乳腺癌輔助治療規(guī)范的解讀

1、1,乳腺癌輔助治療規(guī)范的解讀,湖北省腫瘤醫(yī)院內科于 丁,2,Treatment Guidelines are useful,Guidelines provide a benchmark and integrate new findings into clinical practiceThey are dynamic documents, which need periodic updateThey are developed t

2、o reduce under-treatment, over-treatment and wrong treatmentCompliance with guidelines has been shown to improve patient outcome,,,3,Adjuvant Therapy for Breast CancerTreatment Guidelines,,,,,,,,,,,78,83,88,92,95,98,01

3、,03,05,,,,,,,80,85,90,2000,,,,,,,,,,Guidelines,St. Gallen,NIH,NCCN,96,yearly,,07,,如何掌握、使用？,4,討論內容,輔助治療對哪些人有益？如何選擇哪種輔助治療方法？化療方案的選擇分子靶向治療作用內分泌治療方法的選擇,,,,,5,,,Adapted from Bonadonna G. Cancer Res. 1992.,All Patients,13

4、579111315 years,LOG-RANK : P = 0.002WILCOXON : P = 0.0001,100500,% Relapse-free survival,CMFSurgery,,,,36%26%,,,13579111315 years,LOG-RANK : P = 0.02WILCOXON : P = 0.02,100500,% O

5、verall survival,CMFSurgery,,,,51%35%,,,Breast Cancer: Adjuvant CMF(12 months) or Surgery Alone,Premenopausal,6,30 year’s follow up of randomised studies of adjuvant CMF in Operable breast cancer : cohort study,Relap

6、se free survival,Overall survival,Bonadonna BMJ 330:217, 2005,復發(fā)相對危險降低 34%HR 0.71 ( P = 0.005 ),各種死亡降低 22%HR 0.79 ( P = 0.04 ),,,7,30 year’s follow up of randomised studies of adjuvant CMF in Operable breast canc

7、er : cohort study,Overall survival,Bonadonna BMJ 330:217, 2005,8,Comparative Efficacy of Adjuvant Chemotherapy: EBCTCG Meta-Analyses,Therapy,Reduction inAnnual Odds, %,Recurrence,Death,,Polychemotherapy vs23.515

8、no chemotherapy (1995)(P < .00001)(P < .00001)Anthracyclines vs1211CMF (1995)(P = .006)(P = .02)Anthracyclines vs10.815.7 CMF (2000)(P = .0005)(P < .00001),,9,2000 Oxf

9、ord Overview AnalysisA/E+ vs CMF: All Deaths,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0.5,1.5,2.0,15.7% (SE 3.)reduction2p < 0.00001,,Deaths/WomenAllocatedAdjustedA/E+ CMF*,,A/E+ DeathsLogrankVariance O–E

10、 of O–E,,Year Codeand 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

11、.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*,4AC±3CMF v 6CMF (+R),716/1562,2(374/776),-14.8,224.7,84K1 GUN-3 Naples,3CMFEV

12、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 10

13、CMF (± 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,

14、 Madrid,6FAC v 6CMF,(no data),89B2 SWOG 8897,6FAC v 6CMF (+R±Tam),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),

15、-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 8CM

16、F,(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 (alloca

17、ted 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 Patie

18、nts),(< 480 Patients),(? Patients),Ratio of annual death ratesA/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

19、,,,ER+,,,,,,,13,,,,BCIRG 001 Study Design,,Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2Cyclophosphamide500 mg/m2,5-FU 500 mg/m2Doxorubicin 50 mg/m2Cyclophosphamide500 mg/m2,R,Dexamethasone premedication, 8 mg bid, 3

20、 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,745,736,710,678,654,373,152,2

21、3,1,746,729,699,656,605,334,150,31,0,,,,,,,,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,745,741,732,718,700,393,171,24,1,746,73

22、8,728,713,678,375,171,33,1,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 byHormonal Status,,

23、,,,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,

24、1,518,497,447,116,0,,,,,,,,50,60,70,80,90,100,Negative,Positive,RR = 0.62p = 0.005,RR = 0.68p = 0.02,17,18,19,20,,,,,EPI 120 mg/m2 D1 Q21D × 4CCTX 600 mg/m2 D1,8 MTX 40 mg/m2

25、 D1,8 Q28D × 4C 5-FU 600 mg/m2 D1,8,R,1998,6-2002,7972 N+,Taxit216 multicenter phase III trialSequential Epirubicin-Docetaxel-CMF as adjuvant therapy of early breast cancer,,A ( E→ CMF ) n= 486,E

26、PI 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 → CM

27、F ) n= 486,,,A. R. Bianco ASCO 2006 LBA520,21,Taxit216 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,

28、 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

29、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,蒽環(huán)類+紫杉類可延生存期,DFS,OS,JCO 2008, 2

30、6(1):44,24,蒽環(huán)類+紫杉類可延生存期,JCO 2008, 26(1):44,25,蒽環(huán)類+紫杉類可延生存期,JCO 2008, 26(1):44,DFS,OS,26,不同紫杉用法的差異,N Engl J Med 2008, 358(16):1663,DFS,27,不同紫杉用法的差異,OS,N Engl J Med 2008, 358(16):1663,28,29,NCCTG N9831,BCIRG 006,FISHN+/

31、-,,,,,AC,P,D,DCarbo,標準方案,HERA,IHC orFISH,,,,赫賽汀1或2年,觀察組,NSABP B-31,,,IHC orFISH,,,,IHC orFISH,IHC, 免疫組織化學;FISH, 熒光原位雜交,赫賽汀治療1年,赫賽汀輔助治療臨床試驗,赫賽汀1年,赫賽汀1年(聯合或序貫),赫賽汀1年(聯合),赫賽汀1年(聯合),AC-T,AC-T,AC-D,TCH,標準方案,30,,,,,,,,,,,,

32、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,NSABP B-31,

33、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

34、 No Herceptin,Arm B,Arm C,,,,,,,,,,,,,,,,,,(1 yr),(2 yr),= trastuzumab q 3 w,,,,,,,,,31,Combined analysis of B31 / N9831,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

35、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Control,Herceptin,Arm 1 (B31),Arm 2 (B31),Arm A (N9831),Arm C (N9831),Combined:n = 3,351; median follow-up 2.0 yrNSABP B-31:n = 1,736; median follow-up 2.4 yrN

36、9831:n = 1,615; median follow-up 1.5 yr,32,,87%,85%,,67%,75%,NEventsAC?T1679261AC?TH1672134,%,HR=0.48, 2P=3x10-12,AC?TH,AC?T,Years From Randomization,Combined Analysis for DFS of NSABP B-31 / NCCTG – N9831,33,

37、,,,,,,,,,,,,,,,Hazard Ratio,,,,,,,,,,,,,,,0.2,0.4,0.6,0.8,1.0,1.2,1.4,Forest Plot For DFS: B31/N9831,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Protocol,No.PositiveNodes,TumorSize,HormoneReceptor,Age,N9831NSABP B-3

38、1,≥ 4.1cm2.1- 4.0 cm<2.0 cm,PositiveNegative,≥6050-5940-49≤39,,,,,ALL DATA,,10+4-91-30,,,,,,,34,Annual Hazard of Distant Recurrence,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,1,2,3,4,0,20,40,60,80,100,120,Rate per 1

39、000 Women /Yr,Years From Randomization,AC?TH,AC?T,35,Combined Analysis for OS of NSABP B-31 / NCCTG – N9831,AC?TH,94%,91%,87%,92%,AC?T,NDeathsAC?T167992AC?TH167262,HR=0.67, 2P=0.015,Years From Randomization,B31

40、/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-yrDFS %,HR,[95% CI],p value,127,85.8,0.54,[0.43, 0.67],<0.0001,220,77.4,,,Trastuzumab

41、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,,3

42、387,,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,,³,4 pos, no neo,-,adjuvant chemotherapy,,No anthracycline or taxane,,Adjuvant chem

43、otherapy 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,,³,60 yrs,,

44、,,,,,,,,,,,,,,,,,,,,,,,,,,,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

45、 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,,³,4 pos, no neo,-,adjuvant chemotherapy,,No anthracycline or tax

46、ane,,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,,5

47、0,-,59 yrs,,³,60 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,,,,,TrastuzumabBetter,,DFS In Patient Subsets: HERA Trial,,,,,,,,

48、,,,,,,,,,,,,,,,,,,,,,,,ObservationBetter,38,赫賽汀可減少三分之一的死亡風險,0,1,2,,B-31 / N9831 AC?PH,3,HERA CTx?H 1 year,2,Median follow-up, years,Overall survival benefit,BCIRG 006 AC?DH,3,BCIRG 006 DCarboH,3,FavoursHerceptin,Favour

49、s noHerceptin,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

50、 sample size; horizontal bars indicate 95% confidence intervals,,39,無論腫瘤大小，赫賽汀均顯示DFS獲益,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.

51、5,2.0,,,,0-2 cm,,N9831 / B-31,,,,0-2 cm,,,,,>5 cm,,AC?DH,<2 cm,,,,,DCarboH,<2 cm,,,,,,,,≥2 cm,,≥2 cm,,,,,Favours Herceptin,Favours no Herceptin,HR,HERA,,,DFS, disease-free survival,40,無論淋巴結情況，赫賽汀均顯示DFS獲益,N, node

52、,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

53、 006,N-,,,,,AC?DH,N-,,,,,HERA,,,HR,Slamon et al 2006 Perez et al 2007; Smith et al 2007,41,無論年齡大小，赫賽汀均顯示DFS獲益,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

54、-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 Herceptinbecause

55、 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

56、 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

57、 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 analysi

58、s 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

59、,This analysis from B31 data alone.,45,Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008,赫賽汀輔助治療的心臟安全性,aData not comparable due to different assessment criteriaCHF, congestive heart failure; cum,

60、 cumulative incidenceLVEF, left ventricular ejection fraction; NR, not reported,,,3.0NRNR18.08.6,Asymptomatic LVEF decline, %a,H 1 yearAC?PHAC?PHAC?DHDCarboH,Arm,,HERANSABP B-31NCCTG N9831 BCIRG 006,1,67894

61、75701,0681,056,n,Severe CHF, %,0.63.8cum (5 yr)3.3cum (3 yr)1.90.4,Cardiac death, n,00000,46,,HER2狀態(tài)判斷,IHC免疫組化FISH熒光原位雜交CISH顯色原位雜交SISH銀染原位雜交,47,Estimation of the epidemiological effect of trastuzumab ov

62、er 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陽性乳腺癌治療原則,使早期乳腺癌患者復發(fā)風險降低36%~52

63、%,死亡風險降低33% AC→T→H: ( H4 mg/kg,與首次T同時使用; 然后H 2 mg/kg維持1年?；騎結束后,H6 mg/kg維持1年 ) 每3周方案, 目前推薦治療時間為1年 在開始治療的第3、6、9、18個月監(jiān)測心臟情況H輔助治療的標準療程為1年,至少應治療6個月以保證患者最大獲益,50,St.Gallen 2003,51,St.Gallen 2003,52,St.Gallen 2003,53,,

64、Evolution of Adjuvant Treatment of Breast Cancer,1970’,1980’,1990’,2000’,,,,非蒽環(huán)類方案,含蒽環(huán)類方案,含紫杉類方案,含赫賽丁方案,,,,54,,,55,CHEMOTHERAPY REGIMENS- ST.GALLEN 2005IMPLICATIONS FOR PATIENT CARE,,,,,,,,,,,,,,AC x 4CMF x 6,,FAC, FEC

65、 x 6CAF, CEF x 6A (E) CMF,,Without Taxanes,,TACAC P or D,,With Taxanes,,H,56,CHEMOTHERAPY REGIMENS- ST.GALLEN 2005IMPLICATIONS FOR PATIENT CARE,,,,,,,,,,,,,,StandardEfficacy,SuperiorEfficacy,AC x 4CMF x

66、 6,,FAC, FEC x 6CAF, CEF x 6A (E) CMF,,Without Taxanes,,TACAC P or D,,With Taxanes,ComplexityToxicityEconomic cost,,But greater,,H,57,Choice of Adjuvant Regimens,58,低?；颊撸?CMF×6周期或AC、EC×4～6周期

67、 中?；颊撸?FAC或FEC×6周期 高?；颊撸?AC→T，FEC×3→T×3， TAC，A→T→C， 密集化療,乳腺癌按不同危險度治療,59,Changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for stage I to II

68、I breast cancer,60,小 結,CMF有最長的遠期療效結果，至今仍用含蒽環(huán)類化療是目前最基礎的標準方案含紫杉類的地位已得到不斷證實及鞏固 (某些亞組的療效待進一步觀察)赫賽丁可增加化療的效果劑量密度已開始動搖了傳統的三周療法,61,62,,,,,100個月的結果：T— 21.8%A—17.0%Absolute Difference: 4.8%,63,,,64,,,,65,MA.17: Trial De