乳腺癌化疗进展.ppt

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1、乳腺癌的辅助化疗,乳腺癌的内科治疗,乳腺癌是女性最常见的肿瘤，女性肿瘤死因第二位。美国85岁以下女性每9人中1人患乳腺癌。乳腺癌是一种全身性疾病，在乳腺癌早期可能存在着微小转移灶，除0或1期较早的病人以外，几乎各期病人都在一定时期需要内科治疗。早期乳腺癌经过综合治疗，可以治愈，但是有超过1/3的患者会发展成为晚期。5%的转移性乳腺癌能够长期生存，患者的中位中位生存时间2-3年，治疗的目的是姑息性，旨在控制肿瘤，减轻症状，高质量地延长生存,内科治疗主要包括化疗和内分泌治疗，单克隆抗体等。乳癌的内科治疗在减少复发，控制症状，提高生存质量，延长生存等方面都已经取得了很大的进步。乳腺癌综合治疗在成人实

2、体瘤中最具有临床意义。,早期乳腺癌的辅助化疗,辅助化疗的作用辅助化疗的适应症如何选择化疗方案,早期乳腺癌联合化疗EBCTCG Overview of randomized trials(1998),化疗减少复发主要出现在头5年,减少死亡持续在头10年.化疗减少淋巴结阴性或淋巴结阳性的死亡相等.与年龄性观的疗效,与月经状态,ER状态,和TAM的使用无关.,乳腺癌辅助化疗的适应症,NIH Consensus Development Conference 2000 4th,大多数局限期乳癌，只要肿瘤直径 1 cm，无论病人有无绝经，淋巴结有无转移，以及激素受体状况，都应该接受辅助化疗。对于肿瘤 1c

3、m，淋巴结阴性病人，是否需要化疗应个体化。,2003年St Gallen 会议精要,第8届St Gallen 会议早期乳腺癌治疗专家共识,Difinition of Risk for Patients With Node-Negative Breast Cancer,Adjuvant Systemic Teatment for Patients With Oprable Breast Cancer,Treatment According to Responsiveness to Edocrine Therapy,Endocrine-Response Disease,Endocrine-Nonr

4、esponse Disease,Premenopausal Postmenopausal,Premenopausal Postmenopausal,Risk Group,乳腺癌辅助化疗方案,CMF（Milan）最早的 化疗方案，改善DFS和OS，通常化疗6个月。含蒽环类较无蒽环类方案显著减少复发（12%）和死亡率（11%）（1995 EBCTCG）。NSABP:AC4 vs CMF 6复发率和死亡率无差别AC Taxol 显示减少复发和死亡率，进一步的研究正在进行中。,乳腺癌常用辅助化疗方案,CMF CTX 100mg/m2 po d1-14 MTX 40mg/m2 IV d1,d8 5-FU

5、 600mg/m2 IV d1,d8CAF CTX 500mg/m2 IV D1,d8 ADR 30mg/m2 IV d1,d8 5-FU 500mg/m2 IV d1,d8 q4wor CTX 500mg/m2 IV d1 ADR 50mg/m2 IV d1 5-FU 500mg/m2 IV d1,d8 q3w,乳腺癌常用辅助化疗方案,FEC 50FEC 100CEF120ADR4 CMF 3-4,乳腺癌辅助化疗方案,AC:ADR 60mg/m2 IV d1 CTX 600mg/m2 IV d1 q3w4ACT:AC 4 Paclitaxol 175mg/m2 q3w4TAC:TAC（75/

6、50/500mg/m2）Q3wk 6 cycle,乳腺癌辅助化疗方案,CMF（Milan）6个月化疗,改善DFS(24%减少)和OS。AC4 vs CMF 6(NSABP)复发率和死亡率无差别.含蒽环类较无蒽环类方案显著减少复发（12%）和死亡率（11%）（1998 EBCTCG）。含紫杉类方案AC Taxol（C9344/NB28）显示减少复发危险17%和死亡率18%。BCIRG 001试验TAC vs FAC,前者明显改善DFS和OS.C9741 进一步改善AC-Paclitaxel 疗效.,含紫杉类辅助化疗研究,紫杉类辅助化疗随机临床试验,Intergroup Trial 9344 an

7、d NSABP B-28AC x 4 vs.AC x 4 paclitaxel x 4paclitaxel x 4NSABP B-27AC x 4 vs.AC x 4 docetaxel x 4MD AndersonFAC x 8 vs.paclitaxel x 4 FAC x 4BCIRG 001FAC x 6 vs.TAC x 6AberdeenCVAP x 8 vs.CVAP x 4 docetaxel x 4US OncologyAC x 4 paclitaxel x 4 vs AC x 4 weeklypaclitaxel x 4ECTOA x 4 CMF x 4 vs.AT x 4

8、 CMF x 4ECOG 2197AD x 4 vs AC x 4 PACS 01FEC x6 vs FEC x 3 docetaxel x3,CALGB 9344 trial(3170):ACT 方案与AC方案的随机对照研究：,RegimenGroup 1 AC4(ADR 60/75/90mg/m2)Group 2 AC4 Paclitaxel 175mg/m2 4(q3w)ER(+)TAM for 5yrs,Date Henderson等SNDA Henderson 等Henderson等Source(1998)(1999)(2000)(2003)中数随访（月）21 30 52 69事件数

9、目 复发 453 624 901 1054 死亡 200 342 589 742相对风险下降(%)复发 22*22*13*17*死亡 26*26*14 18*.P 0.0 5,CALGB 9344的中期分析,CALGB 9344:评述,阿霉素剂量增加不增加疗效(与评估蒽环类剂量强度辅助治疗乳腺癌的其它临床研究结果相一致-B-22 and B-25)未计划的分析最初导致了关于激素受体作用的争论(提示在ER+乳腺癌中具有更低的临床效益),NSABP B28 trial:LN+,Regimen:group 1 AC 4 Paclitaxel 225mg/m2 4(q3w)group 2 AC 4 o

10、nly both group:TAM 50y all TAM 50y ER+和或PR+,+/-TAM 结果无差别，paclitaxel 对无TAM 组有作用。AC Paclitaxel 组有5 例AL。,NSABP-28研究结果,3060 pts，ER+66%，PR61%，服用TAM 84%。中位随访65月。,AC(1529)AC-P(1531)HREvents 461 400 0.83(P=0.008)Deths 255 243 0.94(P=0.46)5y DFS 72%76%5yOS 85%85%,NSABP B-28:结论,将泰素加入到 AC方案中辅助治疗早期乳腺癌明显改善了DFS(R

11、R=0.83,p=0.008)疗效和与受体状态之间无明显相互作用 总生存无明显改善(?由于较佳的预后因素),CALGB 9344/NSABP B-28:结论,在B-28 研究中将泰素加入到AC方案中产生的 DFS 效益与 CALGB 9344 研究结果相一致(17%复发风险降低)B-28 和 9344 研究结果支持将泰素加入到AC方案中辅助治疗早期乳腺癌,q 2 wk(w/G-CSF),q 3 wk,24 weeks,16 weeks,24 weeks,36 weeks,阿霉素 60 mg/m2,环磷酰胺 600 mg/m2,泰素 175 mg/m2 over 3 hours,CALGB 97

12、41 2 x 2 因子设计,剂量密度辅助化疗,M.Citron,et al.SABCC 12/02,n=2,005 T 0-3,N 1-2,M 0,无病生存,q 2,q 3,RR=0.74 p=0.01,总生存,q 2,q 3,RR=0.69 p=0.013,总结:36 月中位随访,主要终点:剂量密集治疗使得疾病复发风险下降了26%(p=0.010)次要终点:剂量密集治疗使得疾病死亡风险下降了31%(p=0.013)4-year DFS 剂量密集方案：82%常规3周方案：75%3-year OS 剂量密集方案：92%常规3周方案：90%尽管应用了GCSF，除贫血外其它毒性无明显增加,TAC（7

13、5/50/500mg/m2）Q3wk 6 cycle-FAC（500/50/500 mg/m2）Q3w 6 cycle,泰索帝在淋巴结阳性乳腺癌辅助治疗研究 BCIRG001 Trial-FAC vs TAC,HR+口服Tamoxifen,20 mg/d,5 年 多数患者接受了计划的6个疗程(97%FAC vs 91%TAC).,1491例可手术EBC中位年龄49岁，1-3淋巴结阳性 62%，69%ER和/或 PR+,20%HER2/neu-阳性，中位随访55月,研究方案,BCIRG001-TAC vs FAC,BCIRG 001 study NEJM 2005,DFS and OS,NEJM

14、 2005,BCIRG-001 Trial,结论：中位随访55月,对淋巴结阳性乳腺癌,TAC辅助治疗较 CAF 显著改善DFS和OS.TAC引起更多的发热性中性粒细胞减少,但不增加G3/4感染和相关死亡的发生率.,AC vs AC-Taxotere(术前或术后)方案乳腺癌辅助化疗-NSABP B-27,研究目的：术前或术后 T，与单纯术前AC的DFS和OS。临床疗效，病理有效率，临床分期，保存乳腺。（I+III vs II)）淋巴结和分期对DFS和OS的影响。(I vs III)N=2,411可以手术 乳腺癌随机分组：术前AC 4 surgery(Group I)术前AC 4 T 4 surg

15、ery(Group II),术前AC 4 surgery 术后T 4(Group III).,Results:pCR Group I（DCIS only and Non-tumor）12.8%;II 26.1%;III 14.3%各治疗组间OS（P=.53-.56）和DFS（P=.06）没有区别。Group II 较Group I 减少RFS。Group II/III较 Group I 显著减少局部复发，P=.0014 pCR vs Non-pCR:显著改善DFS和OS,P=.0001。无论那一个治疗组，pCR的DFS都显著优于Non-pCR,P.00000001淋巴结状态可以预测DFS和OS

16、，且与治疗后是否pCR无关。,NSABP B-27,PACS 01 trial 5年随访结果 FEC1006 vs FEC100 3 docetaxel(D)3 淋巴结阳性乳腺癌辅助化疗,研究目的:评价两个不同方案治疗淋巴结阳性乳腺癌 DFS和OS.继BCIRG001 后第二个泰索帝辅助化疗大型临床研究.,French and Belgian,n=1999例，1-3可切除,淋巴结阳性乳癌，术后42天内开始化疗，预防性G-CSF，保乳者接受放射治疗，HR+Tamoxifen 5 years,Arm A:FEC100 6,Q3 W,Arm B:FEC100 3-D 100 mg/m 3,Q3W,R

17、,Results:1997-2000,n=1999 French and Belgian centres.M-age 50 yrs,保乳手术57%,grade III 39%,HR 21%,both HR+60%,LN+1-3 62%.完成治疗95%and 93.4%（arms A and B,respectively）毒性(2003 SABCS abstract 144).More febrile neutropenia and nail disorders in Arm B and a more decreased and subnormal LVEF in Arm A.Five case

18、s of leukaemia(3 Arm A;2 Arm B).No toxic deaths.到2004/04，465 pts have event:93 loco regional relapses,324 metastasis,38 controlateral breast cancer,and 10 deaths as first event.A total number of 37 second cancers and 210 deaths are registered.,结果：,结论OS有改善趋势加Doce对LN+和50岁DFS/OS更好，50yrs加D与FEC没有区别进一步研究F

19、EC vs EPI+Doce Or 序贯Doce,Five-Year Disease-Free and Overall Survival Results From 5 Randomized Clinical Trials Evaluating a Taxane-Containing vs a Non-Taxane-Containing Adjuvant Chemotherapy Regimen,CALGB NSABP PACS NSABP BCIRG 9344 B-28 01 B-27*001 AC AC AC AC FEC FEC AC AC FAC TAC T T Tx Tx 5-year

20、 DFS(%)65 70 72 76 73 78 67 72 68 755-year OS(%)77 80 85 85 87 91 81 83 81 87RR for recurrence 0.83 0.83 0.83 0.86 0.72 P=.0023 P=.008 P=.041 P=.10 P=.001RR for mortality 0.82 0.94 0.77 0.94 0.70 P=.0064 P=.46 P=.05 P=.57 P=.008,SABCS 27th,ACT vs ATwT 乳腺癌辅助化疗US Oncology,ACT ATwT Hazard(n=916)(n=914)

21、Ratio P=3-year DFS(%)84.6 88.4 0.74.05(ITT)86.1 90.3 0.69.023-year OS(%)91.8 94.6 0.65.005(ITT)92.1 95.5 0.57.02,Loesch D Greco FA,OShaughnessy J,SABCS 2004,N=1830 高危可手术乳癌，HR+TAM/AIs 5年。主要目的DFS，次要目的OS。,A vs B;B vs C.End-points:disease free&overall survival*since December 2000 in ER+ve and/or PgR+ve

22、only N=1355,ECTO Study Design,T 2 cmStratification:T,ER/PgR,grade,TAM x 5 yrs*RT,TAM x 5 yrs*RT,TAM x 5 yrs*RT,A,B,C,Main planned analyses-1,T 2 cmStratification:T,ER/PgR,grade,TAM x 5 yrs*RT,TAM x 5 yrs*RT,A,B,Does addition of Paclitaxel to Doxorubicin followed by CMF(ATCMF)improve efficacy of ACMF

23、?,Freedom From ProgressionAdjuvant ACMF v.ATCMF,.25,.50,.75,1.0,1,2,3,4,5,SACMF 453 91,Pts Events HR p,SATCMF 451 63,0.66 0.01,Probability of FFP,years,Main planned analyses-2,Is ATCMF before surgery better than adjuvant?,.25,.50,.75,1.0,1,2,3,4,5,Pts Events HR p,SATCMF 451 63,ATCMFS 451 78,1.22 0.2

24、4,Freedom From Progression:Adjuvant v.Primary Chemotherapy,Probability of FFP,years,.25,.50,.75,1.0,1,2,3,4,5,pCR 102 8,Pts Events HR p,non pCR 349 70,2.80 0.006,Freedom From Progression:pCR v.non pCR,Probability of FFP,years,Multivariate Analysis of FFP:Primary Chemotherapy Arm,.25,.50,.75,1.0,1,2,

25、3,4,5,SACMF 453 41,Pts Events HR p,S ATCMF 451 30,ATCMFS 451 32,0.71 0.16,1.06 0.81,Overall Survival-All Patients,probability,years,A vs AP-CMF ECTO Trial,HR=hazard ratio;S=surgery;A=doxorubicin 75 mg/m2s;P=paclitaxel 200 mg/m2 intravenously over 3 hours;CMF=cyclophosphamide/methotrexate/5-flurourac

26、il;CI=confidence interval,Goldstein et al.ASCO 2005.Abstract 512.,AT Arm:Doxorubicin 60 mg/m2Docetaxel 60 mg/m2 every 3 wks for 4 cycles(n=1444),AC Arm:Doxorubicin 60 mg/m2Cyclophosphamide 600 mg/m2every 3 wks for 4 cycles(n=1441),Patients with LN+or high-risk LN-breast cancer(N=2885),Stratified by

27、nodal status,HR status,menopausal status,Tamoxifen 20 mg/dfor 5 yrs in patients withER+and/or PR+tumors,ER,estrogen receptor;HR,hormone receptor;LN,lymph node;PR,progesterone receptor.,12 wks,5 yrs,AT vs AC Phase III trial EGOG 2197,AT vs AC Phase III trial EGOG 2197,两组的DFS and OS相似4-year DFS:两组均为 8

28、7%.4-year OS:AT组 94%,AC组 93%.DFS:AT方案对PR-的患者疗效优于AC方案.ER-/PR-:HR=1.30(95%CI,0.96-1.20)favoring ATER-/PR+:HR=.30(95%CI,0.10-0.95)favoring ACER+/PR-:HR=1.64(95%CI,0.96-2.80)favoring ATER+/PR+:HR=.79(95%CI,0.58-1.10)favoring AC,Goldstein et al.ASCO 2005.Abstract 512.,Herceptin 在乳腺癌辅助治疗研究进展,4 cycles,4 cy

29、cles,Dox/Cyc,Pax HD q 3 wk,Trastuzumab,Pax HD q 3 wk,4 cycles,4 cycles,52 wks,NSABP B-31,NCCTG 9831,Dox/Cyc,Pax LD/wk,Trastuzumab,Pax LD/wk,Trastuzumab,Pax LD/wk,12 wks,52 wks,64 wks,HERA,Trastuzumab,No therapy,StandardChemoRx,1 Yr,2 Yr,BCIRG 006,Dox/Cyc,4 cycles,Docetaxel,Docetaxel,Trastuzumab,Doce

30、taxel,Carboplatin,Trastuzumab,Trastuzumab,Summary of Trastuzumab Trials,Patients with HER-2positiveinvasive breast cancer(N=5090),Trastuzumab 6-8 mg/kg every 3 wks for 2 years(n=1703),Trastuzumab 6-8 mg/kg every 3 wks for 1 year(n=1694),Observation(n=1693),Stratification by age,region,nodal status,a

31、djuvant chemotherapy,hormone receptor status,endocrine therapy,Observation,Trastuzumab Following Adjuvant Chemotherapy in HER-2+Disease,HERA:Interim analysis of multicenter randomized trialCurrent analysis:observation and 1-yr trastuzumab arms,Piccart-Gebart.ASCO 2005.Oral presentation during sympos

32、ium,Advances in Monoclonal Antibody Therapy for Breast Cancer.,Superior disease-free,recurrence-free,and distant disease-free survival with 1 year of trastuzumabHigher but statistically insignificant cardiac toxicity with trastuzumabEjection fraction drop 10 points and LVEF 50%,7.1%vs 2.2%Symptomati

33、c congestive heart failure,0.5%vs 0.0%Cardiac death,0.1%vs 0%,Piccart-Gebart.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.,Trastuzumab Following Adjuvant Chemotherapy in HER-2+Disease,Adjuvant Paclitaxel/Trastuzumab After AC in HER-2Positive

34、Disease,HER-2-positive breast cancer patients(N=1736),Trastuzumab*4 mg/kg initial dose+2 mg/kg/wk for 52 wks+Paclitaxel 175 mg/m2 once every 3 wks for 4 cycles(n=864),Paclitaxel 175 mg/m2 once every 3 wks for 4 cycles(n=872),HER-2-positive breast cancer patients(N=1615),AC:Doxorubicin 60 mg/m2+Cyclo

35、phosphamide 600 mg/m2 once every 3 wks for 4 cycles,Trastuzumab*4 mg/kg initial dose+2 mg/kg/wk for 52 wks+Paclitaxel 80 mg/m2/wk for 12 wks(n=808),Paclitaxel 80 mg/m2/wk for 12 wks(n=807),NSABP B-31,NCCTG N9831,One of 3 N9831treatment arms not included in current analysis,Romond.ASCO 2005.Oral pres

36、entation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.,AC:Doxorubicin 60 mg/m2+Cyclophosphamide 600 mg/m2 once every 3 wks for 4 cycles,Romond.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.,Adjuvant Paclitaxel/Tra

37、stuzumab After AC in HER-2Positive Disease,DFS significantly longer for patients treated with trastuzumab(median follow-up,2 years)Estimated 4-year overall survival,91%vs 87%Hazard ratio=0.67(2-sided P=.015),Perez et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody The

38、rapy for Breast Cancer.,HER-2+patients(N=2804),Doxorubicin 60 mg/m2+Cyclophosphamide 600 mg/m2 once every 3 wks for 4 cycles,Paclitaxel 80 mg/m2/wk for 12 wks+Trastuzumab*4 mg/kg initial dose+2 mg/kg/wk(n=840),Paclitaxel 80 mg/m2/wk for 12 wks(n=985),*LVEF evaluated at Mos 3,6,9,and 18 for trastuzum

39、ab patients;trastuzumab discontinued if LVEF 1%below lower limit of normal with absolute decrease of 5%-10%,or if absolute decrease 16%,Observation,Trastuzumab*4 mg/kg initial dose+2 mg/kg/wk for 52 wks,Paclitaxel 80 mg/m2/wk for 12 wks(n=979),Trastuzumab*4 mg/kg initial dose+2 mg/kg/wk for 40 wks,A

40、djuvant Paclitaxel/Trastuzumab After AC in HER-2Positive Disease,North Central Cancer Treatment Group(NCCTG)N9831 trial:further analysis,Perez et al.ASCO 2005.Oral presentation during symposium,Advances in Monoclonal Antibody Therapy for Breast Cancer.,Adjuvant Paclitaxel/Trastuzumab After AC in HER

41、-2Positive Disease,Concurrent paclitaxel/trastuzumab treatment following AC significantly prolonged DFS and OS vs sequential paclitaxel/trastuzumab,Perez et al.ASCO 2005.Abstract 556.,18-Month Safety Analysis:Paclitaxel+Trastuzumab in Adjuvant Setting,Comparison of sequential AC paclitaxel trastuzum

42、ab(Arm B)vs AC paclitaxel(Arm A)Arm A,0 cardiovascular events;0%(95%CI,0%to 0.7%)Arm B,13 cardiovascular events;2.2%(95%CI,1.2%to 3.8%)Congestive heart failure,n=12 Cardiac arrest,n=1 Most patients maintained LVEF near baseline levels and lower limit of normal,Perez et al.ASCO 2005.Abstract 556.,18-

43、Month Safety Analysis:Paclitaxel+Trastuzumab in Adjuvant Setting,Comparison of concurrent AC paclitaxel+trastuzumab(Arm C)vs AC paclitaxel(Arm A)Arm A,0 cardiovascular events;0%(95%CI,0%to 0.7%)Arm C,20 cardiovascular events;3.3%(95%CI,2.0%to 5.1%)Congestive heart failure,n=19 Cardiac failure,n=1Mos

44、t patients maintained LVEF near baseline levels and lower limit of normal,Monoclonal Antibody Therapy for Breast Cancer:Conclusions,Adjuvant trastuzumab improves survival outcomesTrastuzumab added to paclitaxel as adjuvant therapy following doxorubicin/cyclophosphamide prolongs disease-free and over

45、all survivalConcurrent trastuzumab/paclitaxel appears superior to sequentialIncreased cardiac toxicity in patients receiving trastuzumab+paclitaxel:within 4%acceptable range,乳腺癌 的辅助化疗,淋巴结阴性CMFFAC/CAFAC,淋巴结阳性FAC/CAF/CEFAC-TA-CMFCMF,NCCN 2004,乳腺癌 的辅助化疗(续),含蒽环类方案对her2过表达疗效优于无蒽环类方案除了CMF方案可以与放疗同时应用，其他方案应于放疗前使用。淋巴结阳性应选用蒽环类方案AC-T方案对ER阴性更有效，需要进一步观察。A-CMF方案应限于淋巴结阳性/=4,NCCN 2004,Thanks,