1、早期乳腺癌輔助化療進展早期乳腺癌輔助化療進展中國醫學科學院腫瘤醫院中國醫學科學院腫瘤醫院 徐兵河徐兵河breast cancer incidence trends over timeper 100,000 cagr 2.98%cagr 4.5%cagr 0.65%cagr 2.35%cagr 0.99%cagr 2.60% source: estimates of cancer incidence in china for 2000 and projections for 2005, yang l, et al.中國乳腺癌發病概況中國乳腺癌發病概況v每年約有19萬新發乳腺癌病例 2002年全國

2、乳腺癌年齡標化發病率:18.7/100,000；死亡率: 5.5/100,000v發病率：城市農村v高發年齡段：4550歲v早期診斷 v綜合治療the benefits of chemotherapy data from clinical trailsnearly breast cancer trialists collaborative group (ebctcg).194 randomised trials of adjuvant chemotherapy (cmf,caf,cef) or hormonal therapy (tam) that began by 1995.lancet 2

3、005placebo53.3%37.147.90102030405060time (years)051510recurrence(%)15-year gain 12.3% (se 1.6)log-rank 2p0.00001polychemotherapy41.1%35.524.6younger women, 35% node-positive; older women, 70% node-positive;se=standard errorebctcg. lancet 2005; 365: 1687-1717placebo42.4%20.435.00102030405060breastcan

4、cermortality(%)15-year gain 10.0% (se 1.6)log-rank 2p0.00001polychemotherapy32.4%time (years)05151015.727.1ebctcg. lancet 2005; 365: 1687-1717younger women, 35% node-positive; older women, 70% node-positive010203040506015-year gain 4.1% (se 1.2)log-rank 2p0.00001placebo57.6%polychemotherapy53.4%48.8

5、05151035.444.129.4time (years)ebctcg. lancet 2005; 365: 1687-1717recurrence(%)younger women, 35% node-positive; older women, 70% node-positiveplacebo50.4%21.338.3010203040506015-year gain 3.0% (se 1.3)log-rank 2p0.00001polychemotherapy47.4%18.705151035.4time (years)younger women, 35% node-positive;

6、older women, 70% node-positiveebctcg. lancet 2005; 365: 1687-1717breastcancermortality(%)placebo45.0%38.326.5010203040506015-year gain 11.8% (se 1.3)log-rank 2p0.00001about 5 years tamoxifen33.2%time (years)05151015.124.7er=oestrogen receptor; 10,386 women: 20% er-unknown, 30% node-positiveebctcg. l

7、ancet 2005; 365: 1687-1717recurrence(%)010203040506015-year gain 9.2% (se 1.2)log-rank 2p0.00001placebo34.8%about 5 years tamoxifen25.6%25.705151011.98.317.8time (years) 10,386 women: 20% er-unknown, 30% node-positiveebctcg. lancet 2005; 365: 1687-1717breastcancermortality(%)010203040506001354time (

8、years)25-year gain 11.9% (se 1.0)log-rank 2p0.00001nil25.8%about 5 years tamoxifen alone13.9%ebctcg. lancet 2005; 365: 1687-1717recurrence(%) 7056 women: 19% node-positive01020304050600135425-year gain 10.6% (se 1.5)log-rank 2p0.00001chemotherapy alone28.1%chemotherapy + about 5 years tamoxifen17.5%

9、time (years)ebctcg. lancet 2005; 365: 1687-1717recurrence(%) 3330 women: 53% node-positivelin premenopausal women, polychemotherapy improves 15-year recurrence by 12.4% and survival by 10.0%lin postmenopausal women, 15-year gains in recurrence and survival are smaller (4.2% and 3.0%, respectively) l

10、anthracycline-based polychemotherapy reduces the annual death rate by 38% for women 50 years and by 20% for those of age 50-69 yearsebctcg. lancet 2005; 365: 1687-1717lin patients with er+ disease, tamoxifen improves 15-year recurrence by 11.8% and survival by 9.2%lgains made with tamoxifen treatmen

11、t appear to be irrespective of adjuvant chemotherapyebctcg. lancet 2005; 365: 1687-1717乳腺癌輔助化療進展乳腺癌輔助化療進展手術手術cmf1蒽環類藥物蒽環類藥物ac2, caf3,fec4dose5,6cef1207, 15fec1008ec9meta-analysis12紫杉類藥物紫杉類藥物10,11,13di14 sequene 生物治療生物治療 1 bonadonna 1976 2 b-15, b-23 1990, 2000 3 secsg 1994 4 coombes 1996 5 bonadonna

12、 1995 6 wood 1994 7 ma-05 1998 8 fasg 2001 9 belgium 2001 10 calgb 200011 b-28 200012 ebctcg 1998, 200013 tac vs fac14 calgb 974115 ma.05 10 years!評估紫杉類乳腺癌輔助化療的評估紫杉類乳腺癌輔助化療的隨機臨床試驗隨機臨床試驗lcalgb 9344 ac vs ac plnsabp b-28 ac vs ac p*lecto a cmf vs ap cmflbcirg 001 tac vs faclnsabp b-27 ac vs actlpacs 0

13、1 fec vs fec tlecog 2197 at vs aclecog 1199 acp3 vs p1 vs d3 vs d1l.t=多西他賽 p=泰素* 在化療時同時給予三苯氧胺紫杉烷輔助化療薈萃分析紫杉烷輔助化療薈萃分析:方法方法l目的目的: 比較含紫杉烷輔助化療方案與不含紫杉烷比較含紫杉烷輔助化療方案與不含紫杉烷輔助化療方案輔助化療方案u主要結局指標主要結局指標: osu次要結局指標次要結局指標: dfs, 毒性毒性l11項隨機對照試驗項隨機對照試驗, 17056名患者名患者l平均中位隨訪平均中位隨訪54.6個月個月l總結果有利于紫杉烷總結果有利于紫杉烷uos: hr 0.81 (

14、95% ci, 0.75-0.88; p.00001)udfs: hr 0.81 (95% ci, 0.75-0.86; p.00001)nowak 等等. asco 2007. 文摘號文摘號 545. five year follow-up of int c9741: five year follow-up of int c9741: dose-dense chemotherapy is safe and dose-dense chemotherapy is safe and effectiveeffectivehudis c, citron m, berry d, cirrincione

15、c, gradishar w, davidson n, martino s, livingstonr, ingle j, perez e, abrams j, schilsky r, ellism, carpenter j, muss h, norton l, & winer eon behalf of calgb/ecog/swog/ncctginvestigatorsher2+ breast cancer her2+ breast cancer and adjuvant therapyand adjuvant therapylher-2是一種原癌基因，該基因與乳腺癌細胞增殖有關。

16、l約2530%的乳腺癌her-2過度表達。 lher-2的過度表達的乳腺癌患者生存期短，預后差。l成為乳腺癌治療的理想靶點。 her2her2陽性對生存期的影響陽性對生存期的影響her2her2陽性的乳腺癌患者的生存率降低！陽性的乳腺癌患者的生存率降低！中位生存期中位生存期her2 her2 陽性陽性3 3 年年her2 陰性陰性67 年年slamon dj et al. science 1987;235:17782her2 her2 狀態狀態: : 預示腫瘤對治療的反應預示腫瘤對治療的反應 內分泌治療內分泌治療 her2her2陽性患者相對耐藥陽性患者相對耐藥 cmfcmf方案方案 her2

17、her2陽性患者相對耐藥陽性患者相對耐藥 蒽環類蒽環類 對蒽環類相對敏感對蒽環類相對敏感 紫杉類藥物紫杉類藥物相對敏感相對敏感l全球第一種治療實體瘤的單克隆抗體，為全球第一種治療實體瘤的單克隆抗體，為her2her2癌基因癌基因陽性的腫瘤患者帶來了新的希望！陽性的腫瘤患者帶來了新的希望！ltrastuzumab是包含了完整的mumab 4d5抗原決定簇的人類igg1的人體球蛋白killer cellkiller cellmacrophagemacrophageherceptinherceptin stimulates adccstimulates adcc(antibody-dependent

18、 cell-mediated (antibody-dependent cell-mediated cytotoxicitycytotoxicity) )fcfc receptor receptortrastuzumab in adjuvant , phase iii studiestrial n selection criteria design primary endpoint nsabp b31 2,700 node+, ihc 3+ or fish+ 4ac 4t+/- h os intergroup n9831 3,000 node+, ihc 3+ or fish+ 4ac 4t+/

19、- h dfs hera trial 3,192 node+ and ihc 3+ or fish+ chimio+/-h 1 ou 2 ans dfs bcirg 006 3,000 node+ and fish+ 4ac 4t+/- h ou tch dfs 新英格蘭雜志新英格蘭雜志20052005年年1010月月北美研究結果發表北美研究結果發表新英格蘭雜志新英格蘭雜志20052005年年1010月月herahera研究結果發表研究結果發表新英格蘭雜志新英格蘭雜志20062006年年2 2月月finherfinher結果發表結果發表17031591143411277423831401698

20、15351330984639334127100806040200patients(%)months from randomisation12361 year trastuzumabobservation0186no. at risk 2430eventshr95% cip value0.640.54, 0.76 0.00013-yeardfs80.674.32183216.3%months since randomisation1703162714981190794407146100806040200patients(%)months from randomisationobservation

21、no. at risk 16981608145310977113661391 year trastuzumabeventshr95% cip value0.660.47, 0.910.01153-yearos92.489.71236018624305990median fu 2 yrs2.7%隨機分組后年隨機分組后年romondromond et al n et al n englengl j med 2005; 353: 1673-1684 j med 2005; 353: 1673-168487%85%67%75%hr=0.48; p0.000110090807060500123452-y

22、ear median follow-up ac pac phneventsacph1672133acp1679261patients (%)18%romondromond et al n et al n englengl j med 2005; 353: 1673-1684 j med 2005; 353: 1673-168401234020406080100120rate per 1000 women /yr隨機分組后年隨機分組后年actn9831/b31n9831/b31遠處轉移風險遠處轉移風險87%92%actndeathsact167992acth 167262hr=0.67, 2p=

23、0.015years from randomizationpatients (%)years10090807001234593%86%84%80%80%91%86%77%73%n107410751073events7798147acdhdcarbohacd6050hr=0.49hr=0.61slamon et al 2005 sabcs (abstract #1) 無病生存率無病生存率總生存率總生存率hr (95% ci)p值值hr (95% ci)p值值n9831/b-310.48 (0.410.57)0.000010.65 (0.510.84)0.0007hera 0.54 (0.430.

24、67)0.00010.76 (0.471.23)0.26finher0.42 (0.210.83)0.010.41 (0.161.08)0.07bcirg ac-th tch0.61 (0.480.86)0.67 (0.540.83)1 cm輔助內分泌治療輔助內分泌治療+輔助化療輔助化療+曲妥珠單抗（曲妥珠單抗（1類）類）淋巴結陽性（指淋巴結陽性（指1個或多個個或多個同側腋窩淋巴結有同側腋窩淋巴結有1個或多個或多個轉移灶個轉移灶2 mm）輔助內分泌治療輔助內分泌治療+輔助化療輔助化療+曲妥珠單抗（曲妥珠單抗（1類）類）binv-5輔助化療輔助化療不含曲妥珠單抗的化療方案（均為不含曲妥珠單抗的化

25、療方案（均為1類）類）lfac/caf（氟尿嘧啶（氟尿嘧啶/多柔比星多柔比星/環磷酰胺）或環磷酰胺）或fec/cef（環磷酰胺（環磷酰胺/表柔比星表柔比星/ 氟尿嘧啶）氟尿嘧啶）lac（多柔比星（多柔比星/環磷酰胺）環磷酰胺）序貫紫杉醇序貫紫杉醇lec（表柔比星（表柔比星/環磷酰胺）環磷酰胺）ltac（多西他賽（多西他賽/多柔比星多柔比星/環磷酰胺）聯合非格司亭支持環磷酰胺）聯合非格司亭支持lacmf（多柔比星序貫環磷酰胺（多柔比星序貫環磷酰胺/甲氨喋呤甲氨喋呤/氟尿嘧啶）氟尿嘧啶）lecmf（表柔比星序貫環磷酰胺（表柔比星序貫環磷酰胺/甲氨喋呤甲氨喋呤/氟尿嘧啶）氟尿嘧啶）lcmf（環磷酰胺

26、（環磷酰胺/甲氨喋呤甲氨喋呤/ 氟尿嘧啶）氟尿嘧啶）lac4 （多柔比星（多柔比星/環磷酰胺）序貫環磷酰胺）序貫紫杉醇紫杉醇4，每，每2周周1次，聯合非格司亭支持次，聯合非格司亭支持latc（多柔比星序貫紫杉醇再序貫環磷酰胺）（多柔比星序貫紫杉醇再序貫環磷酰胺）每每2周周1次，聯合非格司亭支持次，聯合非格司亭支持lfect（ 氟尿嘧啶氟尿嘧啶/表柔比星表柔比星/環磷酰胺序貫多西他賽）環磷酰胺序貫多西他賽）ltc（多西他賽和環磷酰胺）（多西他賽和環磷酰胺）含曲妥珠單抗的化療方案（均為含曲妥珠單抗的化療方案（均為1類）類）首選的輔助方案：首選的輔助方案：lact同步曲妥珠單抗（多柔比星同步曲妥珠單

27、抗（多柔比星/環磷酰胺環磷酰胺序貫紫杉醇曲妥珠單抗序貫紫杉醇曲妥珠單抗)l其他輔助方案：其他輔助方案：l多西他賽曲妥珠單抗多西他賽曲妥珠單抗 fecltch（多西他賽、卡鉑、曲妥珠單抗）（多西他賽、卡鉑、曲妥珠單抗）l化療后序貫曲妥珠單抗化療后序貫曲妥珠單抗lac多西他賽曲妥珠單抗多西他賽曲妥珠單抗新輔助化療：新輔助化療：lt曲妥珠單抗曲妥珠單抗cef+曲妥珠單抗曲妥珠單抗（紫杉醇曲妥珠單抗序貫（紫杉醇曲妥珠單抗序貫環磷酰胺環磷酰胺/表柔比星表柔比星/ 氟尿嘧啶曲妥珠氟尿嘧啶曲妥珠單抗）單抗）binv-jtamoxifenchemotherapy(cmf / fac / fec)hot flu

28、shesvaginal drynessvaginal dischargethromboembolic eventsendometrial cancernauseavomitingfatiguehair losspaincns problemsimmune system problemsebctcg. lancet 2005; 365: 1687-1717cmf=cyclophosphamide, methotrexate and fluorouracilfac=fluorouracil, doxorubicin and cyclophosphamidefec=fluorouracil, epi

29、rubicin and cyclophosphamidelthe adjuvant treatment of hr+ early breast cancer has been revolutionised in the last 5 yearslais have challenged 5 years tamoxifen use as the optimum adjuvant treatment for postmenopausal women in this setting lais have been investigated inunewly diagnosed patientsupati

30、ents who have started adjuvant tamoxifenupatients who have completed 5 years tamoxifen treatmentai=aromatase inhibitor;hr+=hormone receptor-positivelma17試驗：三苯氧胺試驗：三苯氧胺5年來曲唑年來曲唑5年年 vs 三苯氧胺三苯氧胺5年年lies031試驗：三苯氧胺依西美試驗：三苯氧胺依西美5年年 vs 三苯氧胺三苯氧胺5年年latac試驗：阿那曲唑試驗：阿那曲唑5年年 vs 三苯氧胺三苯氧胺5年年lbig-198試驗：試驗：三苯氧胺三苯氧胺5年

31、年 vs 來曲唑來曲唑5年年 vs 三苯氧三苯氧胺胺2年年來曲唑來曲唑3年年 vs 來曲唑來曲唑2年年三苯氧胺三苯氧胺3年年輔助內分泌治療輔助內分泌治療輔助內分泌治療輔助內分泌治療絕經后絕經后芳香化酶抑制劑芳香化酶抑制劑5年（年（1類）類）他莫昔芬他莫昔芬23年年芳香化酶抑制劑芳香化酶抑制劑直至直至5年（年（1類）類）或更久或更久(2b類）類）他莫昔芬他莫昔芬4.56年年芳香化酶抑制劑芳香化酶抑制劑5年（年（1類）類）患者有芳香化酶抑制劑禁忌證或不能接受芳香化酶抑制劑，患者有芳香化酶抑制劑禁忌證或不能接受芳香化酶抑制劑，或不能耐受芳香化酶抑制劑，可以服用他莫昔芬或不能耐受芳香化酶抑制劑，可以服

32、用他莫昔芬5年（年（1類）類）binv-1輔助內分泌治療輔助內分泌治療輔助內分泌治療輔助內分泌治療絕經前絕經前他莫昔芬他莫昔芬23年（年（1類）類）卵巢抑制卵巢抑制/切除（切除（2b類）類）絕經后絕經后絕經前絕經前binv-i輔助內分泌治療輔助內分泌治療絕經后絕經后他莫昔芬直至他莫昔芬直至5年（年（1類）類）芳香化酶抑制劑芳香化酶抑制劑直至直至5年（年（1類）類）或更久或更久（2b類）類）芳香化酶抑制劑芳香化酶抑制劑5年（年（1類）類）絕經前絕經前絕經后絕經后芳香化酶抑制劑芳香化酶抑制劑5年（年（1類）類）絕經前絕經前不進行進一步內分泌治療不進行進一步內分泌治療binv-i 他莫昔芬直至他莫昔

33、芬直至5年（年（1類）類）lendocrine therapy is an effective and well-tolerated long-term treatment strategy in reducing the risk of recurrence after primary surgerylthird-generation ais are becoming the new gold standard in endocrine therapylthe erbb familyutargeting her2 and egfr in breast cancerlanti-angiogenesisutargeting vegf signaling pathways with monoclonal antibodies and tkislother important pathways potential benefits through inhibition of parp, src and other pathwaysltailored therapy個體化治療（個體化治療（tailored therapy) )化療化療化療化療化療化療16 cancer and 5 refere