1、乳腺癌辅助治疗规范的解读乳腺癌辅助治疗规范的解读湖北省肿瘤医院内科湖北省肿瘤医院内科于于 丁丁1Treatment 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 Compl
2、iance with guidelines has been shown to improve patient outcome2Adjuvant Therapy for Breast CancerTreatment Guidelines7883889295980103058085902000GuidelinesSt.GallenNIHNCCN96yearly07如何掌握、使用如何掌握、使用？3讨论内容讨论内容 辅助治疗对哪些人有益？辅助治疗对哪些人有益？如何选择哪种辅助治疗方法？如何选择哪种辅助治疗方法？化疗方案的选择化疗方案的选择 分子靶向治疗作用分子靶向治疗作用 内分泌治疗方法的选择内分泌
3、治疗方法的选择4Adapted from Bonadonna G.Cancer Res.1992.Breast Cancer:Adjuvant CMF(12 months)or Surgery Alone530 years follow up of randomised studies of adjuvant CMF in Operable breast cancer:cohort studyRelapse free survival Overall survival Bonadonna BMJ 330:217,2005复发相对危险降低复发相对危险降低 34%HR 0.71 (P=0.005)
4、各种死亡降低各种死亡降低 22%HR 0.79 (P=0.04)630 years follow up of randomised studies of adjuvant CMF in Operable breast cancer:cohort studyOverall survival Bonadonna BMJ 330:217,20057TherapyReduction inAnnual Odds,%RecurrenceDeathPolychemotherapy vs23.515no chemotherapy(1995)(P .00001)(P .00001)Anthracyclines
5、vs1211CMF(1995)(P=.006)(P=.02)Anthracyclines vs10.8 15.7 CMF(2000)(P=.0005)(P .00001)82000 Oxford Overview AnalysisA/E+vs CMF:All Deaths0.51.52.015.7%(SE 3.)reduction2p 0.00001 Deaths/WomenAllocatedAdjustedA/E+CMF*A/E+DeathsLogrankVariance OE of OEYear Codeand Study NameMonths&Treatment76A4 SECSG 26
6、FAC v 6CMF93/26089/268-2.941.678L2 ONCOFRANCE12FACV v 12CMF52/13858/113-10.925.080C1 SE Sweden BCG A8AC v 7CMF(+R)8/2113/22-2.25.080M INT Milan8CMF+4A v 12CMF-/211-/212(no data)83A NSABC Israel Br02832CMF+4AVbCMF v 6CMF23/5521/50-1.310.184B NSABP B-15*4AC3CMF v 6CMF(+R)716/15622(374/776)-14.8224.784
7、K1 GUN-3 Naples3CMFEV v 6CMF45/10558/115-5.223.784L ICCG Charing Cross8/6FEC v 6CMF20/25632/259-5.511.884Q2 Austrian BCSG 36CMFVA v 6CMF67/12175/124-3.130.885Y1 PRONACAM85 N+/PreFECM v CMF(no data)86G2 NHG Japan10FAC c 10CMF(Tam)(no data)87D4+5+6 GABG 3 Germany6FEC v 6CMF(Tam)52/14260/146-7.523.687Q
8、1 PRONACAM 874/5CMFEP v 6CMF(no data)88R Brussels Belgium*8EC v 6CMF138/5372(69/267)2.144.188V H San Carlos,Madrid6FAC v 6CMF(no data)89B2 SWOG 88976FAC v 6CMF(+RTam)173/1461223/1470-25.997.189R NCI-C MA.56FEC v 6CMF118/356135/360-10.159.189W123456c Denmark-Sweden*9FEC V9CMF(+Pmd)150/6010.8(290/781)
9、-31.891.091H NSABP B-23 ER-AC v CMF(+Tam)91/1003100/1005-5.546.891Q GUN MAM1 NaplesZolTaM+(A;CMF v CMF)34/23243/234-3.818.294J1+2+3 GOIRC SANG 2B Italy6CMFEV v 6CMF(+Tam)(no data)Scottish4E;4CMF v 8CMF(no data)1780/6850(26.0%)-128.42019/6906(29.2%)752.5Total*99%or 95%CIA/E+betterCMF betterTreatment
10、effect 2p 0.1;NS14 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.1.00(?Patients)(100 Patients)(322 Patients)(158 Patients)(480 Patients)(?
11、Patients)Ratio of annual death ratesA/E+:CMF91011HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer:CALGB 9344 D.F.Hayes ASCO 2006 Abs510ALLER-HER2-2%(-3,8)8%(-2,18)-1%(-8,5)HER2+22%(12,32)31%(17,44)9%(-6,24)ALL7%(2,12)16%(8,24)0%(-6,7)ER+12BCIRG 001 Study DesignD
12、ocetaxel 75 mg/m2 Doxorubicin 50 mg/m2Cyclophosphamide 500 mg/m25-FU 500 mg/m2Doxorubicin 50 mg/m2Cyclophosphamide 500 mg/m2FACTACRDexamethasone premedication,8 mg bid,3 days Prophylactic Cipro 500 mg bid,day 5-14Every 3 weeks x 6 cyclesStratification:Nodes:1-3 4+Center13TACFAC0612182430364248Months
13、Number at RiskTACFAC7457367106786543731522317467296996566053341503105060708090100%Alive and Disease Free#EventsRRp-valueTAC1190.680.0011FAC170Total289Disease Free Survival(ITT)BCIRG 001Median follow-up:33 months82%74%14Number at RiskTACFAC745741732718700393171241746738728713678375171331#EventsRRp-va
14、lueTAC 570.760.11FAC 76Total133Overall Survival(ITT)BCIRG 001TACFAC0612182430364248Months5060708090100%Alive 92%87%Median follow-up:33 months15Disease Free Survival byHormonal StatusTACFAC012243648MonthsN at RiskTACFAC2312171884702282021583405060708090100%Alive and Disease FreeTACFAC012243648MonthsN
15、 at RiskTACFAC514493466105151849744711605060708090100NegativePositiveRR=0.62p=0.005RR=0.68p=0.0216171819EPI 120 mg/m2 D1 Q21D 4CCTX 600 mg/m2 D1,8 MTX 40 mg/m2 D1,8 Q28D 4C 5-FU 600 mg/m2 D1,8 R1998,6-2002,7972 N+Taxit216 multicenter phase III trialSequential Epirubicin-Docetaxel-CMF as adjuvant the
16、rapy of early breast cancer A (E CMF)n=486EPI 120 mg/m2 D1 Q21D 4CD 100mg/m2 D1 Q21D 4CCTX 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=486A.R.Bianco ASCO 2006 LBA52020Taxit216 multicenter phase III trialSequential Epirubicin-Docetaxel-CMF as adjuvant therapy of early br
17、east cancer A.R.Bianco ASCO 2006 LBA520 As of March 27th 2006,median followup was 53 monthsDFS 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).
18、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 ongoing2122蒽环类蒽环类+紫杉类可延生存期紫杉类可延生存期DFSOSJCO 2008,26(1):4423蒽环类蒽环类+紫杉类可延生存期紫杉类可延生存期JCO 2008,26(1):4424蒽环类蒽环类+紫杉类可延生存期紫杉类可延生存期JCO 2008,26(1):44DFSOS25不同紫杉用法的差异不同紫杉用法的差异N Engl J Med 2008,358(16):1663DFS2
19、6不同紫杉用法的差异不同紫杉用法的差异OSN Engl J Med 2008,358(16):16632728NCCTG N9831BCIRG 006FISHN+/-ACPDDCarbo标准方案标准方案HERAIHC orFISH赫赛汀赫赛汀1或或2年年观察组观察组NSABP B-31IHC orFISHIHC orFISHIHC,免疫组织化学免疫组织化学;FISH,荧光原位杂交荧光原位杂交 赫赛汀赫赛汀治疗治疗1年年赫赛汀辅助治疗赫赛汀辅助治疗临床试验临床试验赫赛汀赫赛汀1年年赫赛汀赫赛汀1年年(联合或序贯联合或序贯)赫赛汀赫赛汀1年年(联合联合)赫赛汀赫赛汀1年年(联合联合)29NSABP
20、 B-31NCCTG N9831Arm 1Arm 2Arm AArm BArm CAC q 3 wk*4=paclitaxel q 3 wk*4=paclitaxel q 1 wk*12=trastuzumab q 1 wHERA(Randomization after chemotherapy)Arm A No HerceptinArm BArm C(1 yr)(2 yr)=trastuzumab q 3 w30Combined analysis of B31/N9831ControlHerceptinArm 1(B31)Arm 2(B31)Arm A(N9831)Arm C(N9831)C
21、ombined:n=3,351;median follow-up 2.0 yrNSABP B-31:n=1,736;median follow-up 2.4 yrN9831:n=1,615;median follow-up 1.5 yr3167%75%NEventsACT1679261ACTH1672134%HR=0.48,2P=3x10-12ACTYears From RandomizationCombined Analysis for DFS of NSABP B-31/NCCTG N983132Hazard Ratio0.20.40.60.81.01.21.4Forest Plot Fo
22、r DFS:B31/N9831ProtocolNo.PositiveNodesTumorSizeHormoneReceptorAgeN9831NSABP B-31 4.1cm2.1-4.0 cm2.0 cmPositiveNegative 6050-5940-4939ALL DATA10+4-91-3033Annual Hazard of Distant Recurrence01234020406080100120Rate per 1000 Women/YrYears From RandomizationACT34Combined Analysis for OS of NSABP B-31/N
23、CCTG N9831 87%92%ACTNDeathsACT167992ACTH 167262HR=0.67,2P=0.015Years From RandomizationB31/N983135DFS:HERA Trial36012AllAny,neo-adjuvant chemotherapyNodal status0 pos,no neo-adjuvant chemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3 pos,no neo-adjuvant chemotherapy 4 pos,no ne
24、o-adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimenAnthracycline,no taxaneAnthracycline+taxaneNegativeReceptor status/endocrine therapyPos+no endocrine therapyPos+endocrine therapy35 yrs35-49 yrs50-59 yrs 60 yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.5354
25、90.70AllAny,neo-adjuvant chemotherapyNodal status0 pos,no neo-adjuvant chemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3 pos,no neo-adjuvant chemotherapy 4 pos,no neo-adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimenAnthracycline,no taxaneAnthracycli
26、ne+taxaneNegativeReceptor status/endocrine therapyPos+no endocrine therapyPos+endocrine therapy2-5 cmBCIRG 0062-5 cm5 cm0.00.52.51.01.52.00-2 cmN9831/B-310-2 cm5 cmACDH2 cmDCarboH10+nodesDCarboHN-N+N+BCIRG 006N-ACDHN-HERAHRSlamon et al 2006 Perez et al 2007;Smith et al 200740无论年龄大小，赫赛汀均显示无论年龄大小，赫赛汀均
27、显示DFSDFS获益获益35-49 years0.00.52.51.01.52.0HERA35 years50-59 years60 yearsN9831/B-31 650.6%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
28、 50 is 5%This analysis from B31data alone.43Risk 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.0 01 12 23 34 45 50 01 12 23 3Years Since Starting Herceptin%Risk of Cardiac EventControlHerceptin E
29、nd of Herceptin treatment periodThis analysis from B31 data alone.44Slamon 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赫赛汀辅助治疗的心脏安全性aData not comparable due to different assessment criteriaCHF,congestive heart failure;cum,cumulative incidenceLVEF,left ventricular eje
30、ction fraction;NR,not reported 3.0NRNR18.08.6Asymptomatic LVEF decline,%aH 1 yearACPHACPHACDHDCarboHArmHERANSABP B-31NCCTG N9831 BCIRG 0061,6789475701,0681,056nSevere CHF,%0.63.8cum(5 yr)3.3cum(3 yr)1.90.4Cardiac death,n0000045HER2状态判断状态判断 IHC免疫组化免疫组化FISH荧光原位杂交荧光原位杂交CISH显色原位杂交显色原位杂交SISH银染原位杂交银染原位杂交4
31、6Estimation of the epidemiological effect of trastuzumab over 20 years in five European countriesASCO 2008,abst,661147ASCO 2008,abst,6611Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries48HER2阳性乳腺癌治疗原则阳性乳腺癌治疗原则 使早期乳腺癌患者复发风险降低使早期乳腺癌患者复发风险降低36%52%,死亡风险死亡风
32、险降低降低33%ACTH:(H4 mg/kg,与首次与首次T同时使用同时使用;然后然后H 2 mg/kg维持维持1年。或年。或T结束后结束后,H6 mg/kg维持维持1年年)每每3周方案周方案,目前推荐治疗时间为目前推荐治疗时间为1年年 在开始治疗的第在开始治疗的第3、6、9、18个月监测心脏情况个月监测心脏情况 H辅助治疗的标准疗程为辅助治疗的标准疗程为1年年,至少应治疗至少应治疗6个月以保个月以保证患者最大获益证患者最大获益 49St.Gallen 200350St.Gallen 200351St.Gallen 2003525354CHEMOTHERAPY REGIMENS-ST.GALL
33、EN 2005IMPLICATIONS FOR PATIENT CAREAC x 4CMF x 6FAC,FEC x 6CAF,CEF x 6A(E)CMFWithout TaxanesTACAC P or DWith TaxanesH55CHEMOTHERAPY REGIMENS-ST.GALLEN 2005IMPLICATIONS FOR PATIENT CAREStandardEfficacySuperiorEfficacyAC x 4CMF x 6FAC,FEC x 6CAF,CEF x 6A(E)CMFWithout TaxanesTACAC P or DWith TaxanesCo
34、mplexityToxicityEconomic costBut greaterH56Choice of Adjuvant Regimens57 低危患者：低危患者：CMF6周期或周期或AC、EC46周期周期 中危患者：中危患者：FAC或或FEC6周期周期 高危患者：高危患者：ACT，FEC3T3，TAC，ATC，密集化疗密集化疗 乳腺癌按不同危险度治疗乳腺癌按不同危险度治疗58Changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for st
35、age I to III breast cancer59小小 结结 CMF有最长的远期疗效结果，至今仍用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某些亚组的疗效待进一步观察)赫赛丁可增加化疗的效果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剂量密度已开始动摇了传统的三周疗法6061100个月的结果：个月的结果：T 21.8%A17.0%Absolute Difference:4.8%626364MA.17:Trial Des
36、ign Primary end point:DFSSecondary 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)TamoxifenPlacebo qdFEMARA(Letrozole)2.5 mg qd*5 years early adjuvant5 years exten
37、ded adjuvant65MA.17 Results:Disease-Free Survival by Treatment Duration(contd)80828486889092949698100Year 1Year 1Year 2Year 2Year 3Year 3Year 4Year 4Treatment duration%Disease-free survivalLetrozole(Femara)PlaceboGoss et al.N Engl J Med.2003;349:TBD.87%93%Increasing benefit in estimated DFS with tre
38、atment duration6667686970717273ATACEXEMBIG 1.98(BIG FEMTA)TAMOXIFENAIPLACEBO ARNO(J)MA-17NSABP B33 EXEM 027TEAM EXETrial Strategies in Adjuvant Therapy:AIs747576AI.Adjuvant Trials:DFS0 00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91 1A AB BC CD DE EF FTAMATACBIG 1-98IESABCSG/ARNOMA-1710.820
39、.810.60.60.5P-values 0.01 0.003 0.00005 0.0018 0.00008Median follow-up(m)33 26 30.6 26 28UPFRONT AIDELAYED AI77AI与与TAM的随机对照临床试验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：初始治疗：Aromatase inhibitor vs.TAMATAC 100 Anastrozole 0.85 0.84
40、 0.97BIG 1-98 51 Letozole 0.82 0.81 0.91IES 56 Exemestane 0.76 0.83 0.85ABCSG-8/ARNO-95 28 Anastrozole 0.60 0.54 NRITA 64 Anastrozole 0.56 NR NR 序贯治疗：序贯治疗：TAM 5年后年后Aromatase inhibitorMA.17 30 Letozole 0.58 0.60 0.82ABCSG 6a 60 Anastrozol 0.62 0.53 0.89NSABP B-33 30 Exemestane 0.68 0.69 1.278Endocrin
41、e Treatment Strategies in Early Breast Cancer(Postmenopausal women)19801990200219701-2 years5 yearsTamoxifen3rd generation AISequence of Tam/AI79乳腺癌的内分泌治疗乳腺癌的内分泌治疗80Systemic Treatment Modalities in Early Stage Breast CancerCONCLUSIONEndocrine TherapyPROGRESS+ChemotherapyPROGRESS+Biologic TherapyPROG
42、RESS+We need to move to“tailored”Smart clinical trials!200881乳腺癌危险度乳腺癌危险度9th St Gallen 200582乳腺癌危险度乳腺癌危险度10th St Gallen 200783Treatment recommendation for“houmone-responsive”tumous Primary Breast Cancer:ESMO Clinical RecommendationAnnals of Oncology,19:7-10,200884Adjuvant ChemotherapyPrimary Breast Cancer:ESMO Clinical RecommendationAnnals of Oncology,19:7-10,20088586Prognosis8788899091个体化治疗个体化治疗92THANK YOU!93
