早期乳腺癌辅助化疗中文.ppt

1、早期乳腺癌化疗现状紫衫类药物进展,哈尔滨医科大学附属二院乳腺外科 张建国,乳腺癌辅助化疗的发展,Development of Adjuvant Breast Cancer Chemotherapy,1970s,1980s,1990s,2000s,CMF,Anthracycclines,Taxanes,初始 AC 1975,CALGB 40101 III期临床试验 4或 6疗程AC 或 紫杉醇方案:研究设计,患者人群: 浸润性乳腺癌 0-3个腋淋巴结转移 若腋淋巴结阴性, 必须接受化疗的高危乳腺癌 分层因素 月经状态 ER/PgR状态 HER2 状态 目的 主要目的: 不同方案及疗程的RFS 次

2、要目的: OS,毒性, 对月经的影响, 生活质量,4 Cycles,6 Cycles,4 Cycles,6 Cycles,曲妥珠单抗 HER2+者(2005年后),2 x 2 阶乘设计,AC,PACLITAXEL,三苯氧胺或 AI若ER+,Schulman et al. SABCS 2010. Abstract S6-3.,CALGB 40101: RFS 和 OS (N=3173),Schulman et al. SABCS 2010. Abstract S6-3.,S0221: 计划 2 x 2 阶乘设计 “节拍治疗”,入组条件 I-III期乳腺癌 “高危,” 定义为 淋巴结+ (N1-3

3、) 任何原发灶2 cm 肿瘤1 cm 或 ER- 且PR- 或 ER+ 或 PR+ 如果复发分值26,Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Peg-filgrastim q 2 weeks x 6,Doxorubicin 24 mg/m2 Cyclophosphamide 60 mg/m2 po GCSF d2-7 Weekly x 15 weeks,Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Peg-filgrastim q 2 weeks x 6,Doxorubicin 24 mg

4、/m2 Cyclophosphamide 60 mg/m2 po GCSF d2-7 Weekly x 15 weeks,Paclitaxel 175 mg/m2 Peg-filgrastim q 2 wks x 6,Paclitaxel 175 mg/m2 Peg-filgrastim q 2 wks x 6,Paclitaxel 80 mg/m2 Weekly x 12,Paclitaxel 80 mg/m2 Weekly x 12,Budd et al. ASCO 2011. Abstract 1004.,S0221: 中期分析更新,Budd et al. ASCO 2011. Abst

5、ract 1004.,在AC方案基础上增加紫杉类药物的进展,AC (AC/P更佳) FAC (TAC更佳) FEC (FEC/T更佳) E (或 A)/CMF (A/T/CMF 更佳) AC (TC 短治疗疗程),BCIRG 001 研究设计,Fluorouracil 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide500 mg/m2,Docetaxel 75 mg/m2Doxorubicin 50 mg/m2 Cyclophosphamide500 mg/m2,F,A,C,地塞米松预出来, 8 mg bid, 3 天 预防性环丙沙星 500 mg

6、 bid, 514天 G-CSF预防性应用是不允许的,每3周共6疗程,分层 淋巴结状态 1-3 4+ 中心,n=1491 20 个国际 112 个中心,TAC: 76%,FAC: 69%,DFS 中位随访 10年 (ITT),Number at Risk,TAC,745,737,710,678,659,639,617,596,583,562,551,541,530,519,508,491,478,463,444,418,387,Disease-free survival probability,0.00,0.20,0.40,0.60,0.80,1.00,Disease-free surviva

7、l time (months),0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,102,108,114,120,HR=0.7295%CI: 0.590.88Log-rank P=0.001,OS 中位随访 10年(ITT),429 deaths: 188 TAC; 241 FAC,Number at Risk,TAC,745,742,732,718,704,693,677,661,650,645,635,622,612,603,594,584,571,563,547,524,495,FAC,746,740,731,724,704,684,657

8、,642,625,608,591,581,573,557,546,532,517,501,482,460,443,Overall survival probability,0.00,0.20,0.40,0.60,0.80,1.00,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,102,108,114,120,TAC: 87%,FAC: 81%,HR=0.7095%CI: 0.530.91Log-rank P=0.008,Survival time (months),累积充血性心力衰竭的发生率,Number at Risk,TAC,744,71

9、3,679,647,620,591,566,540,515,484,437,FAC,736,716,672,621,588,554,522,490,466,429,392,Probability of CHF,0.00,0.01,0.03,0.04,0.06,0.08,Time from randomization to CHF event (months),0,12,24,36,48,60,72,84,96,108,120,0.02,0.05,0.07,TAC,FAC,结 论,充血性心力衰竭在TAC和FAC组患者的发生率分别是 3.5%和2.3% (P=0.17) 大部分充血性心力衰竭为 3

10、级 2例 TAC组患者和4例 FAC组患者死于心力衰竭 显著的 LVEF下降 (20%)在两治疗组中相似 (TAC 17%, FAC 15%) 血液系统恶性肿瘤报道在TAC组有 6例 (0.8%) FAC组有3例(0.4%),Martin et al. ASCO 2008. Abstract 542.,GEICAM 9805: 研究设计,Primary endpoint DFS Secondary endpoints OS, safety, and QoL,GEICAM 9805: 疗效,Martin et al. ASCO 2008. Abstract 542.,GEICAM 9805: D

11、FS 亚组分析HR及HER2状态通过中心实验室回顾,HER2-患者的DFS从TAC治疗中获益最多，无论其激素受体状态如何,Martin et al. N Engl J Med. 2010;363:2200-2210.,PACS-01: 研究设计,手 术,R,6FEC100: ARM A Fluorouracil 500 mg/m d1 Epirubicin 100 mg/m d1 Cyclophosphamide 500 mg/m d1 6 cycles every 21 days,3FEC100-3 Docetaxel: ARM B 3 cycles of FEC 100 every 21

12、days followed by 3 cycles of Docetaxel 100 mg/m d1 every 21 days,RT: 化疗后4周行放疗 HT: 化疗后激素受体阳性的绝经后妇女接受三苯氧胺 20 mg/日5年,分层: 中心 年龄: 50 N: 1-3 vs 4,RT,HT,RT,N=1999,HT,PACS-01: DFS第8年(ITT),Coudert B, et al. SABCS 2009. Abstract 603,PACS-01: OS 治疗组(ITT),Coudert B, et al. SABCS 2009. Abstract 603,MEANING OF PA

13、CS-01,Less anthracycline with 3 cycles of FEC All the benefit of Taxotere Significantly less cardiac toxicity and maybe less bone marrow toxicity,多西紫杉醇Meta分析: 临床研究,20,698 例患者,Laporte S, et al. SABCS 2009. Abstract 605.,多西紫杉醇Meta分析: DFS和OS根据淋巴结状态,总体而言，DFS的 HR为 0.82 95% CI 0.75;0.89 (P0.001) 多细紫杉醇为基础的

14、化疗方案更佳 OS的HR为0.82 0.74;0.91 (P0.001),Laporte S, et al. SABCS 2009. Abstract 605.,多西紫杉醇Meta分析: 亚组DFS,与非紫杉类的方案相比，基于多细紫杉醇的化疗能够改善DFS，且无论患者的淋巴结状态，年龄，激素受体或HER2表达如何,Laporte S, et al. SABCS 2009. Abstract 605.,在绝大多数方案中应用 有全球临床研究I级证据证实 OXFORD 回顾分析验证 有双重评估价值,蒽环类和紫杉类化疗药较为常用,EBCTCG Lancet. 365(9472):1687-717 20

15、05,EBCTCG 和蒽环类药物,两项非蒽环类化疗方案的研究,TC (泰索帝/环磷酰胺) TCH (泰索帝/卡铂/赫赛汀) 相关学科,N=1016 71% ER+ 48% N,4 x AC q3w Doxorubicin (60 mg/m2) Cyclophosphamide (600 mg/m2),n=510,入组条件: I, II,或 III期疾病 中位随访: 5.5年,US Oncology 9735: 研究设计,R,Jones et al. J Clin Oncol. 2006;24:5381-87.,化疗剂量基于实际的人体表面积 化疗在放疗前给予 化放疗后ER者给予三苯氧胺,USO

16、9735: 患者特征,Jones et al. J Clin Oncol. 2006;24:5381-87.,Jones et al, 2009.,31% OS,26% DFS,65岁以上患者 (亚组分析),单个研究显著的结果,USO 9735: TC 相比AC的疗效,TC 显示更为有效 无论 HER2的状态,TC AC 在 HER2+ (与一些蒽环类相比CMF的研究报道相反) 然而, 亚组分析总人数 n = 170 (HER2+ n = 46),Jones et al, 2009.,Adjuvant Trastuzumab Options,Remind et al, 2005; Slamon

17、 et al, 2006; Joensuu et al, 2009; Smith et al, 2007; Spielmann et al, 2007.,BCIRG 006,4 x AC60/600 mg/m2,4 x T 100 mg/m2,6 x T and C75 mg/m2 AUC* 6,1 year H,1 year H,AC T,AC TH,TCH,HER2+ (central FISH*) N+ or high-risk N- N = 3222,4 x AC60/600 mg/m2,4 x T 100 mg/m2,Stratified by nodes and hormonal

18、receptor status,* FISH: fluorescence in situ hybridization * AUC: area under the concentration vs. time curve,Slamon D, et al. SABCS 2009. Abstract 62.,BCIRG 006: DFS and OS(3rd Planned Analysis; 65 mo Follow-up),0.4,0.5,0.6,0.7,0.8,0.9,1.0,% alive and disease-free,0,12,24,36,48,60,72,Time (months),

19、PatientsEventsHR (95% CI)P ACT10732571 (reference) ACTH10741850.64 (0.53-0,78)0.001 TCH10752140.75 (0.63-0.90)0.04,Disease-Free Survival 3rd Planned Analysis,84%,81%,75%,0.4,0.5,0.6,0.7,0.8,0.9,1.0,% alive,0,12,24,36,48,60,72,Time (months),PatientsEventsHR (95% CI)P ACT10731411 (reference) ACTH1074

20、940.63 (0.48-0,81)0.001 TCH10751130.77 (0.60-0.99)0.038,Overall Survival 3rd Planned Analysis,92%,91%,87%,SUMMARY OF EVENTS TCH v. ACTH (BCIRG 006),几个疗程 TC?, 最近两个TAC的临床研究关注这一问题 B30 BCIRG 005,几个疗程 TC?,最近两个TAC的临床研究关注这一问题 B30 BCIRG 005 答案: 6个疗程TAC (或 TC),Node-Positive, High Risk Node Negative, HER2 Neg

21、ative Breast Cancer,STRATIFICATION Stage (IA, IIA, IIB, IIIA, IIIB, IIIC),US Oncology 06-090,TC x 6,Accrual goal - 2000 patients DFS - Primary endpoint Study stopped at 1200 pts.,TAC x 6,B-46 USOR 07132,N=3900; 3y DFS; HR .75 TCB USON TC v TAC closed (N=1200) Total TC v TAC N=3600 non inferiority,US

22、ON 07132/NSABP B46,两个目的 在3900例HER2正常的且能够获取到组织标本的乳腺癌妇女中比较TC和TAC 将解决回答蒽环类药物的作用并且将验证其在任何小的亚组中确实的获益 TC 与TC bev 相比较在于观察贝伐单抗在非蒽环类方案中的作用,Bevacizumab in MBC,July 2010: ODAC recommends FDA withdraw bevacizumab approval in MBC June 2011: FDA hearings November 2011: FDA revokes indication,43,B-49 (CTEP),N=1843

23、 (4200 with B-46I and TicTacToe); Median 4+ yr IDFS; 80% Power for Non-Inferiority (HR 1.18) Accrual opened 4/4/2012,N+,TAC q 3 wk,All arms pegfilgrastim or filgrastim EPO: rec for Hgb 11 gm/dl ER positive: hormonal therapy for 5 yrs after chemo,NSABP B-38 Schema,Stratification: # nodes, Hormone rec

24、eptor, Surgery and RT,NSABP B-38 Disease-Free Survival,# at risk 1610 15321424 1331 1217 719 1618 15541452 1348 1240 754 1613 15331453 1350 1244 730,* Stratified log-rank test adjusting for randomization factors,NSABP B-38 Overall Survival,0,1,2,3,4,5,0.0,0.2,0.4,0.6,0.8,1.0,Years since Randomizatio

25、n,Overall Survival,TreatNDeathsP-value* (vs ACPG),TAC16171850.167 ACP16241880.133 ACPG1618167,# at risk 1617 15881539 1487 1433 913 1624 16021557 1504 1439 938 1618 15961557 1514 1446 928,* Stratified log-rank test adjusting for randomization factors,NSABP B-38AML/MDS (N),ACP (1618),TAC (1610),8,ACP

26、G (1613),11,5,P=0.46,Conclusion,Addition of G to DD ACP did not improve outcomes No significant differences in efficacy between DD ACP and TAC Toxicity profiles differed with more neuropathy and anemia on DD arms and more diarrhea and febrile neutropenia on TAC Exploratory analyses: No outcome diffe

27、rences with or without erythropoietin These results are in node positive BC (Applicable to node negative?),Phase II Trial of Adjuvant TC (Docetaxel/Cyclophosphamide) Plus Trastuzumab (HER TC) in HER2 Positive Early Stage Breast Cancer Patients,Steve Jones, MD1,2; Rufus Collea, MD1,3; Devchand Paul,

28、DO, PhD1,4; Ruth Ortiz, MD1,5; Scot Sedlacek, MD1,4; Anne Favret, MD1,6; Ira Gore, Jr, MD1,7; Deborah Lindquist, MD1,8; Frankie Ann Holmes, MD1,9; Mary Ann K. Allison, MD10; Michael S. Steinberg, MD1,11; Christopher Stokoe, MD1,12; Raul M. Portillo, MD1,13; Maria W. Crockett, CCRP1; Yunfei Wang, MS1

29、; Lina Asmar, PhD1; Nicholas Robert, MD1,6; Joyce OShaughnessy, MD1,2 1US Oncology Research, McKesson Specialty Health, The Woodlands, TX; 2Texas Oncology, Baylor-Sammons Cancer Center, Dallas TX ; 3New York Oncology Hematology, Albany, NY; 4Rocky Mountain Cancer, Denver CO; 5New York, NY; 6Virginia

30、 Cancer Specialists, PC, Fairfax, VA; 7Birmingham Hematology and Oncology, Birmingham, AL; 8Arizona Oncology Associates, Sedona AZ; 9Texas Oncology, Houston, TX; 10Comprehensive Cancer Center, Henderson, NV; 11Virginia Oncology Associates, Virginia Beach, VA, 12Texas Oncology, Plano, TX, 13Texas Onc

31、ology, El Paso, TX This study was supported by sanofi.,Poster #PD07-03, San Antonio Breast Cancer Symposium; December 610, 2011, San Antonio, TX, USA,Results,San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011,This presentation is t

32、he intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute.,In 486 patients, there were 14 cases of recurrent breast cancer (local 5, or local/distant 9), which resulted in a 3-year disease-free survival of 96.3%.,目前现状,HER2 阳性. TCH = ACTH 没有心脏毒性，该方案

33、是否是最佳的标准方案? HER2 阴性疾病. TCAC. 我们还需要蒽环类药物吗? 目前美国的现状, 50% 的患者接受非蒽环类药物的化疗方案(TC 或 TCH) 很多问题仍然需要大型的明确的临床试验结果来回答,CONSEQUENCES OF THIS STUDY,TAC is equal to dd AC/paclitaxel and dd AC/gem (ASCO 2012, B38) If TC is equal to TAC, then TC will be the new world wide standard Will anthracyclines still be importa

34、nt in certain subgroups defined by our large clinical trialeg triple negative? What is happening today in the US?,正在进行的直接对照临床研究在HER2阳性的早期乳腺癌中,非蒽环类的方案: TCH 伴或不伴贝伐单抗 (BETH 研究) 含蒽环类方案: ALLTO, 探究不同的抗HER2 治疗 DSMB 近期推荐单用拉帕替尼组改为允许在拉帕替尼治疗后应用曲妥珠单抗(这组可能疗效较差),可能的辅助应用的全新化疗方案,吉西他宾 TANGO: 阴性; 结果仍在等待中 埃坡霉素 大环内酯类抗肿

35、瘤药 无数据 艾日布林 在转移性乳腺癌中的生存优势; 无数据 卡培他宾 2个主要研究的结果: USON 01062 和 FINXX ASCO 2011报道的Ki67的结果,USON 01062: 研究设计,患者人群 可手术切除乳腺癌且切缘阴性 无转移证据 淋巴结阳性或 淋巴结阴性且 肿瘤2cm或 1cm且ER/PgR阴性 N=2611 主要目的: DFS 次要目的: OS 及安全性,注意: HER2+患者在ASCO2005后能够接受曲妥珠单抗治疗 (102/334 HER2+ 患者接受了曲妥珠单抗),AC q3wk x 4 A: 60 mg/m2 C: 600 mg/m2,AC q3wk x

36、4 A: 60 mg/m2 C: 600 mg/m2,T q3wk x 4 T: 100 mg/m2,XT q3wk x 4 T: 75 mg/m2 X: 825 mg/m2 BID d 114 PO,X = 卡培他宾; T = 多西他赛,OShaughnessy et al. SABCS 2010. Abstract S4-2.,5年的疗效结果 无病生存率及总生存率 (ITT),Study month,Treatment group ACT ACXT,HR 0.84 (95% CI: 0.671.05) p=0.125,012243648607284,1.0 0.8 0.6 0.4 0.2

37、0,HR 0.68 (95% CI: 0.510.92) p=0.011,DFS,OS,一项探索分析显示与对照组相比卡培他宾组存在无远处转移生存的改善， 但未达显著统计学差异 (HR 0.80 95% CI: 0.631.02; p=0.0677),87% ACT,89% ACXT,92% ACT,94% ACXT,OShaughnessy, et al. SABCS 2009,1.0 0.8 0.6 0.4 0.2 0,Treatment group ACT ACXT,Survival,012243648607284,Study month,Survival,探索分析:无病生存率及Ki-67,Ki-67 10%,Ki-67 10%,HR