乳腺癌辅助治疗规范的解读

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1、会计学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237883889295980103058085902000GuidelinesSt. GallenNIHNCCN96yearly07如何掌握、使用？45Adapted from Bonadonna G. Cancer Res. 1992.6Relapse 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 )7Overall survival Bona

2、donna BMJ 330:217, 20058TherapyReduction inAnnual Odds, %RecurrenceDeathPolychemotherapy vs23.515no chemotherapy (1995)(P .00001)(P .00001)Anthracyclines vs1211CMF (1995)(P = .006)(P = .02)Anthracyclines vs10.8 15.7 CMF (2000)(P = .0005)(P .00001)92000 Oxford Overview AnalysisA/E+ vs CMF: All Deaths

3、0.51.52.015.7% (SE 3.)reduction2p 0.00001 Deaths/WomenAllocatedAdjustedA/E+ CMF* A/E+ DeathsLogrankVariance OE of OEYear Codeand Study NameMonths & Treatment76A4 SECSG 26FAC 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.

4、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)-14.8224.784K1 GUN-3 Naples3CMFEV v 6CMF45/10558/115-5.223.784L ICCG Charing Cross8/6FEC v 6CMF20/25632/259-5.511.884Q2 Austrian BCSG 36CMF

5、VA 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)52/14260/146-7.523.687Q1 PRONACAM 874/5CMFEP v 6CMF(no data)88R Brussels Belgium*8EC v 6CMF138/5372(69/267)2.144.188V H San Carlos, Madrid6FAC v 6

6、CMF(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)-31.891.091H NSABP B-23 ER-AC v CMF (+Tam)91/1003100/1005-5.546.891Q GUN MAM1 NaplesZolTaM+(A;CMF v CMF)34/23243/234-3.8

7、18.294J1+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 effect 2p 0.1 ; NS14 1 trial with no data does not contribute to total (allocated A/E+: 211; allocated CMF: 212)

8、* 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)(? Patients)Ratio of annual death ratesA/E+ : CMF101112D.F.Hayes ASCO 2006 Abs510ALLER-HER2-2%(-3,8)8%(

9、-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+13BCIRG 001 Study DesignDocetaxel 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

10、 500 mg bid, day 5-14Every 3 weeks x 6 cyclesStratification: Nodes: 1-3 4+ Center14TACFAC0612182430364248MonthsNumber at RiskTACFAC7457367106786543731522317467296996566053341503105060708090100% Alive and Disease Free# EventsRRp-valueTAC1190.680.0011FAC170Total289Disease Free Survival (ITT)BCIRG 001M

11、edian follow-up: 33 months82%74%15Number at RiskTACFAC745741732718700393171241746738728713678375171331# EventsRRp-valueTAC 570.760.11FAC 76Total133Overall Survival (ITT)BCIRG 001TACFAC0612182430364248Months5060708090100% Alive 92%87%Median follow-up: 33 months16TACFAC012243648MonthsN at RiskTACFAC23

12、12171884702282021583405060708090100% Alive and Disease FreeTACFAC012243648MonthsN at RiskTACFAC514493466105151849744711605060708090100NegativePositiveRR = 0.62p = 0.005RR = 0.68p = 0.0217181920EPI 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

13、N+Taxit216 multicenter phase III trialSequential Epirubicin-Docetaxel-CMF as adjuvant therapy 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 LBA52021Taxi

14、t216 multicenter phase III trialSequential 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 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 adju

15、stement 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 ongoing2223DFSOSJCO 2008, 26(1):4424蒽环类+紫杉类可延生存期JCO 2008, 26(1):4425蒽环类+紫杉类可延生存期JC

16、O 2008, 26(1):44DFSOS26N Engl J Med 2008, 358(16):1663DFS27OSN Engl J Med 2008, 358(16):16632829NCCTG N9831BCIRG 006FISHN+/-ACPDDCarbo标准方案HERAIHC orFISH赫赛汀1或2年观察组NSABP B-31IHC orFISHIHC orFISHIHC, 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)30NSABP B-31NCCTG N9831Arm 1Ar

17、m 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 w31Combined analysis of B31 / N9831ControlHerceptinArm 1 (B31)Arm 2 (B31)Arm A (N9831)Arm C (N9831)Combine

18、d: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 yr3267%75%NEventsACT1679261ACTH 1672134%HR=0.48, 2P=3x10-12ACTYears From RandomizationCombined Analysis for DFS of NSABP B-31 / NCCTG N983133Hazard Ratio0.20.40.60.81.01.21.4Forest

19、Plot For DFS: B31/N9831ProtocolNo.PositiveNodesTumorSizeHormoneReceptorAgeN9831NSABP B-31 4.1cm2.1- 4.0 cm2.0 cmPositiveNegative 6050-5940-4939ALL DATA10+4-91-3034Annual Hazard of Distant Recurrence01234020406080100120Rate per 1000 Women /YrYears From RandomizationACT35Combined Analysis for OS of NS

20、ABP B-31 / NCCTG N9831 87%92%ACTNDeathsACT167992ACTH 167262HR=0.67, 2P=0.015Years From RandomizationB31/N983136DFS: HERA Trial37012AllAny, neo -adjuvant chemotherapyNodal status0 pos, no neo -adjuvant chemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3 pos, no neo -adjuvant chem

21、otherapy4 pos, no neo -adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimenAnthracycline, no taxaneAnthracycline + taxaneNegativeReceptor status/endocrine therapyPos + no endocrine therapyPos + endocrine therapy35 yrs35-49 yrs50-59 yrs60 yrs9729530.510.5316740.5146712340.490.

22、682510.47149010910.520.535490.70AllAny, neo -adjuvant chemotherapyNodal status0 pos, no neo -adjuvant chemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3 pos, no neo -adjuvant chemotherapy4 pos, no neo -adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimen

23、Anthracycline, no taxaneAnthracycline + 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 200

24、7; Smith et al 20074135-49 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 i

25、s 2 % and older than 50 is 5%This analysis from B31data alone.44Risk 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

26、EventControlHerceptin End of Herceptin treatment periodThis analysis from B31 data alone.45Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008 aData not comparable due to different assessment criteriaCHF, congestive heart failure; cum, cumulative incidenceLVEF, left ventricular ej

27、ection 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, n0000046HER2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47ASCO 2008, abst,

28、661148ASCO 2008, abst, 66114950St.Gallen 200351St.Gallen 200352St.Gallen 2003535455AC x 4CMF x 6FAC, FEC x 6CAF, CEF x 6A (E) CMFWithout TaxanesTACAC P or DWith TaxanesH56StandardEfficacySuperiorEfficacyAC x 4CMF x 6FAC, FEC x 6CAF, CEF x 6A (E) CMFWithout TaxanesTACAC P or DWith TaxanesComplexityTo

29、xicityEconomic costBut greaterH57Choice of Adjuvant Regimens58乳腺癌按不同危险度治疗59606162100个月的结果：T 21.8%A17.0%Absolute Difference: 4.8%636465MA.17: Trial Design Primary end point: DFSSecondary end points: OS/safety/QOL*n=2575 (efficacy); 2154 (safety) in the FEMARA arm.n=2582 (efficacy); 2145 (safety) in t

30、he 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 extended adjuvant6680828486889092949698100Year 1Year 1Year 2Year 2Year 3Year 3Year 4Year 4Treatment duration% Disease-free survivalLetrozole

31、(Femara)PlaceboGoss et al. N Engl J Med. 2003;349:TBD.87%93% Increasing benefit in estimated DFS with treatment duration6768697071727374ATACEXEMBIG 1.98(BIG FEMTA)TAMOXIFENAIPLACEBO ARNO(J)MA-17NSABP B33 EXEM 027TEAM EXE7576770 00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91 1A AB BC CD DE

32、EF FTAMATACBIG 1-98IESABCSG/ARNOMA-1710.820.810.60.60.5P-values 0.01 0.003 0.00005 0.0018 0.00008Median follow-up(m) 33 26 30.6 26 28UPFRONT AIDELAYED AI78 Hazard ratio Median Aromatase Disease-free Time to distant Fu(m) inhibitor survival metastases OS 初始治疗：Aromatase inhibitor vs.TAMATAC 100 Anastr

33、ozole 0.85 0.84 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：TAM 5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 1.279

34、19801990200219701-2 years5 yearsTamoxifen3rd generation AISequence of Tam/AI80乳腺癌的内分泌治疗81Endocrine TherapyPROGRESS +ChemotherapyPROGRESS +Biologic TherapyPROGRESS +We need to move to “tailored”Smart clinical trials !2008829th St Gallen 20058310th St Gallen 200784Annals of Oncology, 19:7-10,200885Ann

35、als of Oncology, 19:7-10,200886878889909192个体化治疗93THANK YOU !94Overall survival Bonadonna BMJ 330:217, 200595TACFAC0612182430364248MonthsNumber at RiskTACFAC7457367106786543731522317467296996566053341503105060708090100% Alive and Disease Free# EventsRRp-valueTAC1190.680.0011FAC170Total289Disease Fre

36、e Survival (ITT)BCIRG 001Median follow-up: 33 months82%74%96Taxit216 multicenter phase III trialSequential 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 monthsDFS at 5 years : 67% in arm A vs 74% in arm

37、 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 ongoing97012AllAny

38、, neo -adjuvant chemotherapyNodal status0 pos, no neo -adjuvant chemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3 pos, no neo -adjuvant chemotherapy4 pos, no neo -adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimenAnthracycline, no taxaneAnthracycline

39、+ taxaneNegativeReceptor status/endocrine therapyPos + no endocrine therapyPos + endocrine therapy35 yrs35-49 yrs50-59 yrs60 yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.535490.70AllAny, neo -adjuvant chemotherapyNodal status0 pos, no neo -adjuvant chemotherapy338735811008722032307n0

40、.540.530.520.770.640.43Hazardratio1-3 pos, no neo -adjuvant chemotherapy4 pos, no neo -adjuvant chemotherapyNo anthracycline or taxaneAdjuvant chemotherapy regimenAnthracycline, no taxaneAnthracycline + taxaneNegativeReceptor status/endocrine therapyPos + no endocrine therapyPos + endocrine therapy3

41、5 yrsAge group35-49 yrs50-59 yrs60 yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.535490.70TrastuzumabBetterDFS In Patient Subsets: HERA TrialObservationBetter98012B-31 / N9831 ACPH 3HERA CTxH 1 year2Median follow-up, yearsOverall survival benefitBCIRG 006 ACDH3BCIRG 006 DCarboH3Favour

42、sHerceptinFavours noHerceptinHRSlamon et al 2006 Perez et al 2007; Smith et al 2007H, Herceptin; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR, hazard ratioSize of square represents sample size; horizontal bars indicate 95% confidence intervals99HER2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100101