乳腺癌辅助治疗规范解读

1、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2treatment 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 co

2、mpliance with guidelines has been shown to improve patient outcome3adjuvant therapy for breast cancertreatment guidelines7883889295980103058085902000guidelinesst. gallennihnccn96yearly07如何掌握、使用如何掌握、使用？4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

3、的选择内分泌治疗方法的选择5adapted from bonadonna g. cancer res. 1992.breast cancer: adjuvant cmf(12 months) or surgery alone630 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

4、.71 ( p = 0.005 )各种死亡降低各种死亡降低 22%hr 0.79 ( p = 0.04 )730 years follow up of randomised studies of adjuvant cmf in operable breast cancer : cohort studyoverall survival bonadonna bmj 330:217, 20058therapyreduction inannual odds, %recurrencedeathpolychemotherapy vs23.515no chemotherapy (1995)(p .00001

5、)(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 deaths0.51.52.015.7% (se 3.)reduction2p 0.00001 deaths/womenallocatedadjusteda/e+ cmf* a/e+ deathslogrankvariance oe of oeyear codeand

6、 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)8/2113/22-2.25.080m int milan8cmf+4a v 12cmf-/211-/212(no data)83a nsabc israel br02832cmf+4avbcmf v 6cmf23/5521/50-1.310.184b nsabp b-15*4

7、ac3cmf 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 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 ga

8、bg 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 6cmf(no data)89b2 swog 88976fac v 6cmf (+rtam)173/1461223/1470-25.997.189r nci-c ma.56fec v 6cmf118/356135/360-10.159.189w123

9、456c 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)34/23243/234-3.818.294j1+2+3 goirc sang 2b italy6cmfev v 6cmf (+tam)(no data)scottish4e;4cmf v 8cmf(no data)1780/ 6850(26.0%)-128.42019/ 690

10、6(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)* for balance, control patients in 3-way trial strata count half or twice in subtotal(s) and in final total of events/women.

11、1.00(? patients)(100 patients)(322 patients)(158 patients)( 480 patients)(? patients)ratio of annual death ratesa/e+ : cmf101112her2 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%(1

12、2,32)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 500 mg bid, day 5-14ever

13、y 3 weeks x 6 cyclesstratification: nodes: 1-3 4+ center14tacfac0612182430364248monthsnumber at risktacfac7457367106786543731522317467296996566053341503105060708090100% alive and disease freetacfactotal# events119170289rr0.68p-value0.0011disease free survival (itt)bcirg 001median follow-up: 33 month

14、s82%74%15number at risktacfac745741732718700393171241746738728713678375171331tacfactotal# events 57 76133rr0.76p-value0.11overall survival (itt)bcirg 001tacfac0612182430364248months5060708090100% alive 92%87%median follow-up: 33 months16disease free survival byhormonal statustacfac012243648monthsn a

15、t risktacfac2312171884702282021583405060708090100% 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 r199

16、8,6-2002,7972 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 200

17、6 lba52021taxit216 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.

18、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 ongoing2223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):4424蒽环类蒽环类+

19、 +紫杉类可延生存期紫杉类可延生存期jco 2008, 26(1):4425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):44dfsos26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):1663dfs27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):16632829ncctg 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 o

20、rfishihc, 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临床试验赫赛汀辅助治疗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)30nsabp 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 chemothera

21、py)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)combined: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%neve

22、ntsact1679261acth 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 plot for dfs: b31/n9831protocolno.positivenodestumorsizehormonereceptoragen9831nsabp b-31 4.1cm2.1- 4.0 cm2.0 cmpositivenegative 6050

23、-5940-4939all data10+4-91-3034annual hazard of distant recurrence01234020406080100120rate per 1000 women /yryears from randomizationact35combined analysis for os of nsabp b-31 / ncctg n9831 87%92%actndeathsact167992acth 167262hr=0.67, 2p=0.015years from randomizationb31/n983136dfs: hera trial37012al

24、lany, 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 taxaneanthracycline

25、 + taxanenegativereceptor status/endocrine therapypos + no endocrine therapypos + endocrine therapy35 yrs35-49 yrs50-59 yrs 60 yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.535490.70allany, neo-adjuvant chemotherapynodal status0 pos, no neo-adjuvant chemotherapy338735811008722032307n0

26、.540.530.520.770.640.43hazardratio1-3 pos, no neo-adjuvant chemotherapy 4 pos, no neo-adjuvant chemotherapyno anthracycline or taxaneadjuvant chemotherapy regimenanthracycline, no taxaneanthracycline + taxanenegativereceptor status/endocrine therapypos + no endocrine therapypos + endocrine therapy2-

27、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 200741无论年龄大小，赫赛汀均显示无论年龄大小，赫赛汀均显示dfsdfs获益获益35-49 years0.00.52.51.01.52.0hera35 years50-59 years60 yearsn9831 / b-31 650.6 %1

28、.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 50 is 5%this analysis from b31data alone.44risk of cardiac events (no strong evid

29、ence 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 end of herceptin treatment periodthis analysis from b31 data alone.45slamon et a

30、l 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 ejection fraction; nr, not reported 3.0nrnr18.08.6asymptomatic lvef decline, %

31、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47estimation of the epidemiological effect of trastuzumab over 20 yea

32、rs in five european countriesasco 2008, abst, 661148asco 2008, abst, 6611estimation of the epidemiological effect of trastuzumab over 20 years in five european countries49her2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

33、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 50st.gallen 200351st.gallen 200352st.gallen 2003535455chemotherapy regimens- st.gallen 2005implications for patient careac x 4cmf x 6fac, fe

34、c x 6caf, cef x 6a (e) cmfwithout taxanestacac p or dwith taxanesh56chemotherapy regimens- st.gallen 2005implications for patient carestandardefficacysuperiorefficacyac x 4cmf x 6fac, fec x 6caf, cef x 6a (e) cmfwithout taxanestacac p or dwith taxanescomplexitytoxicityeconomic costbut greaterh57choi

35、ce of adjuvant regimens58 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59changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for stage i to iii breast cancer60小小 结结 cmf有最长的远

36、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6162100个月的结果：个月的结果：t 21.8%a17.0%absolute difference: 4.8%636465ma.17: trial design primary end point: dfssecondary end

37、 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 extended adjuvant66ma.17 resul

38、ts: 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 treatment duration676

39、8697071727374atacexembig 1.98(big femta)tamoxifenaiplacebo arno(j)ma-17nsabp b33 exem 027team exetrial strategies in adjuvant therapy: ais757677ai. 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-1710.820.810.60.60.5p-values 0.