雙磷酸鹽乳腺癌中的應(yīng)用研究進展

1、雙膦酸鹽在乳腺癌中的應(yīng)用及研究進展雙膦酸鹽在乳腺癌中的應(yīng)用及研究進展 雙膦酸鹽在乳腺癌骨轉(zhuǎn)移中的應(yīng)用 雙膦酸鹽在乳腺癌治療相關(guān)骨丟失的研究進展 雙磷酸鹽在乳腺癌探索領(lǐng)域正在進行中的臨床雙膦酸鹽在乳腺癌骨轉(zhuǎn)移中的應(yīng)用雙膦酸鹽在乳腺癌骨轉(zhuǎn)移中的應(yīng)用骨轉(zhuǎn)移是常見疾病骨轉(zhuǎn)移是常見疾病全球全球5年的年的患病人數(shù)患病人數(shù)1000 1腫瘤患者腫瘤患者骨轉(zhuǎn)移發(fā)生率骨轉(zhuǎn)移發(fā)生率2中位中位生存時間生存時間 月月2-5疾病疾病1. Ferlay J, et al. IARC GLOBOCAN 2002. Cancer Incidence, Mortality, and Prevalence Worldwide.2.

2、 Coleman RE. Cancer Treat Rev. 2001;27:165-176.3. Coleman RE. Cancer. 1997;80(suppl):1588-1594.4. Zekri J, et al. Int J Oncol. 2001;19:379-382.5. Hussain M, et al. J Clin Oncol. 2001;19:2527-2533.骨髓瘤骨髓瘤 18370 - 956 - 54乳腺癌乳腺癌4,40665 - 7519 - 25前列腺癌前列腺癌 2,36965 - 7512 - 53肺癌肺癌 1,36230 - 406 - 7黑色素瘤黑色

3、素瘤 64314 - 456膀胱癌膀胱癌 1,1104015腎癌腎癌 58620 - 2512約70%的乳腺癌患者發(fā)生骨轉(zhuǎn)移 4050%的患者第1個復(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年乳腺癌骨轉(zhuǎn)移乳腺癌骨轉(zhuǎn)移骨轉(zhuǎn)移及骨相關(guān)事件可帶來嚴重的后果骨轉(zhuǎn)移及骨相關(guān)事件可帶來嚴重的后果骨轉(zhuǎn)移如不經(jīng)治療，骨轉(zhuǎn)移如不經(jīng)治療，SRE將十分常見將十分常見SRE = Skeletal-related event; NSCLC = Non-small cell lung cancer. *PLACEBO ARM FROM ZOLEDRONIC ACID AND PAMIDRON

4、ATE TRIALS; ALL PATIENTS RECEIVED STANDARD ANTINEOPLASTIC THERAPIES.1. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321; 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621.Placebo arm*50%49%51%46%

5、 0 10 20 30 40 50 60 70Breast cancer1 Prostatecancer2Multiplemyeloma3NSCLC and OST 4Patients with an SRE, %Data are from placebo-control arms of bisphosphonate trials.1. Lipton A, et al. Cancer. 2000;88:1082-1090; 2. Rosen LS, et al. Cancer. 2004;100:2613-2621; 3. Berenson JR, et al. J Clin Oncol. 1

6、998;16:593-602; 4. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.2.712.203.701.470.01.02.03.04.0Mean SREs/yearBreast cancer1Lung cancer and other solid tumors2Multiple myeloma3Prostate cancer4Patients with cancer乳腺癌患者每年可能發(fā)生多次骨相關(guān)事件乳腺癌患者每年可能發(fā)生多次骨相關(guān)事件乳腺癌中骨相關(guān)事件的發(fā)生率乳腺癌中骨相關(guān)事件的發(fā)生率Lipton A, et al. Canc

7、er, 2000;88:1082-1090; *總SREs中不包含高鈣血癥乳腺癌骨相關(guān)事件（SREs）發(fā)生率病理性骨折可降低生存病理性骨折可降低生存 病理性骨折與死亡風(fēng)險增加顯著相關(guān)病理性骨折與死亡風(fēng)險增加顯著相關(guān)1,2 乳腺癌乳腺癌 1.52 (1.28, 1.81) P .0001 多發(fā)骨髓瘤多發(fā)骨髓瘤1.44 (1.06, 1.95) P = .02 前列腺癌前列腺癌1.29 (1.01, 1.65) P = .041. Hei Y-J, et al. Presented at: 28th Annual SABCS, 2005, Abstract 6036.2. Saad F, et a

8、l. Presented at: ECCO 2005. Abstract 1265. 兩項大型臨床試驗證實唑來膦酸可有效預(yù)防延兩項大型臨床試驗證實唑來膦酸可有效預(yù)防延緩骨相關(guān)事件，顯著緩解骨痛緩骨相關(guān)事件，顯著緩解骨痛唑來膦酸與帕米膦酸隨機對照唑來膦酸與帕米膦酸隨機對照研究設(shè)計研究設(shè)計（010試驗）試驗）025 月最終分析雙盲、雙模擬研究，旨在證實：與帕米膦酸二鈉相比，唑來膦酸具有非劣效性唑來膦酸 8 /4mg，1次/34 周隨隨機機化化分分組組唑來膦酸 4 mg，1次/34 周n = 564n = 526帕米膦酸二鈉 90 mg ，1次/34 周三組均每日口服維生素 D 400 IU 及鈣

9、500 mgn = 5581,130例IV期乳腺癌患者518例多發(fā)性骨髓瘤患者13月核心分析Rosen LS et al. Cancer J. 2003;98:1735-44唑來膦酸亞洲乳腺癌骨轉(zhuǎn)移患者臨床試驗研究設(shè)計唑來膦酸亞洲乳腺癌骨轉(zhuǎn)移患者臨床試驗研究設(shè)計（1501試驗）試驗）隨機隨機分組分組唑來膦酸唑來膦酸 4 mg ，靜脈輸注靜脈輸注15min，每每4周，共周，共12個月個月n = 114安慰劑，靜脈輸注安慰劑，靜脈輸注15min，每每4周，共周，共12個月個月n = 114（n=228）多中心、隨機、雙盲、安慰劑對照研究多中心、隨機、雙盲、安慰劑對照研究J Clin Oncol 2

10、005;23:3314-3321唑來膦酸顯著減少骨相關(guān)事件發(fā)生率唑來膦酸顯著減少骨相關(guān)事件發(fā)生率Cumulative expected SREs, (n) per 100 patientsMonths since randomizationPamidronateZoledronic acid 4 mgP = .04636912151821250204060100120080Breast cancerCook and Lawless approach, pooled stratified multiple event analysis.Major PP, et al. Presented at:

11、 2003 ASCO Annual Meeting. Abstract 3062.唑來膦酸延遲乳腺癌首次骨相關(guān)事件的發(fā)生唑來膦酸延遲乳腺癌首次骨相關(guān)事件的發(fā)生Zoledronic acidPamidronateZoledronic acidPamidronate10090807060504030201000120240360480600720463325191093513927201196Patients without SRE, %Time on study, daysSRE = Skeletal-related event.*Median time to first SRE not rea

12、ched in either treatment group.Costa L, et al. Breast Cancer Res Treat. 2006;100:S62. Abstract 1071.49.629.80102030405060Placebo (N = 113)ZOL 4mg (N = 114)唑來膦酸顯著減低發(fā)生唑來膦酸顯著減低發(fā)生SRE的患者比率的患者比率Percent of patientsP = .003Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 40%唑來膦酸顯著減少骨相關(guān)事件發(fā)生風(fēng)險唑來膦酸顯著減少骨相關(guān)事件發(fā)生風(fēng)

13、險RCC = Renal cell carcinoma; ZOL = Zoledronic acid; Kohno N, et al. J Clin Oncol. 2005;23:3314-332; Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; Rosen LS, et al. Cancer. 2004;100:2613-2621; Lipton A, et al. Cancer. 2003;98:962-969.In favor of ZOLIn favor of placeboRisk reductionP value41%.019

14、36%.00231%.00332%.01658%.010ProstateSolid tumorsLung cancerRCC00.20.40.60.811.21.41.61.82Relative risk of SREBreast唑來膦酸可顯著降低骨相關(guān)事件發(fā)生風(fēng)險唑來膦酸可顯著降低骨相關(guān)事件發(fā)生風(fēng)險In favor of zoledronic acid In favor of pamidronateRosen LS, et al. Cancer. 2003;98:1735-1744.00.20.40.60.811.21.41.61.82Risk ratio (zoledronic acid

15、4 mg versus pamidronate)P value.025Riskreduction.79920%Clinical outcome was assessed after 25 months. 與帕米膦酸相比，唑來膦酸可使骨相關(guān)事件發(fā)生風(fēng)險進一步降低與帕米膦酸相比，唑來膦酸可使骨相關(guān)事件發(fā)生風(fēng)險進一步降低20%20%唑來膦酸顯著降低乳腺癌骨轉(zhuǎn)移患者唑來膦酸顯著降低乳腺癌骨轉(zhuǎn)移患者BPI 骨痛評分骨痛評分Mean change from baseline2 24 48 812121616202024242828323236364040444448485252Time on study,

16、 weeks*P .050 0*BPI = Brief Pain Inventory.Adapted with permission from Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 唑來膦酸顯著改善乳腺癌骨轉(zhuǎn)移患者各種生活質(zhì)量評分唑來膦酸顯著改善乳腺癌骨轉(zhuǎn)移患者各種生活質(zhì)量評分*圖圖中中顯顯示的是示的是9次注射后最后一次隨次注射后最后一次隨訪訪與基與基線線水平相比的水平相比的總總的平均的平均變變化?；?。*與基與基線線相比，相比，P 0.05. EORTC QLQ-C30 = 歐洲研究和治歐洲研究和治療療癌癥癌癥組織組織的患者生活的患者

17、生活質(zhì)質(zhì)量量問問卷卷30 Wardley A, et al. British J Cancer 2005; 92: 1869-76.安慰劑對照試驗中雙膦酸鹽治療乳腺癌的療效安慰劑對照試驗中雙膦酸鹽治療乳腺癌的療效Pavlakis N, et al. Cochrane Database Syst Rev. 2005;4:1-38.唑來膦酸在乳腺癌骨轉(zhuǎn)移的臨床試驗結(jié)論唑來膦酸在乳腺癌骨轉(zhuǎn)移的臨床試驗結(jié)論 SRE發(fā)生顯著延遲 更少的病人發(fā)生SRE 每個病人發(fā)生更少的SRE 發(fā)生SRE 的風(fēng)險減低 可顯著緩解骨痛 與其他雙膦酸鹽相比，唑來膦酸可更顯著降低骨相關(guān)事件發(fā)生風(fēng)險 一、二代雙膦酸鹽治療中發(fā)生一

18、、二代雙膦酸鹽治療中發(fā)生SREs后換用作后換用作用更強的藥物是否有益？用更強的藥物是否有益？唑來膦酸換藥治療：唑來膦酸換藥治療：II期臨床試驗期臨床試驗 目的 評估一、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)移病變進展后，換用唑來膦酸是否獲益 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)證實骨轉(zhuǎn)移病變進展 唑來膦酸、靜脈注射、4mg/月，共3個月 隨訪：第一個月，每周一次；第8周 評估換用唑來膦酸對骨痛、生活質(zhì)量和骨標(biāo)記物的影響 研究開始前1個月和開始后不允許更換化療或內(nèi)分泌治療方案唑來膦酸換藥治療：唑來膦酸換藥治療：II期臨床試驗期臨床試驗 結(jié)

19、果 共有31例患者完成試驗 第8周時患者疼痛顯著減輕(P 0.001) 第8周時，尿NTX水平也出現(xiàn)了下降趨勢 (P 0.008) 換用唑來膦酸治療后，疼痛改善和尿NTX的下降呈正相關(guān) (Spearmans rho r 0.27; P 0.15）唑來膦酸顯著緩解其它雙膦酸鹽失效的乳腺癌骨痛唑來膦酸顯著緩解其它雙膦酸鹽失效的乳腺癌骨痛最差疼痛評分最差疼痛評分Baseline Week 1 Week 2 Week 3 Week 4 Week 8 1.96*SE 1.00*SEMean6.55.54.53.52.51.55.55.04.54.03.53.02.52.01.51.0Baseline W

20、eek 1 Week 2 Week 3 Week 4 Week 8 1.96*SE 1.00*SEMean平均疼痛評分平均疼痛評分Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.唑來膦酸換藥治療：唑來膦酸換藥治療：II期臨床試驗結(jié)論期臨床試驗結(jié)論 第一個臨床研究證實：氯膦酸或帕米膦酸治療期間發(fā)生SREs或骨轉(zhuǎn)移病變進展后，換用更強的雙膦酸鹽（唑來膦酸）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)進一步隨機臨床試驗證實，將對雙膦酸鹽在乳腺癌骨轉(zhuǎn)移和輔助治療領(lǐng)域產(chǎn)生重要影響唑來膦酸何時開始使用，何時停用唑來膦酸何時開始使

21、用，何時停用早期治療預(yù)防骨相關(guān)事件發(fā)生非常重要早期治療預(yù)防骨相關(guān)事件發(fā)生非常重要 乳腺癌患者發(fā)生SRE后，再次發(fā)生SRE 的機率增加2倍1 病理性骨折增加死亡風(fēng)險2SRE = Skeletal-related event; hazard ratio reflects multivariate model adjusted for previous SREs and performance status.1. Kaminski M, et al. Presented at: Primary Therapy of Early Breast Cancer 9th International Conf

22、erence; January 26-29, 2005. Abstract 107; 2. Saad F, et al. Cancer. 2007;110:1860-1867. Hazard ratio00.2 0.4 0.6 0.811.2 1.4 1.6 1.82Decreased mortalityIncreased mortalityP valueRiskincrease.00332%1.32Breast cancer出現(xiàn)骨痛前使用唑來膦酸可使乳腺癌患者獲益更多出現(xiàn)骨痛前使用唑來膦酸可使乳腺癌患者獲益更多Costa L, et al. Breast Cancer Res Treat.

23、2006;100:S62. Abstract 1071.15% relative reduction; P = .097.RiskreductionExtension phase only (months 13 - 25)Relative risk00.20.40.60.811.21.41.61.82.026P value0.59141%.0250.79920%25-month follow-up 唑來膦酸可使乳腺癌患者長期持續(xù)獲益唑來膦酸可使乳腺癌患者長期持續(xù)獲益In patients on their second year of zoledronic acid treatment, th

24、e relative risk of experiencing an SRE remained lower than with pamidronate*As determined by Andersen-Gill multiple event analysis.Adapted from Zheng M, et al. Presented at: Primary Therapy of Early Breast Cancer 9th International Conference; January 26-29, 2005; Abstract 104.唑來膦酸可顯著降低乳腺癌患者再次發(fā)生唑來膦酸可

25、顯著降低乳腺癌患者再次發(fā)生SRE的風(fēng)險的風(fēng)險RiskreductionRelative risk00.20.40.60.811.21.41.61.82P valueAll SREs.0150.71129%.0450.69031%Excluding first SRE Zoledronic acid reduced the risk of experiencing a second SRE by about one third compared with pamidronate*As determined by Andersen-Gill multiple event analysis.Adap

26、ted from Zheng M, et al. Presented at: Primary Therapy of Early Breast Cancer 9th International Conference; January 26-29, 2005; Abstract 104.ASCO 乳腺癌骨轉(zhuǎn)移治療指南乳腺癌骨轉(zhuǎn)移治療指南 推薦X線/CT/MRI等影像學(xué)檢查有骨破壞時開始使用靜脈雙膦酸鹽 推薦每3-4周使用靜脈唑來膦酸(4 mg via 15-minute infusion)或帕米膦酸(90 mg via 2-hour infusion) 未推薦口服雙膦酸鹽 雙膦酸鹽應(yīng)持續(xù)使用直至患

27、者不能耐受或一般狀況顯著下降Hillner B, et al. J Clin Oncol. 2003;21:4042-4057.歐洲指南：雙膦酸鹽在實體腫瘤的應(yīng)用歐洲指南：雙膦酸鹽在實體腫瘤的應(yīng)用 雙膦酸鹽作為有效的輔助支持治療，減少頻繁而嚴重的各種實體瘤骨轉(zhuǎn)移患者的骨并發(fā)癥 預(yù)防，減少和延遲腫瘤相關(guān)的骨并發(fā)癥的出現(xiàn) 并持續(xù)減少后續(xù)事件的發(fā)生 有效治療腫瘤治療相關(guān)的骨丟失（CTIBL) 國際專家委員會根據(jù)大量循證證據(jù)推薦： 乳腺癌骨轉(zhuǎn)移的患者使用含氮雙膦酸鹽 其他實體腫瘤骨轉(zhuǎn)移使用唑來膦酸 最好使用靜脈注射的藥物 口服氯屈膦酸僅應(yīng)用在不能接受正規(guī)住院治療的乳腺癌患者 早期癌癥患者如果合并CTI

28、BL的高風(fēng)險，應(yīng)接受雙膦酸鹽預(yù)防性治療。目前根據(jù)最有效的臨床證據(jù)，建議使用唑來膦酸M. Aapro，et al. Annals of Oncology 19: 420432, 2008 總的來說，雙膦酸鹽的耐受性良好 流感樣癥狀 關(guān)節(jié)痛 胃腸道癥狀（僅出現(xiàn)在口服藥物） 在接受雙膦酸鹽治療期間 起始劑量按照腎功能和基線是肌酐清除率來調(diào)整 后續(xù)的治療推薦帕米膦酸和唑來膦酸，治療用量根據(jù)監(jiān)測結(jié)果調(diào)整 定期進行牙科檢查，評估風(fēng)險，減少ONJ發(fā)生歐洲指南：雙膦酸鹽在實體腫瘤的應(yīng)用（續(xù)）歐洲指南：雙膦酸鹽在實體腫瘤的應(yīng)用（續(xù)）M. Aapro，et al. Annals of Oncology 19: 4

29、20432, 2008雙膦酸鹽在雙膦酸鹽在乳腺癌治療相關(guān)骨丟失的研究進展乳腺癌治療相關(guān)骨丟失的研究進展芳香化酶抑制劑治療伴有快速的骨質(zhì)流失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, yearsEstimated % change (mean and 95% CI)Anastrozole420-2-4-6-8-10Baseline12345AnastrozoleTamoxifen420-2-4-6-8-10Baseline123

30、45Lumbar spineTotal hipAdapted 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)險所有芳香化酶抑制劑治療均增加骨折風(fēng)險11. 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

31、. 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.TamoxifenLetrozoleAnastrozolePlaceboFractures, %117.75.74.05.34.67.05.0P .0001P .00102468101214P = .003P = .25ExemestaneATAC2(68 months)IES3(58 months)BIG 1-984(26 mon

32、ths)MA.175(30 months)正在進行的唑來膦酸預(yù)防正在進行的唑來膦酸預(yù)防芳香化酶抑制劑誘導(dǎo)的骨質(zhì)丟失芳香化酶抑制劑誘導(dǎo)的骨質(zhì)丟失(AIBL)研究研究 絕經(jīng)期前婦女絕經(jīng)期前婦女 ABCSG-12 (n= 404) 絕經(jīng)后婦女絕經(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 = 2,599ABCSG-12: 激素輔助治療激素輔助治療的絕經(jīng)前婦女的骨密度（的絕經(jīng)前婦女的骨密度（BMD）研究）研究入組時間：入組時間：1999-2006 1,800絕經(jīng)

33、期前患者絕經(jīng)期前患者 測定測定BMD的亞組：的亞組：(n=404)Stage I & II, 10 pos nodes, ER+ and/or PR+療程：療程：3年年P(guān)reoperative CT allowed骨相關(guān)研究于骨相關(guān)研究于6/03停止入組停止入組TamoxifenTamoxifen +Zoledronic acid (4 mg)* q 6 moAnastrozole +Zoledronic acid (4 mg)* q 6 moAnastrozole 3 years,BMDBMD = Bone mineral density; ER = Estrogen recepto

34、r; 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)Goserelin3.6 mg/28 daysBaselineBMD6-month BMDABCSG-12 (5年隨訪結(jié)果年隨訪結(jié)果): 腰椎骨密度的變化情況腰椎骨密度的變化情況3660366036603660TamoxifenAnastrozoleTamoxifenA

35、nastrozoleNo Zoledronic AcidZoledronic AcidAdapted 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 試驗設(shè)計試驗設(shè)計05 yearsFinal analysis 3 years1 yearER = Estrogen receptor; PR =

36、 Progesterone receptor; BC = Breast cancer; PMW = Postmenopausal women; CT = Chemotherapy; LET = Letrozole;ZOL = Zoledronic acid.*延遲唑來膦酸治療定義為：當(dāng)基線入組后延遲唑來膦酸治療定義為：當(dāng)基線入組后36個月內(nèi)出現(xiàn)個月內(nèi)出現(xiàn)BMD T-score 1 or between 1 and 2 )Z-FAST: 唑來膦酸早期治療唑來膦酸早期治療可增加腰椎和髖關(guān)節(jié)可增加腰椎和髖關(guān)節(jié)BMD （36個月結(jié)果）個月結(jié)果）SEM = Standard error of the m

37、ean; 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, 2

38、007; San Antonio, TX.Month 24Lumbar spineTotal hipMean (SEM) % change BMD P .0001*P .0001*P .0001*P .0001*Month 12Month24Month124%3%2%1%0%1%2%3%4%Upfront ZOL (4 mg/6 months)Delayed ZOL (4 mg/6 months)Month 36Month 36P .001*P .001*n=251n=256n=204n=199n=189n=188n=251n=256n=206n=197n=189n=187 4.4% 5.9%

39、 6.7% 3.3% 4.7% 5.2%ZO-FAST: 唑來膦酸早期治療唑來膦酸早期治療增加腰椎和髖關(guān)節(jié)增加腰椎和髖關(guān)節(jié)BMD（24個月結(jié)果）個月結(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. Abstra

40、ct 501.Upfront ZOL (4 mg/6 months)Delayed ZOL (4 mg/6 months)Lumbar spine642024HipP .0001P .0001BMD, % changeP .0001P .0001Month 242Month 121Month 242Month 1218642024PostmenopausalRecently postmenopausalLumbar spineHipLumbar spineHipP .0001P .0001P .0001P .0001BMD, % changeMonth 121Month 121E-ZO-FAS

41、T: 唑來膦酸早期治療唑來膦酸早期治療增加腰椎和髖關(guān)節(jié)增加腰椎和髖關(guān)節(jié)BMD （12個月結(jié)果）個月結(jié)果）Lumbar spineHipUpfront ZOL(4 mg/6 months)Delayed ZOL(4 mg/6 months)P .0001P -1BMD T-score between -1 and -2.5BMD T-score -2.5提供生活方式的指導(dǎo)提供生活方式的指導(dǎo)補充鈣和補充鈣和 vitamin DProvide reassurance開始藥物治療開始藥物治療 Alendronate ( 福善美福善美 ） Risedronate Zoledronate （ 擇泰擇泰 ）

42、根據(jù)病人個體情況考慮根據(jù)病人個體情況考慮藥物治療藥物治療CTIBL= cancer treatment induced bone lossHillner et al. J Clin Oncol. 2003; 21:4042T-score 2.0Any 2 of the following risk factors:T-score 65 yearsLow BMI ( 6 monthsSmoking (current or history of)T-score 2.0, No risk factors Monitor risk status and BMD every 1 to 2 years*Z

43、oledronic acid (4 mg / 6 months)calcium and vitamin D supplementsMonitor BMD every 2 yearsCalcium and vitamin D supplements* 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 months). Use lowest T-score from 3 sites.Hadji P, et al. Presented at: SABCS 2007. Abstract 504. Data for ora

44、l bisphosphonates are emerging Evidence from 4 clinical trials indicate that zoledronic acid prevents AI-associated bone loss開始芳香化酶抑制劑治療的乳腺癌婦女的推薦開始芳香化酶抑制劑治療的乳腺癌婦女的推薦雙磷酸鹽在乳腺癌探索領(lǐng)域雙磷酸鹽在乳腺癌探索領(lǐng)域正在進行的臨床研究正在進行的臨床研究骨標(biāo)志物在乳腺癌骨轉(zhuǎn)移領(lǐng)域骨標(biāo)志物在乳腺癌骨轉(zhuǎn)移領(lǐng)域臨床研究進展臨床研究進展多數(shù)腫瘤骨轉(zhuǎn)移病人基線多數(shù)腫瘤骨轉(zhuǎn)移病人基線NTX 升高升高NTX levels (nmol/mmol cre

45、atinine): Low .2; E-E = Patients whose NTX levels remained elevated at 3 months. Lipton A, et al. Presented at ESMO 2006. Abstract 870P.First SREBreast cancer0Death490.5050.4730.821Risk reduction, %53.002 P value.00248.0020.51.01.52.0Increased risk versus E-EDecreased risk versus E-E1st Fracture/Bon

46、e surgeryBone lesion progression0.517NS唑來膦酸可延長唑來膦酸可延長NTX正常化乳腺癌患者生存正?；橄侔┗颊呱鍱-NE-E1008060402003691215182124Proportion deceased, % patientsTime 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 w

47、hose NTX levels normalized at 3 months from elevated baseline levels. Lipton A, et al. Presented at ESMO 2006. Abstract 870P.Breast cancerP = .0017唑來膦酸治療后唑來膦酸治療后NTX正常化組可獲與基線正?；M可獲與基線NTX正常組相似生存正常組相似生存NTX = N-telopeptide of type I collagen; E-E = Persistently elevated NTX; E-N = Elevated baseline NTX

48、that normalized at 3 months; N-N = Normal NTX at baseline and 3 months.Lipton A, et al. Presented at SABCS 2005. Abstract 3015.60801004020003691215182124N-N (132 at risk, 49 events)E-N (160 at risk, 79 events)E-E (36 at risk, 27 events)Time since randomization, monthsPatients who died, %小結(jié)小結(jié) 唑來膦酸治療3

49、個月使大多數(shù)NTX升高的乳腺癌患者NTX水平下降至正常，同時在這些患者中： 顯著降低首次SRE的發(fā)生風(fēng)險 顯著降低死亡風(fēng)險 下一步應(yīng)進行前瞻性、隨機臨床試驗以進一步證實上述結(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. 雙磷酸鹽在乳腺癌預(yù)防骨轉(zhuǎn)移領(lǐng)域雙磷酸鹽在乳腺癌預(yù)防骨轉(zhuǎn)移領(lǐng)域正在進行的臨床研究正在進行的臨床研

50、究唑來膦酸預(yù)防乳腺癌骨轉(zhuǎn)移：唑來膦酸預(yù)防乳腺癌骨轉(zhuǎn)移：AZURE試驗試驗主要終點: 無病生存期 次要重點: 無骨轉(zhuǎn)移生存期, SREs, 總生存, 副反應(yīng), 預(yù)測性的生物標(biāo)志物第一次中期分析時間：2008Standard TherapyStandard TherapyStandard TherapyZoledronic acid 4 mgZoledronic acid 4 mg 6 doses (q 3-4 wk) 6 doses (q 3-4 wk)8 doses (q 3 months)8 doses (q 3 months)5 doses (q 6 months) 3,360 patie

51、ntsBC stage II/III Stratification: N+/N- T Stage ER Status Chemotherapy type Pre-/ Postmenopausal StatinsRFollow-up without treatment:5 years for recurrence and survivalTreatment duration 5 yearsPI: Rob ColemanSREs = Skeletal-related events; BC = Breast cancer; ER = Estrogen receptor.Accrual completed February 2006唑來膦酸預(yù)防乳腺癌骨轉(zhuǎn)移：唑來膦酸預(yù)防乳腺癌骨轉(zhuǎn)移：SUCCESS 試驗試