課件：唑來(lái)膦酸治療乳腺癌骨相關(guān)疾病.pptVIP

唑來(lái)膦酸治療和預(yù)防 乳腺癌骨相關(guān)疾病研究進(jìn)展,乳腺癌骨轉(zhuǎn)移,約70%的乳腺癌患者發(fā)生骨轉(zhuǎn)移 4050%的患者第1個(gè)復(fù)發(fā)部位 癥狀：骨痛、高鈣血癥、骨折 僅20%發(fā)生骨轉(zhuǎn)移的乳腺癌患者存活5年,雙膦酸鹽類藥物的共性和個(gè)性,由于雙膦酸鹽的化學(xué)結(jié)構(gòu)和中心碳原子連接的側(cè)鏈不同，其活性和功效亦有所不同 第一代：氯膦酸二鈉為代表 第二代：含氮雙膦酸鹽，包括帕米膦酸二鈉、阿侖膦酸鈉 抑制骨吸收的體外活性作用強(qiáng)于第一代 第三代：唑來(lái)膦酸（具有含氮的雜環(huán)結(jié)構(gòu)）和伊班膦酸（含氮但不含環(huán)狀結(jié)構(gòu)） 在強(qiáng)度和療效方面比第二代有了進(jìn)一步的提高,雙膦酸鹽可用于乳腺癌骨轉(zhuǎn)移患者，治療惡性高鈣血癥、骨痛、治療和預(yù)防骨相關(guān)事件（SREs）,內(nèi)容提要,乳腺癌骨轉(zhuǎn)移唑來(lái)膦酸臨床研究回顧 唑來(lái)膦酸對(duì)乳腺癌SRE的控制 乳腺癌骨相關(guān)疾病唑來(lái)膦酸臨床應(yīng)用最新研究進(jìn)展 一、二代雙膦酸鹽治療中發(fā)生SREs后換用更強(qiáng)的雙膦酸鹽（唑來(lái)膦酸）可以獲益 預(yù)防芳香化酶抑制劑誘導(dǎo)的骨質(zhì)丟失(AIBL) 有效降低骨標(biāo)記物水平并改善部分患者生存 唑來(lái)膦酸抗腫瘤機(jī)理研究 雙膦酸鹽臨床應(yīng)用常見(jiàn)問(wèn)題 乳腺癌骨轉(zhuǎn)移雙膦酸鹽臨床診療專家共識(shí)2008更新討論,乳腺癌骨轉(zhuǎn)移唑來(lái)膦酸臨床研究回顧,氯屈膦酸（口服）1,600 mg (Kristensen) 31% (Paterson) 17% (Tubiana-Hulin) 8%,P 值,唑來(lái)膦酸 4 mg 41% .001 (Kohno 2005),帕米膦酸 90 mg 23% .001 (Aredia study 18 & 19),伊班膦酸 6 mg 18% .004 (Body 2003),伊班膦酸 50 mg 14% .08 (Body 2004),.92,.03,Pavlakis N, et al. Cochrane Database Syst Rev. 2005;4:1-38.,安慰劑對(duì)照試驗(yàn)中雙膦酸鹽治療乳腺癌的療效,唑來(lái)膦酸顯著降低SRE發(fā)生風(fēng)險(xiǎn),Andersen-Gill 多事件分析,Rosen LS, et al. Cancer. 2003;98:1735-1744.,唑來(lái)膦酸更有效,帕米膦酸更有效,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,P 值,.025,.799,20%,25個(gè)月后的臨床結(jié)果評(píng)價(jià),風(fēng)險(xiǎn) 降低,唑來(lái)膦酸4mg,r,安慰劑,0,50,100,150,200,250,300,350,400,開(kāi)始用藥后的時(shí)間，天,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,未發(fā)生SRE的患者比例（）,唑來(lái)膦酸顯著推遲首次SRE發(fā)生,Kohno N et al. J Clin Oncol. 2005;23:3314-3321.,唑來(lái)膦酸顯著降低發(fā)生一次SRE的患者比例,患者比例（）,P = .003,Kohno N et al. J Clin Oncol. 2005;23:3314-3321., 39%,唑來(lái)膦酸顯著降低平均復(fù)合BPI疼痛評(píng)分,較基線變化的平均值,2,4,8,12,16,20,24,28,32,36,40,44,48,52,自研究開(kāi)始的時(shí)間，周,*,*,*,*,*,*,*,*,*,*,*,0,*,*,*P .05. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.,減輕骨痛,增加骨痛,唑來(lái)膦酸顯著改善乳腺癌骨轉(zhuǎn)移患者的大多數(shù)生活質(zhì)量指標(biāo),圖中顯示的是9次注射后最后一次隨訪與基線水平相比的總的平均變化。 *與基線相比，P 0.05. EORTC QLQ-C30 = 歐洲研究和治療癌癥組織的患者生活質(zhì)量問(wèn)卷30 Wardley A, et al. British J Cancer 2005; 92: 1869-76.,乳腺癌骨相關(guān)疾病唑來(lái)膦酸 臨床應(yīng)用最新研究進(jìn)展,一、二代雙膦酸鹽治療中發(fā)生SREs后換用更強(qiáng)的雙膦酸鹽（唑來(lái)膦酸）可以獲益,唑來(lái)膦酸換藥治療：II期臨床試驗(yàn),目的 評(píng)估一、二代雙膦酸鹽（氯屈膦酸、帕米膦酸）治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進(jìn)展后，換用唑來(lái)膦酸是否獲益 方法 收入乳腺癌骨轉(zhuǎn)移患者，經(jīng)氯屈膦酸、帕米膦酸治療出現(xiàn)SREs或影像學(xué)證實(shí)骨轉(zhuǎn)移病變進(jìn)展 唑來(lái)膦酸、靜脈注射、4mg/月，共3個(gè)月 隨訪：第一個(gè)月，每周一次；第8周 評(píng)估換用唑來(lái)膦酸對(duì)骨痛、生活質(zhì)量和骨標(biāo)記物的影響 研究開(kāi)始前1個(gè)月和開(kāi)始后不允許更換化療或內(nèi)分泌治療方案,Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.,唑來(lái)膦酸換藥治療：II期臨床試驗(yàn),結(jié)果 共有31例患者完成試驗(yàn) 第8周時(shí)患者疼痛顯著減輕(P 0.001) 第8周時(shí)，尿NTX水平也出現(xiàn)了下降趨勢(shì) (P 0.008) 換用唑來(lái)膦酸治療后，疼痛改善和尿NTX的下降呈正相關(guān) (Spearmans rho r 0.27; P 0.15）,Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.,唑來(lái)膦酸顯著緩解氯膦酸、帕米膦酸失效的乳腺癌骨痛,Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.,唑來(lái)膦酸換藥治療：II期臨床試驗(yàn)結(jié)論,第一個(gè)可以證實(shí)換藥獲益的臨床研究：氯膦酸或帕米膦酸治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進(jìn)展后，換用更強(qiáng)的雙膦酸鹽（唑來(lái)膦酸）可獲得收益。包括： 顯著減輕骨痛 顯著降低骨標(biāo)記物水平 如上述結(jié)果如經(jīng)進(jìn)一步隨機(jī)臨床試驗(yàn)證實(shí)，將對(duì)雙膦酸鹽在乳腺癌骨轉(zhuǎn)移和輔助治療領(lǐng)域產(chǎn)生重要影響,Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.,唑來(lái)膦酸預(yù)防芳香化酶抑制劑誘導(dǎo)的 骨質(zhì)丟失(AIBL)的研究,芳香化酶抑制劑治療伴有快速的骨質(zhì)流失,Statistically significantly more BMD loss on anastrozole than tamoxifen (p 0.0001),Time, years,Estimated % change (mean and 95% CI),Anastrozole,4,2,0,-2,-4,-6,-8,-10,Baseline,1,2,3,4,5,Anastrozole,Tamoxifen,4,2,0,-2,-4,-6,-8,-10,Baseline,1,2,3,4,5,Lumbar spine,Total hip,Adapted from Coleman RE, et al. J Clin Oncol. 2006;24(suppl):5s. Abstract 511.,Tamoxifen,所有芳香化酶抑制劑治療均增加骨折風(fēng)險(xiǎn)1,1. Adapted from Hadji P, et al. US Oncological Disease 2007. 2007;1:18-21; 2. Howell A, et al. Lancet. 2005;365:60-62; 3. Coleman RE, et al. Lancet Oncol. 2007;8:119-127; 4. Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757; 5. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.,Tamoxifen,Letrozole,Anastrozole,Placebo,Fractures, %,11,7.7,5.7,4.0,5.3,4.6,7.0,5.0,P .0001,P .001,P = .003,P = .25,Exemestane,ATAC2 (68 months),IES3 (58 months),BIG 1-984 (26 months),MA.175 (30 months),唑來(lái)膦酸預(yù)防 芳香化酶抑制劑誘導(dǎo)的骨質(zhì)丟失(AIBL)相關(guān)研究,絕經(jīng)期前婦女 ABCSG-12 (n= 404) 絕經(jīng)后婦女 Z-FAST (N= 602) ZO-FAST (N=1,066) E-ZO-FAST (N= 527) Total of number of patients enrolled N = 2,599,ABCSG-12: 激素輔助治療 的絕經(jīng)前婦女的骨密度（BMD）研究,入組時(shí)間：1999-2006 1,800絕經(jīng)期前患者 測(cè)定BMD的亞組：(n=404) Stage I & II, 10 pos nodes, ER+ and/or PR+ 療程：3年 Preoperative CT allowed 骨相關(guān)研究于6/03停止入組,Tamoxifen,Tamoxifen + Zoledronic acid (4 mg)* q 6 mo,Anastrozole + Zoledronic acid (4 mg)* q 6 mo,Anastrozole,3 years, BMD,R A N D O M I Z E,BMD = Bone mineral density; ER = Estrogen receptor; PR = Progesterone receptor; CT = Chemotherapy; XRT = Preoperative radiotherapy. *8 mg reduced to 4 mg. Gnant MF, et al. J Clin Oncol. 2007;25:820-828.,Surgery (+XRT),Goserelin 3.6 mg/28 days,Baseline BMD,6-month BMD,ABCSG-12 (5年隨訪結(jié)果): 腰椎骨密度的變化情況,36,60,36,60,36,60,36,60,Tamoxifen,Anastrozole,Tamoxifen,Anastrozole,No Zoledronic Acid,Zoledronic Acid,Adapted from Gnant MF et al. Presented at: San Antonio Breast Cancer Conference Dec. 13-16, 2007; Abstract 26.,-9.0%,-4.5%,-13.6%,-7.8%,+1.0%,+5.2%,-0.1%,+3.1%,Z-FAST,1 ZO-FAST2, and E-ZO-FAST3 試驗(yàn)設(shè)計(jì),0,5 years Final analysis,LET (2.5 mg/day) + 延遲* ZOL 4 mg q 6 mo,LET (2.5 mg/day) + 早期 ZOL 4 mg q 6 mo,R A N D O M I Z E D,3 years,1 year,ER = Estrogen receptor; PR = Progesterone receptor; BC = Breast cancer; PMW = Postmenopausal women; CT = Chemotherapy; LET = Letrozole; ZOL = Zoledronic acid. *延遲唑來(lái)膦酸治療定義為：當(dāng)基線入組后36個(gè)月內(nèi)出現(xiàn)BMD T-score 2.0，任何有臨床癥狀的骨折或無(wú)臨床癥狀的骨折時(shí)，開(kāi)始唑來(lái)膦酸治療 1. Brufsky , et al. Presented at: 30th Annual SABCS; December 13-16, 2007; San Antonio, Texas. Abstract 27; 2. DeBoer R, et al. Presented at: 30th Annual SABCS; December 13-16, 2007; San Antonio, Texas. Abstract 501; 3. Llombart A, et al. Presented at: 14th ECCO Conference; September 23-27, 2007; Barcelona, Spain. Abstract 2044.,Accrual completed: Z-FAST: N = 602 ZO-FAST: N = 1,066 E-ZO-FAST: N = 527 Total: N = 2,195,入組條件 ER+/PR+ BC 絕經(jīng)后患者，且 T-score 2 分層 Adjuvant CT (yes or no) T score ( 1 or between 1 and 2 ),Z-FAST: 唑來(lái)膦酸早期治療 可增加腰椎和髖關(guān)節(jié)BMD （36個(gè)月結(jié)果）,SEM = Standard error of the mean; BMD = Bone mineral density; ZOL = Zoledronic acid. *P values correspond to intergroup comparisons. Adapted from Brufsky A, et al. Presented at: 29th Annual SABCS; December 14-17, 2006; San Antonio, TX. Abstract 5060. Adapted from Brufsky A, et al. Presented at: 30th Annual SABCS; December 13-16, 2007; San Antonio, TX.,Month 24,Lumbar spine,Total hip,Mean (SEM) % change BMD,P .0001*,P .0001*,P .0001*,P .0001*,Month 12,Month 24,Month 12,4%,3%,2%,1%,0%,1%,2%,3%,4%,Upfront ZOL (4 mg/6 months),Delayed ZOL (4 mg/6 months),Month 36,Month 36,P .001*,P .001*,n=251,n=256,n=204,n=199,n=189,n=188,n=251,n=256,n=206,n=197,n=189,n=187, 4.4%, 5.9%, 6.7%, 3.3%, 4.7%, 5.2%,ZO-FAST: 唑來(lái)膦酸早期治療 增加腰椎和髖關(guān)節(jié)BMD（24個(gè)月結(jié)果）,BMD = Bone mineral density; ZOL = Zoledronic acid. 1. Bundred N, et al. Presented at: 5th EBCC; March 21-25, 2006; Nice, France. Abstract 12; 2. De Boer R, et al. Presented at: 30th Annual SABCS; December 13-16, 2007. Abstract 501.,Upfront ZOL (4 mg/6 months),Delayed ZOL (4 mg/6 months),Lumbar spine,6,4,2,0,2,4,Hip,P .0001,P .0001,BMD, % change,P .0001,P .0001,Month 242,Month 121,Month 242,Month 121,8,6,4,2,0,2,4,Postmenopausal,Recently postmenopausal,Lumbar spine,Hip,Lumbar spine,Hip,P .0001,P .0001,P .0001,P .0001,BMD, % change,Month 121,Month 121,E-ZO-FAST: 唑來(lái)膦酸早期治療 增加腰椎和髖關(guān)節(jié)BMD （12個(gè)月結(jié)果）,Lumbar spine,Hip,Upfront ZOL (4 mg/6 months),Delayed ZOL (4 mg/6 months),P .0001,P .0001,BMD = Bone mineral density; ZOL = Zoledronic acid. Llombart A et al. Presented at: ECCO 14; September 23-27, 2007 Barcelona, Spain. Abstract 2044.,5.2%,3.3%,小結(jié)：唑來(lái)膦酸預(yù)防AIBL,與三苯氧胺相比，芳香化酶抑制劑可顯著延長(zhǎng)乳腺癌患者的無(wú)疾病生存時(shí)間 AIBL在接受芳香化酶抑制劑輔助治療的乳腺癌患者常見(jiàn) 唑來(lái)膦酸每年注射2次（4mg/每6個(gè)月）可有效預(yù)防AIBL：4項(xiàng)試驗(yàn)均獲一致結(jié)果,AI = Aromatase inhibitor; ZOL = Zoledronic acid.,唑來(lái)膦酸可有效降低骨標(biāo)記物（NTX）水平并改善部分患者生存,2019/9/3,30,可編輯,中至高NTX水平與不良事件風(fēng)險(xiǎn)呈負(fù)相關(guān)（乳腺癌）,NTX levels (nmol/mmol creatinine): Low 50, Moderate 50-99, High 100. Horizontal lines represent 95% CI. Coleman et al. J Clin Oncol. 2005;23:4925-4935.,P .001 for all analyses shown,唑來(lái)膦酸治療3個(gè)月大多數(shù)患者NTX水平正常化,NTX = N-telopeptide of type I collagen; HRPC = Hormone-refractory prostate cancer; NSCLC = Non-small cell lung cancer; OST = Other solid tumors. Lipton A, et al. Presented at: ECCO 2007. Abstract 304.,唑來(lái)膦酸治療后NTX正?；c SREs和死亡風(fēng)險(xiǎn)均降低顯著相關(guān),NTX = N-telopeptide of type I collagen; SRE = Skeletal-related event; BC = Breast cancer; NS = P .2; E-E = Patients whose NTX levels remained elevated at 3 months. Lipton A, et al. Presented at ESMO 2006. Abstract 870P.,First SRE,Breast cancer,0,Death,49,0.505,0.473,0.821,Risk reduction, %,53,.002,P value,.002,48,.002,0.5,1.0,1.5,2.0,Increased risk versus E-E,Decreased risk versus E-E,1st Fracture/Bone surgery,Bone lesion progression,0.517,NS,唑來(lái)膦酸可延長(zhǎng)NTX正?；橄侔┗颊呱?E-N,E-E,100,80,60,40,20,0,3,6,9,12,15,18,21,24,Proportion deceased, % patients,Time on study, months (starting at month 3),NTX = N-telopeptide of type I collagen; E-E = Patients whose NTX levels remained elevated at 3 months; E-N = Patients whose NTX levels normalized at 3 months from elevated baseline levels. Lipton A, et al. Presented at ESMO 2006. Abstract 870P.,Breast cancer,P = .0017,小結(jié),唑來(lái)膦酸治療3個(gè)月使大多數(shù)NTX升高的乳腺癌患者NTX水平下降至正常，同時(shí)在這些患者中： 顯著降低首次SRE的發(fā)生風(fēng)險(xiǎn) 顯著降低死亡風(fēng)險(xiǎn) 下一步應(yīng)進(jìn)行前瞻性、隨機(jī)臨床試驗(yàn)以進(jìn)一步證實(shí)上述結(jié)果,NTX = N-telopeptide of type I collagen; BC = Breast cancer; HRPC = Hormone-refractory prostate cancer; NSCLC = Non-small cell lung cancer; OST = Other solid tumors.,唑來(lái)膦酸抗腫瘤機(jī)理研究,含氮雙膦酸鹽的抗腫瘤機(jī)制,NBPs, 含氮雙膦酸鹽 Adapted from Clzardin P, et al. Cancer Res 2005;65(12):4971-4974.,NBPs,NBPs,NBPs的直接抗腫瘤效果,腫瘤細(xì)胞的浸潤(rùn)和粘附 腫瘤細(xì)胞的增殖 腫瘤細(xì)胞的凋亡 協(xié)同其他抗腫瘤藥物,NBPs的間接抗腫瘤效果,破骨細(xì)胞活性 腫瘤血管生成 T細(xì)胞抗腫瘤活性,腫瘤細(xì)胞浸潤(rùn),腫瘤細(xì) 胞增值,激活破骨 細(xì)胞活性,骨轉(zhuǎn)移,雙膦酸鹽作用于腫瘤轉(zhuǎn)移的不同階段,Adapted from Mundy GR, et al. Nature Reviews Cancer 2002;2:584-593.,間接抗腫瘤,直接抗腫瘤,抑制骨吸收,體外及動(dòng)物模型證實(shí)唑來(lái)膦酸和 化療序貫有協(xié)同作用,圖1：多柔比星與唑來(lái)膦酸的序貫治療協(xié)同增加體外MCF-7乳腺癌細(xì)胞的凋亡,圖2：多柔比星與唑來(lái)膦酸單藥，聯(lián)合，或序貫治療對(duì)皮下MDA-G8腫瘤生長(zhǎng)的影響,Tumour volume (mm3),DOX,ZOL,DOX+ZOL,DOX then ZOL,ZOLthen DOX,1.Neville-Webbe et al. Int J Cancer 2005; 113:364-71 2.Ottewell et al. J. Natl. Cancer Inst. 2008 100(16):1167-1178,直接抗腫瘤,ABCSG-12 試驗(yàn)設(shè)計(jì),1999-2006年 1,803例絕經(jīng)前乳腺癌患者 內(nèi)分泌治療有效 (ER和/或PR陽(yáng)性) I&II期, 10個(gè)淋巴結(jié)轉(zhuǎn)移 除新輔助化療外未接受其他化療 治療期：3年 骨亞組分析包括404例患者,Adapted from Gnant M, et al. N Engl J Med. 2009;360(7):679-691.,5年隨訪的研究終點(diǎn) (三苯氧胺 vs 阿那曲唑; 唑來(lái)膦酸 vs 不使用唑來(lái)膦酸),主要終點(diǎn) 無(wú)病生存率 (DFS) DFS事件: 局部復(fù)發(fā), 對(duì)側(cè)乳腺癌, 遠(yuǎn)處轉(zhuǎn)移, 繼發(fā)性癌, 死亡 次要終點(diǎn) 無(wú)復(fù)發(fā)生存率(RFS): 局部復(fù)發(fā), 對(duì)側(cè)乳腺癌, 遠(yuǎn)處轉(zhuǎn)移, 繼發(fā)性癌 總體生存率 安全性 探索性終點(diǎn) 無(wú)骨轉(zhuǎn)移生存率,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,治療時(shí)間，月,無(wú)病生存率, %,事件數(shù) 風(fēng)險(xiǎn)比 (95% CI) vs No ZOL P ZOL 54/904 0.643 (0.46 to 0.91) 0.01 No ZOL 83/899,ABCSG-12:加用與不加用唑來(lái)膦酸的DFS比較 （中位隨訪48個(gè)月結(jié)果）,Adapted from Gnant M, et al. N Engl J Med. 2009;360(7):679-691.,與單獨(dú)使用內(nèi)分泌療法相比， 唑來(lái)膦酸顯著提高無(wú)復(fù)發(fā)生存率,平均隨訪時(shí)間 = 60月. RFS = 無(wú)復(fù)發(fā)生存率; CI = 可信區(qū)間; ZOL = 唑來(lái)膦酸. Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,經(jīng)唑來(lái)膦酸治療的病人中表現(xiàn)出 非顯著性趨勢(shì)：總生存率增高,平均隨訪時(shí)間 = 60月. OS = 總生存率; CI = 可信區(qū)間; ZOL = 唑來(lái)膦酸. Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,(n = 904),(n = 899),10,41,29,10,6,10,9,2,0,20,0,10,20,30,40,50,60,70,80,90,No ZOL,ZOL,第一事件患者， n,首次DFS事件:唑來(lái)膦酸減少骨和骨外復(fù)發(fā),Gnant M, et al. Presented at: ASCO 2008. Chicago, IL, USA. Abstract LBA4.,83 例事件,54例事件,接受唑來(lái)膦酸治療的病人發(fā)生骨轉(zhuǎn)移少,平均隨訪時(shí)間 = 60月. BMF = 無(wú)骨轉(zhuǎn)移; CI = 置信區(qū)間; ZOL = 唑來(lái)膦酸.,絕經(jīng)后乳腺癌：AZURE(新輔助亞組回顧性分析),標(biāo)準(zhǔn)輔助治療,標(biāo)準(zhǔn)輔助治療 唑來(lái)膦酸 4 mg，依次 3-4周1次，用6次 3個(gè)月1次，用8次 6個(gè)月1次，用5次,3,360 患者 BC， II/III期 分層: N+/N- T 分期 ER 狀況 化療方法 是否絕經(jīng) 他汀類藥物,隨 機(jī) 分 組,治療后隨訪: 5 年復(fù)發(fā)和生存率,治療5年,主要終點(diǎn)：無(wú)病生存率 次要終點(diǎn)：無(wú)骨轉(zhuǎn)移生存率，骨相關(guān)事件總生存率，不良反應(yīng)，生化標(biāo)記物,Winter et al. Presented at SABCS 2008, Abs# 5101,N=206 (6.1%),新輔助化療/+ ZOL,新輔助治療 AZURE,Winter MC, et al. SABCS, 2008 (Abst #5101),結(jié)論： 新輔助治療+ZOL能縮小腫瘤體積，并提高病理學(xué)完全應(yīng)答率 顯示ZOL可能有直接的抗腫瘤作用,a 多元分析 (N=171). RITS： 殘余浸潤(rùn)性腫瘤大小,正在進(jìn)行中的評(píng)估雙膦酸鹽抗腫瘤活性的臨床研究,已完成入組； 正在入組,總結(jié)1：唑來(lái)膦酸預(yù)防和治療乳腺癌骨相關(guān)疾病,與一、二代雙膦酸鹽相比，唑來(lái)膦酸降低SRE風(fēng)險(xiǎn)的療效更好 氯膦酸或帕米膦酸治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進(jìn)展后，換用更強(qiáng)的雙膦酸鹽（唑來(lái)膦酸）可獲得收益。包括： 顯著減輕骨痛 顯著降低骨標(biāo)記物水平 尚待進(jìn)一步研究證實(shí) 唑來(lái)膦酸每年注射2次（4mg/每6個(gè)月）可有效預(yù)防AIBL 4項(xiàng)試驗(yàn)均獲一致結(jié)果,總結(jié)1：唑來(lái)膦酸預(yù)防和治療乳腺癌骨相關(guān)疾病,唑來(lái)膦酸可有效降低骨標(biāo)記物（NTX）水平并改善部分患者生存 顯著降低首次SRE的發(fā)生風(fēng)險(xiǎn) 顯著降低死亡風(fēng)險(xiǎn) 唑來(lái)膦酸抗腫瘤活性可能在將來(lái)使乳腺癌患者更多獲益，無(wú)疾病生存時(shí)間更長(zhǎng) ABCSG-12試驗(yàn)、AZURE試驗(yàn),雙膦酸鹽臨床應(yīng)用常見(jiàn)問(wèn)題,骨痛不能做為雙膦酸鹽使用的唯一標(biāo)準(zhǔn),雙膦酸鹽使用時(shí)機(jī)： “影像學(xué)診斷是骨破壞，即使沒(méi)有骨痛癥狀”1 ECT異常，X線片、C