乳腺癌辅助治疗规范的解读.ppt

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,*,*,*,乳腺癌辅助治疗规范的解读,湖北省肿瘤医院内科,于 丁,1,Treatment Guidelines are useful,Guidelines provide a benchmark and integrate new findings into clinical practice,They are dynamic documents,which need periodic update,They are developed to reduce under-treatment,over-treatment and wrong treatment,Compliance with guidelines has been shown to improve patient outcome,2,Adjuvant Therapy for Breast CancerTreatment Guidelines,78,83,88,92,95,98,01,03,05,80,85,90,2000,Guidelines,St.Gallen,NIH,NCCN,96,yearly,07,如何掌握、使用,？,3,讨论内容,辅助治疗对哪些人有益？,如何选择哪种辅助治疗方法？,化疗方案的选择,分子靶向治疗作用,内分泌治疗方法的选择,4,Adapted from Bonadonna G.,Cancer Res.,1992.,All Patients,13579111315 years,LOG-RANK:P=0.002,WILCOXON:P=0.0001,100,50,0,%Relapse-free survival,CMF,Surgery,36%,26%,13579111315 years,LOG-RANK:P=0.02,WILCOXON:P=0.02,100,50,0,%Overall survival,CMF,Surgery,51%,35%,Breast Cancer:Adjuvant CMF(12 months)or Surgery Alone,Premenopausal,5,Comparative Efficacy of Adjuvant Chemotherapy:EBCTCG Meta-Analyses,Therapy,Reduction inAnnual Odds,%,Recurrence,Death,Polychemotherapy vs23.515no chemotherapy(1995)(,P,.00001)(,P,.00001),Anthracyclines vs1211CMF(1995)(,P,=.006)(,P,=.02),Anthracyclines vs10.815.7 CMF(2000)(,P,=.0005)(,P,.00001),8,2000 Oxford Overview AnalysisA/E+vs CMF:All Deaths,0.5,1.5,2.0,15.7%(SE 3.)reduction2p 0.00001,Deaths/Women,AllocatedAdjustedA/E+CMF*,A/E+Deaths,LogrankVariance OE of OE,Year Codeand Study Name,Months&Treatment,76A,4,SECSG 2,6FAC v 6CMF,93/260,89/268,-2.9,41.6,78L,2,ONCOFRANCE,12FACV v 12CMF,52/138,58/113,-10.9,25.0,80C,1,SE Sweden BCG A,8AC v 7CMF(+R),8/21,13/22,-2.2,5.0,80M INT Milan,8CMF+4A v 12CMF,-/211,-/212,(no data),83A NSABC Israel Br0283,2CMF+4AVbCMF v 6CMF,23/55,21/50,-1.3,10.1,84B NSABP B-15*,4AC3CMF v 6CMF(+R),716/1562,2(374/776),-14.8,224.7,84K,1,GUN-3 Naples,3CMFEV v 6CMF,45/105,58/115,-5.2,23.7,84L ICCG Charing Cross,8/6FEC v 6CMF,20/256,32/259,-5.5,11.8,84Q,2,Austrian BCSG 3,6CMFVA v 6CMF,67/121,75/124,-3.1,30.8,85Y,1,PRONACAM85,N+/Pre,FECM v CMF,(no data),86G,2,NHG Japan,10FAC c 10CMF(Tam),(no data),87D,4+5+6,GABG 3 Germany,6FEC v 6CMF(Tam),52/142,60/146,-7.5,23.6,87Q,1,PRONACAM 87,4/5CMFEP v 6CMF,(no data),88R Brussels Belgium*,8EC v 6CMF,138/537,2(69/267),2.1,44.1,88V H San Carlos,Madrid,6FAC v 6CMF,(no data),89B,2,SWOG 8897,6FAC v 6CMF(+RTam),173/1461,223/1470,-25.9,97.1,89R NCI-C MA.5,6FEC v 6CMF,118/356,135/360,-10.1,59.1,89W,123456c,Denmark-Sweden*,9FEC V9CMF(+Pmd),150/601,0.8(290/781),-31.8,91.0,91H NSABP B-23,ER-,AC v CMF(+Tam),91/1003,100/1005,-5.5,46.8,91Q GUN MAM1 Naples,ZolTaM+(A;CMF v CMF),34/232,43/234,-3.8,18.2,94J,1+2+3,GOIRC SANG 2B Italy,6CMFEV v 6CMF(+Tam),(no data),Scottish,4E;4CMF v 8CMF,(no data),1780/6850(26.0%),-128.4,2019/6906(29.2%),752.5,Total*,99%or 95%CI,A/E+better,CMF better,Treatment effect 2p 0.1;NS,14,1 trial with no data does not contribute to total(allocated A/E+:211;allocated CMF:212),*For balance,control patients in 3-way trial strata count half or twice in subtotal(s)and in final total of events/women.,1.0,0,(?Patients),(100 Patients),(322 Patients),(158 Patients),(480 Patients),(?Patients),Ratio of annual death ratesA/E+:CMF,9,10,11,HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer:CALGB 9344,D.F.Hayes ASCO 2006 Abs510,ALL,ER-,HER2-,2%(-3,8),8%(-2,18),-1%(-8,5),HER2+,22%(12,32),31%(17,44),9%(-6,24),ALL,7%(2,12),16%(8,24),0%(-6,7),ER+,12,BCIRG 001 Study Design,Docetaxel 75 mg/m,2,Doxorubicin 50 mg/m,2,Cyclophosphamide500 mg/m,2,5-FU 500 mg/m,2,Doxorubicin 50 mg/m,2,Cyclophosphamide500 mg/m,2,F,A,C,T,A,C,R,Dexamethasone premedication,8 mg bid,3 days,Prophylactic Cipro,500 mg bid,day 5-14,Every 3 weeks x 6 cycles,Stratification:,Nodes:1-3 4+,Center,13,TAC,FAC,0,6,12,18,24,30,36,42,48,Months,Number at Risk,TAC,FAC,745,736,710,678,654,373,152,23,1,746,729,699,656,605,334,150,31,0,50,60,70,80,90,100,%Alive and Disease Free,#Events,RR,p-value,TAC,119,0.68,0.0011,FAC,170,Total,289,Disease Free Survival(ITT),BCIRG 001,Median follow-up:33 months,82%,74%,14,Number at Risk,TAC,FAC,745,741,732,718,700,393,171,24,1,746,738,728,713,678,375,171,33,1,#Events,RR,p-value,TAC,57,0.76,0.11,FAC,76,Total,133,Overall Survival(ITT),BCIRG 001,TAC,FAC,0,6,12,18,24,30,36,42,48,Months,50,60,70,80,90,100,%Alive,92%,87%,Median follow-up:33 months,15,Disease Free Survival byHormonal Status,TAC,FAC,0,12,24,36,48,Months,N at Risk,TAC,FAC,231,217,188,47,0,228,202,158,34,0,50,60,70,80,90,100,%Alive and Disease Free,TAC,FAC,0,12,24,36,48,Months,N at Risk,TAC,FAC,514,493,466,105,1,518,497,447,116,0,50,60,70,80,90,100,Negative,Positive,RR=0.62,p=0.005,RR=0.68,p=0.02,16,17,18,19,EPI 120 mg/m,2,D1 Q21D 4C,CTX 600 mg/m,2,D1,8 MTX 40 mg/m,2,D1,8 Q28D 4C,5-FU 600 mg/m,2,D1,8,R,1998,6-2002,7,972 N+,Taxit216 multicenter phase III trial,Sequential Epirubicin-Docetaxel-CMF as adjuvant therapy of early breast cancer,A (E CMF)n=486,EPI 120 mg/m,2,D1 Q21D 4C,D 100mg/m2 D1 Q21D 4C,CTX 600 mg/m,2,D1,8 MTX 40 mg/m,2,D1,8 Q28D 4C,5-FU 600 mg/m,2,D1,8,B (E T CMF)n=486,A.R,.,Bianco ASCO 2006 LBA520,20,Taxit216 multicenter phase III trial,Sequential Epirubicin-Docetaxel-CMF as adjuvant therapy of early breast cancer,A.R,.,Bianco ASCO 2006 LBA520,As of March 27th 2006,median followup was 53 months,DFS at 5 years:,67%in arm A,vs,74%in arm B,Hazard Ratio(HR)of 0.80(95%CI:0.62-1.03,p=0.079),After,adjustement,by predefined balancing factors,(ER,Nodal and menopausal status),HR was 0.78(95%CIs:0.61-1.00;p=0.05).,As for OS,117 deaths were observed with HR of 0.74,(95%CIs:0.51-1.07,p=0.10),Followup,update is still ongoing,21,22,蒽环类+紫杉类可延生存期,DFS,OS,JCO 2008,26(1):44,23,蒽环类+紫杉类可延生存期,JCO 2008,26(1):44,24,蒽环类+紫杉类可延生存期,JCO 2008,26(1):44,DFS,OS,25,不同紫杉用法的差异,N Engl J Med 2008,358(16):1663,DFS,26,不同紫杉用法的差异,OS,N Engl J Med 2008,358(16):1663,27,28,NCCTG N9831,BCIRG 006,FISH,N+/-,AC,P,D,DCarbo,标准方案,HERA,IHC orFISH,赫赛汀,1或2年,观察组,NSABP B-31,IHC orFISH,IHC orFISH,IHC,免疫组织化学;,FISH,荧光原位杂交,赫赛汀,治疗1年,赫赛汀辅助治疗临床试验,赫赛汀,1年,赫赛汀,1年,(,联合或序贯,),赫赛汀,1年,(,联合,),赫赛汀,1年,(,联合,),AC-T,AC-T,AC-D,TCH,标准方案,29,NSABP B-31,NCCTG N9831,Arm 1,Arm 2,Arm A,Arm B,Arm C,AC q 3 wk*4,=paclitaxel q 3 wk*4,=paclitaxel q 1 wk*12,=trastuzumab q 1 w,HERA,(Randomization after chemotherapy),Arm A,No Herceptin,Arm B,Arm C,(1 yr),(2 yr),=trastuzumab q 3 w,30,Combined analysis of B31/N9831,Control,Herceptin,Arm 1(B31),Arm 2(B31),Arm A(N9831),Arm C(N9831),Combined:n=3,351;median follow-up 2.0 yr,NSABP B-31:n=1,736;median follow-up 2.4 yr,N9831:n=1,615;median follow-up 1.5 yr,31,87%,85%,67%,75%,NEvents,AC,T1679261,AC,TH1672134,%,HR=0.48,2P=3x10,-12,AC,TH,AC,T,Years From Randomization,Combined Analysis for,DFS,of,NSABP B-31/NCCTG N9831,32,Hazard Ratio,0.2,0.4,0.6,0.8,1.0,1.2,1.4,Forest Plot For,DFS,:B31/N9831,Protocol,No.,Positive,Nodes,Tumor,Size,Hormone,Receptor,Age,N9831,NSABP B-31,4.1cm,2.1-4.0 cm,2.0 cm,Positive,Negative,60,50-59,40-49,39,ALL DATA,10+,4-9,1-3,0,33,Annual Hazard of Distant Recurrence,0,1,2,3,4,0,20,40,60,80,100,120,Rate per 1000 Women/Yr,Years From Randomization,AC,TH,AC,T,34,Combined Analysis for,OS,of,NSABP B-31/NCCTG N9831,AC,TH,94%,91%,87%,92%,AC,T,NDeaths,AC,T167992,AC,TH167262,HR=0.67,2P=0.015,Years From Randomization,B31/N9831,35,Months from randomization,0,5,10,15,20,25,1693,1428,994,580,280,87,1694,1472,1067,629,303,102,Events,2-yrDFS%,HR,95%CI,p value,127,85.8,0.54,0.43,0.67,0.0001,220,77.4,Trastuzumab 1 yr,Observation,%alive and disease free,100,90,80,70,60,50,40,30,20,10,0,No.at risk,DFS:HERA Trial,36,0,1,2,All,Any,neo,-,adjuvant chemotherapy,Nodal,status,0 pos,no neo,-,adjuvant chemotherapy,3387,358,1100,872,203,2307,n,0.54,0.53,0.52,0.77,0.64,0.43,Hazard,ratio,1,-,3 pos,no neo,-,adjuvant chemotherapy,4 pos,no neo,-,adjuvant chemotherapy,No anthracycline or taxane,Adjuvant chemotherapy regimen,Anthracycline,no taxane,Anthracycline+taxane,Negative,Receptor status/endocrine therapy,Pos+no endocrine therapy,Pos+endocrine therapy,35 yrs,35,-,49 yrs,50,-,59 yrs,60 yrs,972,953,0.51,0.53,1674,0.51,467,1234,0.49,0.68,251,0.47,1490,1091,0.52,0.53,549,0.70,All,Any,neo,-,adjuvant chemotherapy,Nodal,status,0 pos,no neo,-,adjuvant chemotherapy,3387,358,1100,872,203,2307,n,0.54,0.53,0.52,0.77,0.64,0.43,Hazard,ratio,1,-,3 pos,no neo,-,adjuvant chemotherapy,4 pos,no neo,-,adjuvant chemotherapy,No anthracycline or taxane,Adjuvant chemotherapy regimen,Anthracycline,no taxane,Anthracycline+taxane,Negative,Receptor status/endocrine therapy,Pos+no endocrine therapy,Pos+endocrine therapy,2-5 cm,BCIRG 006,2-5 cm,5 cm,0.0,0.5,2.5,1.0,1.5,2.0,0-2 cm,N9831/B-31,0-2 cm,5 cm,AC,DH,2 cm,DCarboH,10+nodes,DCarboH,N-,N+,N+,BCIRG 006,N-,AC,DH,N-,HERA,HR,Slamon et al 2006 Perez et al 2007;Smith et al 2007,40,无论年龄大小，赫赛汀均显示,DFS,获益,35-49 years,0.0,0.5,2.5,1.0,1.5,2.0,HERA,35 years,50-59 years,60 years,N9831/B-31,65,0.6%,1.3,%,In both age groups about 10%of the patients had a LVEF of 50-54,about 50%of the patients had a LVEF of 55-64,and 35%had a LVEF of,65%.Average risk of early CHF for patient younger than 50 is 2%and older than 50 is 5%,This analysis from B31data alone,.,43,Risk of Cardiac Events,(no strong evidence of an major delayed toxicity),The only cardiac death that occurred during this study occurred in a control patient.,End of Herceptin treatment period,This analysis from B31 data alone.,44,Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008,赫赛汀辅助治疗的心脏安全性,a,Data not comparable due to different assessment criteriaCHF,congestive heart failure;,cum,cumulative incidenceLVEF,left ventricular ejection fraction;NR,not reported,3.0,NR,NR,18.0,8.6,Asymptomatic LVEF decline,%,a,H 1 year,AC,PH,AC,PH,AC,DH,DCarboH,Arm,HERA,NSABP B-31,NCCTG N9831,BCIRG 006,1,678,947,570,1,068,1,056,n,Severe CHF,%,0.6,3.8,cum(5 yr),3.3,cum(3 yr),1.9,0.4,Cardiac death,n,0,0,0,0,0,45,HER2,状态判断,IHC免疫组化,FISH荧光原位杂交,CISH显色原位杂交,SISH银染原位杂交,46,Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries,ASCO 2008,abst,6611,47,ASCO 2008,abst,6611,Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries,48,HER2,阳性乳腺癌治疗原则,使早期乳腺癌患者复发风险降低36%52%,死亡风险降低33%,ACTH:(H4 mg/kg,与首次T同时使用;然后H 2 mg/kg维持1年。或T结束后,H6 mg/kg维持1年),每3周方案,目前推荐治疗时间为1年,在开始治疗的第3、6、9、18个月监测心脏情况,H辅助治疗的标准疗程为1年,至少应治疗6个月以保证患者最大获益,49,St.Gallen 2003,50,St.Gallen 2003,51,St.Gallen 2003,52,Evolution of Adjuvant Treatment of Breast Cancer,1970,1980,1990,2000,非蒽环类方案,含蒽环类方案,含紫杉类方案,含赫赛丁方案,53,54,CHEMOTHERAPY REGIMENS-ST.GALLEN 2005IMPLICATIONS FOR PATIENT CARE,AC,x 4,CMF x 6,FAC,FEC,x 6,CAF,CEF x 6,A(E)CMF,Without Taxanes,TAC,AC P or D,With Taxanes,H,55,CHEMOTHERAPY REGIMENS-ST.GALLEN 2005IMPLICATIONS FOR PATIENT CARE,Standard,Efficacy,Superior,Efficacy,AC,x 4,CMF x 6,FAC,FEC,x 6,CAF,CEF x 6,A(E)CMF,Without Taxanes,TAC,AC P or D,With Taxanes,Complexity,Toxicity,Economic cost,But greater,H,56,Choice of Adjuvant Regimens,57,低危患者：,CMF6,周期或,AC,、,EC4,6,周期,中危患者：,FAC,或,FEC6,周期,高危患者：,ACT,，,FEC3T3,，,TAC,，,ATC,，,密集化疗,乳腺癌按不同危险度治疗,58,Changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for stage I to III breast cancer,59,小 结,CMF有最长的远期疗效结果，至今仍用,含蒽环类化疗是目前最基础的标准方案,含紫杉类的地位已得到不断证实及巩固,(某些亚组的疗效待进一步观察),赫赛丁可增加化疗的效果,剂量密度已开始动摇了传统的三周疗法,60,61,100个月的结果：,T 21.8%,A17.0%,Absolute Difference:4.8%,62,63,64,MA.17:Trial Design,Primary end point:DFS,Secondary end points:OS/safety/QOL,*n=2575(efficacy);2154(safety)in the FEMARA arm.,n=2582(efficacy);2145(safety)in the placebo arm.,Goss et al.,N Engl J Med,.2003;349:TBD.,Randomization,(Disease-free),Tamoxifen,Placebo qd,FEMARA(Letrozole)2.5 mg qd*,5 years early adjuvant,5 years extended adjuvant,65,MA.17 Results:Disease-Free Survival by Treatment Duration(contd),Goss et al.,N Engl J Med,.2003;349:TBD.,87%,93%,Increasing benefit in estimated DFS with treatment duration,66,67,68,69,70,71,72,73,ATAC,EXEM,BIG 1.98,(BIG FEMTA),TAMOXIFEN,AI,PLACEBO,ARNO,(J)MA-17,NSABP B33,EXEM 027,TEAM EXE,Trial Strategies in Adjuvant Therapy:AIs,74,75,76,AI.Adjuvant Trials:DFS,TAM,ATAC,BIG 1-98,IES,ABCSG,/ARNO,MA-17,1,0.82,0.81,0.6,0.6,0.5,P-values,0.01 0.003 0.00005,0.0018 0.00008,Median follow-up(m)33 26 30.6 26 28,UPFRONT AI,DELAYED AI,77,AI与TAM的随机对照临床试验,Hazard ratio,Median Aromatase Disease-free Time to distant,Fu(m)inhibitor survival metastases OS,初始治疗：,Aromatase inhibitor vs.TAM,ATAC 100 Anastrozole 0.85 0.84 0.97,BIG 1-98 51 Letozole 0.82 0.81 0.91,IES 56 Exemestane 0.76 0.83 0.85,ABCSG-8/ARNO-95 28 Anastrozole 0.60 0.54 NR,ITA 64 Anastrozole 0.56 NR NR,序贯治疗：,TAM 5年后Aromatase inhibitor,MA.17 30 Letozole 0.58 0.60 0.82,ABCSG 6a 60 Anastrozol 0.62 0.53 0.89,NSABP B-33 30 Exemestane 0.68 0.69 1.2,78,Endocrine Treatment Strategies in Early Breast Cancer,(Postmenopausal women),1980,1990,2002,1970,1-2 years,5 years,Tamoxifen,3,rd,generation AI,Sequence of Tam/AI,79,乳腺癌的内分泌治疗,80,Systemic Treatment Modalities in Early Stage Breast CancerCONCLUSION,Endocrine Therapy,PROGRESS+,Chemotherapy,PROGRESS+,Biologic Therapy,PROGRESS+,We need to move to“tailored”,Smart clinical trials!,2008,81,乳腺癌危险度,9th,St,Gallen 2005,82,乳腺癌危险度,10th,St,Gallen 2007,83,Treatment recommendation for“houmone-responsive”tumous,Primary Breast Cancer:ESMO Clinical Recommendation,Annals of Oncology,19:7-10,2008,84,Adjuvant Chemotherapy,Primary Breast Cancer:ESMO Clinical Recommendation,Annals of Oncology,19:7-10,2008,85,86,Prognosis,87,88,89,90,91,个体化治疗,92,THANK YOU!,93,