乳腺癌辅助治疗规范的解读.ppt

1,乳腺癌辅助治疗规范的解读,湖北省肿瘤医院内科 于 丁,2,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,3,Adjuvant Therapy for Breast Cancer Treatment 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？,4,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,5,Adapted from Bonadonna G. Cancer Res. 1992.,All Patients,1 3 5 7 9 11 13 15 years,LOG-RANK : P = 0.002 WILCOXON : P = 0.0001,100 50 0,% Relapse-free survival,CMF Surgery,36% 26%,1 3 5 7 9 11 13 15 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,6,30 years follow up of randomised studies of adjuvant CMF in Operable breast cancer : cohort study,Relapse free survival,Overall survival,Bonadonna BMJ 330:217, 2005,复发相对危险降低 34% HR 0.71 ( P = 0.005 ),各种死亡降低 22% HR 0.79 ( P = 0.04 ),7,30 years follow up of randomised studies of adjuvant CMF in Operable breast cancer : cohort study,Overall survival,Bonadonna BMJ 330:217, 2005,8,Comparative Efficacy of Adjuvant Chemotherapy: EBCTCG Meta-Analyses,Therapy,Reduction in Annual Odds, %,Recurrence,Death,Polychemotherapy vs 23.5 15 no chemotherapy (1995) (P .00001) (P .00001) Anthracyclines vs 12 11 CMF (1995) (P = .006) (P = .02) Anthracyclines vs 10.8 15.7 CMF (2000) (P = .0005) (P .00001),9,2000 Oxford Overview Analysis A/E+ vs CMF: All Deaths,0.5,1.5,2.0,15.7% (SE 3.) reduction 2p 0.00001,Deaths/Women Allocated Adjusted A/E+ CMF*,A/E+ Deaths Logrank Variance OE of OE,Year Code and Study Name,Months & Treatment,76A4 SECSG 2,6FAC v 6CMF,93/260,89/268,-2.9,41.6,78L2 ONCOFRANCE,12FACV v 12CMF,52/138,58/113,-10.9,25.0,80C1 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),-14.8,224.7,84K1 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,-5.5,11.8,84Q2 Austrian BCSG 3,6CMFVA v 6CMF,67/121,75/124,-3.1,30.8,85Y1 PRONACAM85 N+/Pre,FECM v CMF,(no data),86G2 NHG Japan,10FAC c 10CMF ( Tam),(no data),87D4+5+6 GABG 3 Germany,6FEC v 6CMF ( Tam),52/142,60/146,-7.5,23.6,87Q1 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),89B2 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,-10.1,59.1,89W123456c 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,-3.8,18.2,94J1+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 0.00001, 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 rates A/E+ : CMF,10,11,12,HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344,D.F.Hayes ASCO 2006 Abs510,ER+,13,BCIRG 001 Study Design,Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2,5-FU 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2,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,14,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,Disease Free Survival (ITT),BCIRG 001,Median follow-up: 33 months,15,Number at Risk,TAC,FAC,745,741,732,718,700,393,171,24,1,746,738,728,713,678,375,171,33,1,Overall Survival (ITT),BCIRG 001,TAC,FAC,0,6,12,18,24,30,36,42,48,Months,50,60,70,80,90,100,% Alive,Median follow-up: 33 months,16,Disease Free Survival by Hormonal 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 = 0.02,17,18,19,20,EPI 120 mg/m2 D1 Q21D 4C CTX 600 mg/m2 D1,8 MTX 40 mg/m2 D1,8 Q28D 4C 5-FU 600 mg/m2 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/m2 D1 Q21D 4C D 100mg/m2 D1 Q21D 4C CTX 600 mg/m2 D1,8 MTX 40 mg/m2 D1,8 Q28D 4C 5-FU 600 mg/m2 D1,8,B ( E T CMF ) n= 486,A. R. Bianco ASCO 2006 LBA520,21,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,22,23,蒽环类+紫杉类可延生存期,DFS,OS,JCO 2008, 26(1):44,24,蒽环类+紫杉类可延生存期,JCO 2008, 26(1):44,25,蒽环类+紫杉类可延生存期,JCO 2008, 26(1):44,DFS,OS,26,不同紫杉用法的差异,N Engl J Med 2008, 358(16):1663,DFS,27,不同紫杉用法的差异,OS,N Engl J Med 2008, 358(16):1663,28,29,NCCTG N9831,BCIRG 006,FISH N+/-,AC,P,D,DCarbo,标准方案,HERA,IHC or FISH,赫赛汀1或2年,观察组,NSABP B-31,IHC or FISH,IHC or FISH,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,30,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,31,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,32,87%,85%,67%,75%,N Events ACT 1679 261 ACTH 1672 134,%,HR=0.48, 2P=3x10-12,ACTH,ACT,Years From Randomization,Combined Analysis for DFS of NSABP B-31 / NCCTG N9831,33,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 0,34,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,ACTH,ACT,35,Combined Analysis for OS of NSABP B-31 / NCCTG N9831,ACTH,94%,91%,87%,92%,ACT,N Deaths ACT 1679 92 ACTH 1672 62,HR=0.67, 2P=0.015,Years From Randomization,B31/N9831,36,Months from randomization,0,5,10,15,20,25,1693,1428,994,580,280,87,1694,1472,1067,629,303,102,Events,2-yr DFS %,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,37,0,1,2,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,35 yrs,Age group,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,Trastuzumab Better,DFS In Patient Subsets: HERA Trial,Observation Better,38,赫赛汀可减少三分之一的死亡风险,0,1,2,B-31 / N9831 ACPH,3,HERA CTxH 1 year,2,Median follow-up, years,Overall survival benefit,BCIRG 006 ACDH,3,BCIRG 006 DCarboH,3,Favours Herceptin,Favours no Herceptin,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR, hazard ratio,Size of square represents sample size; horizontal bars indicate 95% confidence intervals,39,无论肿瘤大小，赫赛汀均显示DFS获益,Slamon et al 2006 Perez et al 2007; Smith et al 2007,2-5 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,ACDH,2 cm,DCarboH,2 cm,2 cm,2 cm,Favours Herceptin,Favours no Herceptin,HR,HERA,DFS, disease-free survival,40,无论淋巴结情况，赫赛汀均显示DFS获益,N, node,1-3+ nodes,Favours Herceptin,Favours no Herceptin,0.0,0.5,2.5,1.0,1.5,2.0,1-3+ nodes,4+ nodes,Not assessed,N9831 / B-31,N-,4-9+ nodes,10+ nodes,DCarboH,N-,N+,N+,BCIRG 006,N-,ACDH,N-,HERA,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,41,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-31,40 years,60 years,40-49 years,50-59 years,Favours Herceptin,Favours no Herceptin,HR,Perez et al 2007; Smith et al 2007,42,Cardiac Monitoring 20% of the patients discontinued Herceptin because of symptomatic or asymptomatic heart problems,Baseline,3 mns,6 mns,9 mns,18 mns,15 mns,AC * 4,Taxol * 4,Herceptin * 12 mns,2.1%,7.7%,10.1%,% stopping Herceptin by time period,LVEF measurements, 4 % of patients never got Herceptin because of developing a low LVEF post AC * 4.,This analysis from B31data alone.,43,Cardiac Safety Age and Post AC LVEF were predictors of the risk of developing CHF,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.,44,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.,45,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,aData not comparable due to different assessment criteria CHF, congestive heart failure; cum, cumulative incidence LVEF, left ventricular ejection fraction; NR, not reported,3.0 NR NR 18.0 8.6,Asymptomatic LVEF decline, %a,H 1 year ACPH ACPH ACDH DCarboH,Arm,HERA NSABP B-31 NCCTG N9831 BCIRG 006,1,678 947 570 1,068 1,056,n,Severe CHF, %,0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4,Cardiac death, n,0 0 0 0 0,46,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,47,Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries,ASCO 2008, abst, 6611,48,ASCO 2008, abst, 6611,Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries,49,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,50,St.Gallen 2003,51,St.Gallen 2003,52,St.Gallen 2003,53,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,54,55,CHEMOTHERAPY REGIMENS- ST.GALLEN 2005 IMPLICATIONS 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,56,CHEMOTHERAPY REGIMENS- ST.GALLEN 2005 IMPLICATIONS 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,57,Choice of Adjuvant Regimens,58,低危患者： CMF6周期或AC、EC46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,59,Changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for stage I to III breast cancer,60,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,61,62,100个月的结果： T 21.8% A17.0% Absolute Difference: 4.8%,63,64,65,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,66,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,67,68,69,70,71,72,73,74,ATAC,EXEM,BIG 1.98 (BIG FEMTA),TAMOXIFEN,AI,PL