剂量密集,AC ,紫杉醇剂量密集双周方案,剂量,密集,AC ,紫杉醇每周方案,TC (,多西他赛,/,环磷酰胺,),其他化疗方案,：,TAC(,多西他赛,/,多柔比星,/,环磷酰胺,),NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines),. Breast Cancer. Version 3.2012.,NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines),. Breast Cancer. Version 1.2013.,早期乳腺癌术后辅助化疗,2012版指南 vs.2013版指南乳腺癌的辅助化疗方案中，,56,Budd GT, Barlow WE, Moore HCF, et al. S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. J Clin Oncol 31, 2013 (suppl; abstr CRA1008).,早期乳腺癌术后辅助化疗,Budd GT, Barlow WE, Mo