双磷酸盐乳腺癌中的应用研究进展

1、双膦酸盐在乳腺癌中的应用及研究进展双膦酸盐在乳腺癌中的应用及研究进展 双膦酸盐在乳腺癌骨转移中的应用 双膦酸盐在乳腺癌治疗相关骨丢失的研究进展 双磷酸盐在乳腺癌探索领域正在进行中的临床双膦酸盐在乳腺癌骨转移中的应用双膦酸盐在乳腺癌骨转移中的应用骨转移是常见疾病骨转移是常见疾病全球全球5年的年的患病人数患病人数1000 1肿瘤患者肿瘤患者骨转移发生率骨转移发生率2中位中位生存时间生存时间 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肾癌肾癌 58620 - 2512约70%的乳腺癌患者发生骨转移 4050%的患者第1个复发部位 症状：骨痛、高钙血症、骨折仅20%发生骨转移的乳腺癌患者存活5年乳腺癌骨转移乳腺癌骨转移骨转移及骨相关事件可带来严重的后果骨转移及骨相关事件可带来严重的后果骨转移如不经治疗，骨转移如不经治疗，SRE将十分常见将十分常见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发生多次骨相关事件乳腺癌患者每年可能发生多次骨相关事件乳腺癌中骨相关事件的发生率乳腺癌中骨相关事件的发生率Lipton A, et al. Canc

7、er, 2000;88:1082-1090; *总SREs中不包含高钙血症乳腺癌骨相关事件（SREs）发生率病理性骨折可降低生存病理性骨折可降低生存 病理性骨折与死亡风险增加显著相关病理性骨折与死亡风险增加显著相关1,2 乳腺癌乳腺癌 1.52 (1.28, 1.81) P .0001 多发骨髓瘤多发骨髓瘤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. 两项大型临床试验证实唑来膦酸可有效预防延两项大型临床试验证实唑来膦酸可有效预防延缓骨相关事件，显著缓解骨痛缓骨相关事件，显著缓解骨痛唑来膦酸与帕米膦酸随机对照唑来膦酸与帕米膦酸随机对照研究设计研究设计（010试验）试验）025 月最终分析双盲、双模拟研究，旨在证实：与帕米膦酸二钠相比，唑来膦酸具有非劣效性唑来膦酸 8 /4mg，1次/34 周随随机机化化分分组组唑来膦酸 4 mg，1次/34 周n = 564n = 526帕米膦酸二钠 90 mg ，1次/34 周三组均每日口服维生素 D 400 IU 及钙

9、500 mgn = 5581,130例IV期乳腺癌患者518例多发性骨髓瘤患者13月核心分析Rosen LS et al. Cancer J. 2003;98:1735-44唑来膦酸亚洲乳腺癌骨转移患者临床试验研究设计唑来膦酸亚洲乳腺癌骨转移患者临床试验研究设计（1501试验）试验）随机随机分组分组唑来膦酸唑来膦酸 4 mg ，静脉输注静脉输注15min，每每4周，共周，共12个月个月n = 114安慰剂，静脉输注安慰剂，静脉输注15min，每每4周，共周，共12个月个月n = 114（n=228）多中心、随机、双盲、安慰剂对照研究多中心、随机、双盲、安慰剂对照研究J Clin Oncol 2

10、005;23:3314-3321唑来膦酸显著减少骨相关事件发生率唑来膦酸显著减少骨相关事件发生率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.唑来膦酸延迟乳腺癌首次骨相关事件的发生唑来膦酸延迟乳腺癌首次骨相关事件的发生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)唑来膦酸显著减低发生唑来膦酸显著减低发生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%唑来膦酸显著减少骨相关事件发生风险唑来膦酸显著减少骨相关事件发生风

13、险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唑来膦酸可显著降低骨相关事件发生风险唑来膦酸可显著降低骨相关事件发生风险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. 与帕米膦酸相比，唑来膦酸可使骨相关事件发生风险进一步降低与帕米膦酸相比，唑来膦酸可使骨相关事件发生风险进一步降低20%20%唑来膦酸显著降低乳腺癌骨转移患者唑来膦酸显著降低乳腺癌骨转移患者BPI 骨痛评分骨痛评分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. 唑来膦酸显著改善乳腺癌骨转移患者各种生活质量评分唑来膦酸显著改善乳腺癌骨转移患者各种生活质量评分*图图中中显显示的是示的是9次注射后最后一次随次注射后最后一次随访访与基与基线线水平相比的水平相比的总总的平均的平均变变化。化。*与基与基线线相比，相比，P 0.05. EORTC QLQ-C30 = 欧洲研究和治欧洲研究和治疗疗癌症癌症组织组织的患者生活的患者

17、生活质质量量问问卷卷30 Wardley A, et al. British J Cancer 2005; 92: 1869-76.安慰剂对照试验中双膦酸盐治疗乳腺癌的疗效安慰剂对照试验中双膦酸盐治疗乳腺癌的疗效Pavlakis N, et al. Cochrane Database Syst Rev. 2005;4:1-38.唑来膦酸在乳腺癌骨转移的临床试验结论唑来膦酸在乳腺癌骨转移的临床试验结论 SRE发生显著延迟 更少的病人发生SRE 每个病人发生更少的SRE 发生SRE 的风险减低 可显著缓解骨痛 与其他双膦酸盐相比，唑来膦酸可更显著降低骨相关事件发生风险 一、二代双膦酸盐治疗中发生一

18、、二代双膦酸盐治疗中发生SREs后换用作后换用作用更强的药物是否有益？用更强的药物是否有益？唑来膦酸换药治疗：唑来膦酸换药治疗：II期临床试验期临床试验 目的 评估一、二代双膦酸盐（氯屈膦酸、帕米膦酸）治疗期间发生SREs或骨转移病变进展后，换用唑来膦酸是否获益 方法 收入乳腺癌骨转移患者，经氯屈膦酸、帕米膦酸治疗出现SREs或影像学证实骨转移病变进展 唑来膦酸、静脉注射、4mg/月，共3个月 随访：第一个月，每周一次；第8周 评估换用唑来膦酸对骨痛、生活质量和骨标记物的影响 研究开始前1个月和开始后不允许更换化疗或内分泌治疗方案唑来膦酸换药治疗：唑来膦酸换药治疗：II期临床试验期临床试验 结

19、果 共有31例患者完成试验 第8周时患者疼痛显著减轻(P 0.001) 第8周时，尿NTX水平也出现了下降趋势 (P 0.008) 换用唑来膦酸治疗后，疼痛改善和尿NTX的下降呈正相关 (Spearmans rho r 0.27; P 0.15）唑来膦酸显著缓解其它双膦酸盐失效的乳腺癌骨痛唑来膦酸显著缓解其它双膦酸盐失效的乳腺癌骨痛最差疼痛评分最差疼痛评分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平均疼痛评分平均疼痛评分Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.唑来膦酸换药治疗：唑来膦酸换药治疗：II期临床试验结论期临床试验结论 第一个临床研究证实：氯膦酸或帕米膦酸治疗期间发生SREs或骨转移病变进展后，换用更强的双膦酸盐（唑来膦酸）可获得收益。包括： 显著减轻骨痛 显著降低骨标记物水平 如上述结果如经进一步随机临床试验证实，将对双膦酸盐在乳腺癌骨转移和辅助治疗领域产生重要影响唑来膦酸何时开始使用，何时停用唑来膦酸何时开始使

21、用，何时停用早期治疗预防骨相关事件发生非常重要早期治疗预防骨相关事件发生非常重要 乳腺癌患者发生SRE后，再次发生SRE 的机率增加2倍1 病理性骨折增加死亡风险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出现骨痛前使用唑来膦酸可使乳腺癌患者获益更多出现骨痛前使用唑来膦酸可使乳腺癌患者获益更多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 唑来膦酸可使乳腺癌患者长期持续获益唑来膦酸可使乳腺癌患者长期持续获益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.唑来膦酸可显著降低乳腺癌患者再次发生唑来膦酸可

25、显著降低乳腺癌患者再次发生SRE的风险的风险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 乳腺癌骨转移治疗指南乳腺癌骨转移治疗指南 推荐X线/CT/MRI等影像学检查有骨破坏时开始使用静脉双膦酸盐 推荐每3-4周使用静脉唑来膦酸(4 mg via 15-minute infusion)或帕米膦酸(90 mg via 2-hour infusion) 未推荐口服双膦酸盐 双膦酸盐应持续使用直至患

27、者不能耐受或一般状况显著下降Hillner B, et al. J Clin Oncol. 2003;21:4042-4057.欧洲指南：双膦酸盐在实体肿瘤的应用欧洲指南：双膦酸盐在实体肿瘤的应用 双膦酸盐作为有效的辅助支持治疗，减少频繁而严重的各种实体瘤骨转移患者的骨并发症 预防，减少和延迟肿瘤相关的骨并发症的出现 并持续减少后续事件的发生 有效治疗肿瘤治疗相关的骨丢失（CTIBL) 国际专家委员会根据大量循证证据推荐： 乳腺癌骨转移的患者使用含氮双膦酸盐 其他实体肿瘤骨转移使用唑来膦酸 最好使用静脉注射的药物 口服氯屈膦酸仅应用在不能接受正规住院治疗的乳腺癌患者 早期癌症患者如果合并CTI

28、BL的高风险，应接受双膦酸盐预防性治疗。目前根据最有效的临床证据，建议使用唑来膦酸M. Aapro，et al. Annals of Oncology 19: 420432, 2008 总的来说，双膦酸盐的耐受性良好 流感样症状 关节痛 胃肠道症状（仅出现在口服药物） 在接受双膦酸盐治疗期间 起始剂量按照肾功能和基线是肌酐清除率来调整 后续的治疗推荐帕米膦酸和唑来膦酸，治疗用量根据监测结果调整 定期进行牙科检查，评估风险，减少ONJ发生欧洲指南：双膦酸盐在实体肿瘤的应用（续）欧洲指南：双膦酸盐在实体肿瘤的应用（续）M. Aapro，et al. Annals of Oncology 19: 4

29、20432, 2008双膦酸盐在双膦酸盐在乳腺癌治疗相关骨丢失的研究进展乳腺癌治疗相关骨丢失的研究进展芳香化酶抑制剂治疗伴有快速的骨质流失芳香化酶抑制剂治疗伴有快速的骨质流失 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所有芳香化酶抑制剂治疗均增加骨折风险所有芳香化酶抑制剂治疗均增加骨折风险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)正在进行的唑来膦酸预防正在进行的唑来膦酸预防芳香化酶抑制剂诱导的骨质丢失芳香化酶抑制剂诱导的骨质丢失(AIBL)研究研究 绝经期前妇女绝经期前妇女 ABCSG-12 (n= 404) 绝经后妇女绝经后妇女Z-FAST (N= 602)ZO-FAST (N=1,066)E-ZO-FAST (N= 527) Total of number of patients enrolled N = 2,599ABCSG-12: 激素辅助治疗激素辅助治疗的绝经前妇女的骨密度（的绝经前妇女的骨密度（BMD）研究）研究入组时间：入组时间：1999-2006 1,800绝经

33、期前患者绝经期前患者 测定测定BMD的亚组：的亚组：(n=404)Stage I & II, 10 pos nodes, ER+ and/or PR+疗程：疗程：3年年Preoperative CT allowed骨相关研究于骨相关研究于6/03停止入组停止入组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年随访结果年随访结果): 腰椎骨密度的变化情况腰椎骨密度的变化情况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 试验设计试验设计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.*延迟唑来膦酸治疗定义为：当基线入组后延迟唑来膦酸治疗定义为：当基线入组后36个月内出现个月内出现BMD T-score 1 or between 1 and 2 )Z-FAST: 唑来膦酸早期治疗唑来膦酸早期治疗可增加腰椎和髋关节可增加腰椎和髋关节BMD （36个月结果）个月结果）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: 唑来膦酸早期治疗唑来膦酸早期治疗增加腰椎和髋关节增加腰椎和髋关节BMD（24个月结果）个月结果）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: 唑来膦酸早期治疗唑来膦酸早期治疗增加腰椎和髋关节增加腰椎和髋关节BMD （12个月结果）个月结果）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提供生活方式的指导提供生活方式的指导补充钙和补充钙和 vitamin DProvide reassurance开始药物治疗开始药物治疗 Alendronate ( 福善美福善美 ） Risedronate Zoledronate （ 择泰择泰 ）

42、根据病人个体情况考虑根据病人个体情况考虑药物治疗药物治疗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开始芳香化酶抑制剂治疗的乳腺癌妇女的推荐开始芳香化酶抑制剂治疗的乳腺癌妇女的推荐双磷酸盐在乳腺癌探索领域双磷酸盐在乳腺癌探索领域正在进行的临床研究正在进行的临床研究骨标志物在乳腺癌骨转移领域骨标志物在乳腺癌骨转移领域临床研究进展临床研究进展多数肿瘤骨转移病人基线多数肿瘤骨转移病人基线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唑来膦酸可延长唑来膦酸可延长NTX正常化乳腺癌患者生存正常化乳腺癌患者生存E-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唑来膦酸治疗后唑来膦酸治疗后NTX正常化组可获与基线正常化组可获与基线NTX正常组相似生存正常组相似生存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, %小结小结 唑来膦酸治疗3

49、个月使大多数NTX升高的乳腺癌患者NTX水平下降至正常，同时在这些患者中： 显著降低首次SRE的发生风险 显著降低死亡风险 下一步应进行前瞻性、随机临床试验以进一步证实上述结果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. 双磷酸盐在乳腺癌预防骨转移领域双磷酸盐在乳腺癌预防骨转移领域正在进行的临床研究正在进行的临床研

50、究唑来膦酸预防乳腺癌骨转移：唑来膦酸预防乳腺癌骨转移：AZURE试验试验主要终点: 无病生存期 次要重点: 无骨转移生存期, SREs, 总生存, 副反应, 预测性的生物标志物第一次中期分析时间：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唑来膦酸预防乳腺癌骨转移：唑来膦酸预防乳腺癌骨转移：SUCCESS 试验试