双磷酸盐乳腺癌中的应用研究进展

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,骨转移是常见疾病,全球5年的患病人数1000 1,肿瘤患者骨转移发生率2,中位生存时间 月2-5,疾病,1. Ferlay J, et al. IARC GLOBOCAN 2002. Cancer Incidence, Mortality, and Prevalence Worldwide.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,183,70 - 95,6 - 54,乳腺癌,4,406,65 - 75,19 - 25,前列腺癌,2,369,65 - 75,12 - 53,肺癌,1,362,30 - 40,6 - 7,黑色素瘤,643,14 - 45,6,膀胱癌,1,110,40,15,肾癌,586,20 - 25,12,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,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，SRE将十分常见,SRE = Skeletal-related event; NSCLC = Non-small cell lung cancer. *PLACEBO ARM FROM ZOLEDRONIC ACID AND PAMIDRONATE 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%,0,10,20,30,40,50,60,70,Breast cancer1,Prostatecancer2,Multiplemyeloma3,NSCLC and OST 4,Patients 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. 1998;16:593-602; 4. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.,2.71,2.20,3.70,1.47,0.0,1.0,2.0,3.0,4.0,Mean SREs/year,Breast cancer1,Lung cancer and other solid tumors2,Multiple myeloma3,Prostate cancer4,Patients with cancer,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,Lipton A, et al. Cancer, 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,病理性骨折与死亡风险增加显著相关1,2乳腺癌 1.52 (1.28, 1.81) P .0001多发骨髓瘤1.44 (1.06, 1.95) P = .02前列腺癌1.29 (1.01, 1.65) P = .04,1. Hei Y-J, et al. Presented at: 28th Annual SABCS, 2005, Abstract 6036.2. Saad F, et al. 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研究设计（010试验）,0,25 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,随机化分组,唑来膦酸 4 mg，1次/34 周,n = 564,n = 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 500 mg,n = 558,1,130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（1501试验）,随机分组,唑来膦酸 4 mg ，静脉输注15min，每4周，共12个月,n = 114,安慰剂，静脉输注15min，每4周，共12个月,n = 114,（n=228）,多中心、随机、双盲、安慰剂对照研究,J Clin Oncol 2005;23:3314-3321,唑来膦酸显著减少骨相关事件发生率,Cumulative expected SREs, (n) per 100 patients,Months since randomization,Cook and Lawless approach, pooled stratified multiple event analysis.Major PP, et al. Presented at: 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,Zoledronic acid,Pamidronate,Zoledronic acid,Pamidronate,100,90,80,70,60,50,40,30,20,10,0,0,120,240,360,480,600,720,46,33,25,19,10,9,3,51,39,27,20,11,9,6,Patients without SRE, %,Time on study, days,SRE = Skeletal-related event.*Median time to first SRE not reached in either treatment group.Costa L, et al. Breast Cancer Res Treat. 2006;100:S62. Abstract 1071.,49.6,29.8,0,10,20,30,40,50,60,唑来膦酸显著减低发生SRE的患者比率,Percent of patients,P = .003,Kohno 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,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 ZOL,In favor of placebo,Prostate,Solid tumors,Lung cancer,RCC,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,Relative risk of SRE,Breast,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 pamidronate,Rosen LS, et al. Cancer. 2003;98:1735-1744.,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,Risk ratio (zoledronic acid 4 mg versus pamidronate),P value,.025,Riskreduction,.799,20%,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20%,唑来膦酸显著降低乳腺癌骨转移患者BPI 骨痛评分,Mean change from baseline,2,4,8,12,16,20,24,28,32,36,40,44,48,52,Time on study, weeks,*,*,*,*,*,*,*,*,*,*,*,*P .05,0,*,*,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,*,*,*,*,图中显示的是9次注射后最后一次随访与基线水平相比的总的平均变化。*与基线相比，P 0.05. EORTC QLQ-C30 = 欧洲研究和治疗癌症组织的患者生活质量问卷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,氯屈膦酸（口服）1,600 mg(Kristensen)31%(Paterson)17%(Tubiana-Hulin)8%,P 值,唑来膦酸 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.,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SREs后换用作用更强的药物是否有益？,唑来膦酸换药治疗：II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：II期临床试验,结果共有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,Clemons M, et al. J Clin Oncol. 2006;24:4895-4900.,唑来膦酸换药治疗：II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,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2,SRE = 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 Conference; January 26-29, 2005. Abstract 107; 2. Saad F, et al. Cancer. 2007;110:1860-1867.,Hazard ratio,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,Decreased mortality,Increased mortality,P value,Riskincrease,.003,32%,1.32,Breast cancer,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. 2006;100:S62. Abstract 1071.,15% relative reduction; P = .097.,Riskreduction,Extension phase only (months 13 - 25),Relative risk,In favor of zoledronic acid,In favor of pamidronate,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,.026,P value,0.591,41%,.025,0.799,20%,25-month follow-up,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, the 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SRE的风险,Riskreduction,Relative risk,In favor of zoledronic acid,In favor of pamidronate,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,P value,.045,0.690,31%,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.Adapted 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,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,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CTIBL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）,M. Aapro，et al. Annals of Oncology 19: 420432, 2008,双膦酸盐在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,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,所有芳香化酶抑制剂治疗均增加骨折风险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),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(AIBL)研究,绝经期前妇女 ABCSG-12 (n= 404)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 = 2,599,ABCSG-12: 激素辅助治疗的绝经前妇女的骨密度（BMD）研究,入组时间：1999-2006 1,800绝经期前患者 测定BMD的亚组：(n=404)Stage I & II, 10 pos nodes, ER+ and/or PR+疗程：3年Preoperative CT allowed骨相关研究于6/03停止入组,Tamoxifen,Tamoxifen +Zoledronic acid (4 mg)* q 6 mo,Anastrozole + Zoledronic acid (4 mg)* q 6 mo,Anastrozole,3 years,BMD,RANDOMIZE,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),Goserelin3.6 mg/28 days,BaselineBMD,6-month BMD,ABCSG-12 (5年随访结果): 腰椎骨密度的变化情况,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 试验设计,0,5 yearsFinal analysis,LET (2.5 mg/day) + 延迟* ZOL 4 mg q 6 mo,LET (2.5 mg/day) + 早期 ZOL 4 mg q 6 mo,RANDOMIZED,3 years,1 year,ER = Estrogen receptor; PR = 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36个月内出现BMD T-score 1 or between 1 and 2 ),Z-FAST: 唑来膦酸早期治疗可增加腰椎和髋关节BMD （36个月结果）,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,Month24,Month12,4%,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: 唑来膦酸早期治疗增加腰椎和髋关节BMD（24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. 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: 唑来膦酸早期治疗增加腰椎和髋关节BMD （12个月结果）,Lumbar spine,Hip,Upfront ZOL(4 mg/6 months),Delayed ZOL(4 mg/6 months),P .0001,P -1,BMD T-score between -1 and -2.5,BMD T-score -2.5,提供生活方式的指导补充钙和 vitamin D,Provide reassurance,开始药物治疗 Alendronate ( 福善美 ） Risedronate Zoledronate （ 择泰 ）,根据病人个体情况考虑药物治疗,CTIBL= cancer treatment induced bone lossHillner et al. J Clin Oncol. 2003; 21:4042,T-score 2.0,Any 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*,Zoledronic acid (4 mg / 6 months)calcium and vitamin D supplements,Monitor BMD every 2 years,Calcium 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 oral bisphosphonates are emergingEvidence 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,双磷酸盐在乳腺癌探索领域正在进行的临床研究,骨标志物在乳腺癌骨转移领域临床研究进展,多数肿瘤骨转移病人基线NTX 升高,NTX levels (nmol/mmol creatinine): Low .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,唑来膦酸可延长NTX正常化乳腺癌患者生存,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,唑来膦酸治疗后NTX正常化组可获与基线NTX正常组相似生存,NTX = N-telopeptide of type I collagen; E-E = Persistently elevated NTX; E-N = Elevated baseline NTX that normalized at 3 months; N-N = Normal NTX at baseline and 3 months.Lipton A, et al. Presented at SABCS 2005. Abstract 3015.,60,80,100,40,20,0,0,3,6,9,12,15,18,21,24,N-N (132 at risk, 49 events),E-N (160 at risk, 79 events),E-E (36 at risk, 27 events),Time since randomization, months,Patients who died, %,小结,唑来膦酸治疗3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正在进行的临床研究,唑来膦酸预防乳腺癌骨转移：AZURE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：2008,Standard Therapy,Standard Ther