去势抵抗性前列腺癌的治疗进展课件.ppt

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1、去势抵抗性前列腺癌治疗进展,王秀问山东大学齐鲁医院 2010.06.26 淄博,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,Source:American Cancer Society,Cancer Facts and Figures 2007.Atlanta,GA;American Cancer Society:2007.,2009,USA:192,28027.360,摘自:复旦大学肿瘤医院泌尿外科 叶定伟,Prostate CancerTreatment Paradi

2、gms,ClinicallyLocalized,HormoneRefractory,Local treatment,Endocrine,Chemotherapy,RelapsedandNewly diagnosed M+,EORTG22863.,EORTG22961-SADT vs LADT.2010,4505ADT vs RT+ADTIntergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostat

3、e cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). J Clin Oncol (Meeting Abstracts) 2010 28: CRA4504.,Prostate CancerTreatment Paradigms,ClinicallyLocalized,HormoneRefractory,Local treatment,Endocrine,Chemotherapy,RelapsedandNewly diagnosed M+,Safety results of a phase III trial ev

4、aluating ADT+ docetaxel versus ADT alone in hormone-nave metastatic prostate cancer patients (GETUG-AFU 15/0403). J Clin Oncol 28:15s, 2010 (suppl; abstr 4681),前列腺癌的内分泌治疗,时间 (周),注射 戈舍瑞林 3.6 mg 或睾丸切除术后平均血清睾酮浓度,肿瘤治疗-内分泌疗法,内分泌治疗和化学药物治疗一样最终出现耐药现象,即激素治疗抵抗(Resistance to hormone therapy),激素受体基因突变是肿瘤获得性激素抵抗

5、表型的分子机制。正是由于激素受体基因突变,一部分患者存在激素治疗撤退反应(Hormone therapy withdrawal response),如前列腺癌患者抗雄激素药物治疗失败后,停药可使约30%的病人肿瘤缓解或PSA水平下降,并且骨扫描、癌性贫血以及其他相关症状改善,中位缓解时间3.5-5月,个别患者超过2年,停药反应动力学因不同制剂而异。内分泌治疗另一种现象就是激素治疗点火现象(Hormone therapy flare),即激素治疗初期临床症状、肿瘤指标、核素扫描甚至PET扫描有病变加重的现象,但这种现象常预示进一步激素治疗有效。如AA治疗CRPC约半数病人出现骨扫描闪烁现象。,雄

6、激素依赖性前列腺癌(Androgen-dependent Prostate Cancer, ADPC),雄激素非依赖性前列腺癌(androgen-independent prostate cancer,AIPC)激素难治性前列腺癌(hormone-refractory prostate cancer,HRPC),去势抵抗性前列腺癌(Castration resistant prostate cancer,CRPC ),CRPC的自然进程,Smith等对随机对照研究中470例安慰剂对照的CRPC患者的自然进程进行研究。TTP(出现转移)22.4月,TTBM 25.2月,OS 46.8月。PSA1

7、3.1ng/ml则与短TTP(RR2.21, P0.0001)、TTBM (RR1.98, P0.0001)、 OS(RR2.34, P0.0001)有关。,J Clin Oncol 28:15s, 2010 (suppl; abstr 4653),PSA-P(prostate-specific antigen progression ,PSA-P)作为疾病进展的指标近来用于研究的终点。 99共识把PSA-P定义为PSA较基础值或最低值增加50%,并且PSA5ng/ml(07共识2ng/ml),一周后应确认。 以99共识对S9346研究进行分析(激素敏感性前列腺癌),发现在7个月时达PSA-P

8、的患者总生存为10月,而7个月时未达到PSA-P者总生存为43月;对S9916研究进行分析(HRPC),以PSA-P为3个月,则总生存分别为10月和18月。* 这说明不论PSA是否达到最低值,PSA-P定义为PSA较基础值或最低值增加50%,并且PSA25ng/ml,对激素敏感性或激素难治性前列腺癌均能很好的反应总生存。,Hussain MH,et al.ASCO 2008,5015a,PSA进展,Multivariable Proportional Hazards Model of Biochemical PFS at 3 Months as Time-Dependent Covariate

9、 Predicting Overall Survival Stratified on Study(1296pts),Halabi, S. et al. J Clin Oncol; 27:2766-2771 2009,Halabi, S. et al. J Clin Oncol; 27:2766-2771 2009,Kaplan-Meier survival curves by biochemical progression using Prostate-Specific Antigen Working Group 1999 Criteria (PSAWG1) at 3 months,Halab

10、i, S. et al. J Clin Oncol; 27:2766-2771 2009,Kaplan-Meier survival curves by progression-free survival (PFS) at 3 months,6个月的PFSHR 1.9,P0.001,小结,前列腺癌是男性常见肿瘤内分泌治疗是转移性前列腺癌的主要治疗手段几乎所有前列腺癌患者治疗后出现去势抵抗PSA-P(prostate-specific antigen progression ,PSA-P)和PFS可作为疾病进展的指标近来用于研究的终点,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断

11、性雄激素剥夺问题和展望,AIPC的治疗,加用抗雄激素药物:单纯去势,行雄激素全阻断治疗(MAB)更换抗雄激素药物:氟他胺换为康士得,40% PSA下降,3.5 6.3月MDV3100作为小分子雄激素受体(AR)拮抗剂,作用机制不同于康士得,通过阻断核转运、DNA结合,而抑制AR功能。I/II期临床试验可降低去势抵抗前列腺癌(CRPC)患者的PSA水平停药疗法(withdrawal therapy)二线激素治疗(secondary hormone therapies),Scher HI,et al.ASCO 2008,5006a,停药疗法,1993年Kelly等报告与雄激素受体相互作用的制剂均有

12、停药反应30%的病人肿瘤缓解或PSA水平下降,并且有放射性核素骨扫描、癌症相关性贫血以及其它相关症状改善中位有效时间3.5 5月,个别患者超过2年停药反应动力学因不同制剂而异,康士得的血清半衰期约为6 天,而氟他胺的半衰期仅约为6 小时,二线激素治疗,酮康唑通过抑制细胞色素P450,从而抑制睾丸和肾上腺雄激素的产生,也可能对前列腺癌细胞有直接的细胞毒作用。酮康唑用于晚期前列腺癌,其客观有效率为10%,稳定率为35%。以PSA下降50%为指标,大剂量酮康唑(1200mg/d)加用氢化考的松的有效率为62.5%。,CALGB 9583研究,260例AIPC患者随机分为抗雄激素撤退(AAWD)同时给

13、与酮康唑或AAWD后PSA进展再给予酮康唑。PSA的有效率分别为30%和13%,两组之间有明显差别(P0.001)。联合治疗组的客观有效率为14%。但两组的生存期无明显差别(16.7月和15.3月)。 该研究还观察到接受酮康唑治疗后PSA下降50%以上的患者较PSA未下降的患者生存期延长(41月比13月,P0.001),这说明二线激素治疗PSA有效的患者有生存获益。对酮康唑治疗有效的患者可能比化疗的中位生存期长。,Small EJ,et al. J Clin Oncol,2004,22:1025-1033.,醋酸阿比特龙(Abiraterone Acetate,AA),部分CRPC患者雄激素合

14、成酶过表达,而肿瘤生长又依赖雄激素受体的信号传导(继续雄激素受体表达) 醋酸阿比特龙(Abiraterone Acetate,AA)能抑制17-a 羟化酶和C17,20裂解酶,从而使血清雄激素降低到不可测量的水平AA能抑制所有产生睾酮的器官所产生的睾酮不仅包括睾丸,还包括肾上腺和前列腺细胞本身。,Ryan C, Smith MR, Rosenberg JE,et al. Proc Am Sco Clin Oncol,2008,26:5018a.,对33例CRPC患者进行研究,55%(18/33)的患者PSA下降超过50%。30例患者完成12周治疗,13/30(43%)PSA下降超过50%。每日

15、1000mg治疗的12例患者中6例(50%)PSA下降。14例未接受酮康唑治疗的患者中8例(61%)对AA治疗PSA有反应;而19例使用过酮康唑治疗的患者中10例(53%)PSA下降超过50%,其PSA中位反应时间为21周。4例因酮康唑毒副作用停止治疗的患者使用AA有3例PSA有反应,15例使用酮康唑疾病进展的患者,AA治疗后7例(47%)PSA下降,中位进展时间为17周。在19例以前使用酮康唑治疗的患者中,16例(84%)PSA下降,15例(79%)因疾病进展停药,中位治疗时间为15月。该项初步研究说明即使酮康唑治疗进展的CRPC患者给予AA仍然有效,需进一步大规模临床试验研究。,醋酸阿比特

16、龙治疗CRPC,Danila, D. C. et al. J Clin Oncol; 28:1496-1501 2010,Changes in prostate-specific antigen (PSA) levels with abiraterone acetate plus prednisone,Danila, D. C. et al. J Clin Oncol; 28:1496-1501 2010,Time to prostate-specific antigen (PSA) progression with abiraterone acetate and prednisone in

17、patients with and without prior ketoconazole (Keto) exposure,Logothetis CJ, Wen S, Molina A,et al. Proc Am Sco Clin Oncol,2008,26:5017a.,对17例基础血清睾酮(S-T)50%有关。所有骨髓转移病变中均可见非均质性CYP17表达。由于该研究显示基础BM-T与PSA下降有关,可能BM-T可作为预测指标,另外,骨转移病变CYP17表达可能是一种去势后的适应性反应。,醋酸阿比特龙治疗CRPC,小结,CRPC的内分泌治疗目前在研究中,传统的酮康唑对部分病人有一定效果抑制

18、雄激素受体的新的措施包括:更有效的抗雄激素药物,裂解酶抑制剂,5-还原酶抑制剂,等,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,Symptomatic HRPC,Randomization,Modest Palliation,Improved Palliation,Prednison,PrednisonMitoxantrone,Kantoff PW, et al. J Clin Oncol 1999;17(8):2506-13,1.PR 分别为4%,7%;2.生存期分别为12.6和12.3月;3.联合组疼痛控制和生活质量改善优于单药组。,米妥蒽醌+强的松

19、,雌二醇氮芥是一种兼有激素治疗和化疗作用的药物,与微管蛋白结合具有抗有丝分裂作用。由FDA批准使用的治疗复发性前列腺癌的药物。8项II期单药临床试验634例病人显示,雌二醇氮芥可使19%的患者PSA下降50%以上。与其他药物有协同作用,尤其是抗微管药物。,雌二醇氮芥,Estramustine+vinblastine 61%Estramustine+vp16 52%Estramustine+paclitaxel 52%Estramustine+docetaxel 62%,Combination,PSA Decline50%,Estramustine-based Chemotherapy,雌二醇氮

20、芥加化疗治疗CRPC荟萃分析,Fizazi K,et al. Lancet Oncol,2007,8:994-1000.,以多西他赛为基础的化疗,以泰素蒂为基础的化疗与米托蒽醌加波尼松两项III期临床试验的比较,Docetaxel (D) plus high-dose calcitriol versus D plus prednisone (P) for patients (Pts) with progressive castration-resistant prostate cancer (CRPC): Results from the phase III ASCENT2 trial,J C

21、lin Oncol 2010 28, No 15_suppl: 4509,TROPIC: Phase III Cabazitaxel vs Mitoxantrone in Docetaxel-Treated mCRPC,Cabazitaxel: novel semisynthetic taxane developed to overcome taxane resistancePrimary endpoint: OS; secondary endpoints: PFS, response, safety,Sartor AO, et al. ASCO GU 2010. Abstract 9.,Ca

22、bazitaxel 25 mg/m2 q3w + Prednisone* PO 10 mg/day(n = 378),Mitoxantrone 12 mg/m2 q3w + Prednisone* PO 10 mg/day(n = 377),Patients with mCRPC who progressed during/after docetaxel-based treatment (N = 755),Stratified by ECOG PS (0-1 vs 2) and measurable vs nonmeasurable disease,10 cycles,*Prednisone/

23、prednisolone.,TROPIC: Overall Survival,Sartor AO, et al. ASCO GU 2010. Abstract 9.,Cabazitaxel/prednisone 15.1 mos,Mitoxantrone/prednisone 12.7 mos,Median OS,100,80,60,40,20,0,Proportion of OS (%),0 Mos,6 Mos,12 Mos,18 Mos,24 Mos,30 Mos,377,300,188,67,11,378,321,231,90,28,MP,CBZP,Pts at Risk, n,1,4,

24、TROPIC: Progression-Free Survival,Cabazitaxel/prednisone,Mitoxantrone/prednisone,HR: 0.74 (95% CI: 0.64-0.86;P .0001),100,80,60,40,20,0,Proportion of OS (%),0,3,12,18,21,377,115,9,4,2,378,168,15,0,0,MP,CBZP,Pts at Risk, n,15,6,4,6,52,90,9,27,52,Mos,Sartor AO, et al. ASCO GU 2010. Abstract 9.,TROPIC:

25、 Safety,Deaths from AEs more common with cabazitaxel vs mitoxantrone (4.9% vs 1.9%),Sartor AO, et al. ASCO GU 2010. Abstract 9.,DeBono JS,et al.J Clin Oncol 28:7s, 2010 (suppl; abstr 4508),卡铂联合多西紫杉醇二线治疗DRPC,CBP AUC 5 d1;Docetaxel35mg/m2 d1,8,15;q4w结果: -43例DRPC患者PSA下降50%为22/43,51.2%;PSA下降90%为12/43,27

26、.9% -21例可测量病变患者,8例PR均为PSAR,9例SD(其中6例PSAR),4例PD均为PSANR -PFS: PSAR 9.5月 vs PSANR 3.3月(P0.001,HR0.108) -OS: PSAR 24.4月 vs PSANR 7.8月(P=0.001,HR0.232) -3/4度白细胞/粒细胞减少41.9%/39.5结论:每周多西紫杉醇加卡铂可作为二线DRPC的选择。,J Clin Oncol 28:7s, 2010 (suppl; abstr 4682),Satraplatin加泼尼松与单用泼尼松950例,51%一线多西他赛治疗失败PSA有效 (25% vs 12%,

27、P0.00007) ORR (7% vs 1%,P0.002) 疼痛有效率 (24% vs14%,P0.005) 疾病进展风险下降31%(HR0.69,P0.00001) 疼痛进展风险降低33% (HR0.67,P0.00028)总生存未改善,在先前接受多西他赛治疗的亚组有改善总生存的趋势 (HR = 0.78; P=0.06; medians 66.1 vs. 62.9),Satraplatin二线治疗mCRPC:The SPARC Trial,Petrylak D,et al.ASCO 2007 5019aSartor AO,et al. ASCO, 2008,5003a,Sternber

28、g, C. N. et al. J Clin Oncol; 27:5431-5438 2009,(A) Progression-free survival (intent-to-treat population) and (B) overall survival (intent-to-treat population),目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,抗新生血管生成治疗,抗新生血管生成已成为治疗前列腺癌的研究热点 一项随机的期临床试验比较了反应停联合泰索帝与泰索帝单药治疗雄激素非依赖性前列腺癌的结果,联合组18个月生存率为68.2%,泰索帝单

29、药组为42.9%2008年ASCO报告,VEGF单抗(bevacizumab)联合反应停及泰索帝+泼尼松治疗60例去势抵抗的转移性前列腺癌患者,结果PSA下降超过50%者为88%,32例有可测量病变患者的有效率为63%(CR 2例,PR18例),估计中位PFS为18.2月,该研究结果令人鼓舞,需进一步临床试验研究。,Ning YM,et al.ASCO 2008,5000a,Ning YM et al.J Clin Oncology, 2010;28 (12) : 2070-2076,There was also a strong inverse correlation between rel

30、ative change in PSA over 6 weeks and the absolute difference in CAECs (r = 0.82; P .001).,circulating apoptotic endothelial cells (CAECs),A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men wit

31、h metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401,J Clin Oncol 28:7s, 2010 (suppl; abstr LBA4511),Atrasentan,Atrasentan为内皮素A(Endothelin-A)的拮抗剂,作为一种新的细胞生长抑制剂已用于晚期HRPC的治疗Vogelzang等,1002例HRPC患者, atrasentan 10 mg (n=497) or placebo (n=505) 。与对照组比较明显延缓: TTP (log-r

32、ank p=0.045), TTBP (log-rank p=0.025), TTPSA (log-rank p=0.002), and TTBALP progression (log-rank p 0.001),Vogelzang NJ ,et al.ASCO 2005,4563a,Sunitinib,Sunitinib为多靶点的酪氨酸激酶抑制剂已用于GIST及肾癌的治疗Sunitinib可增加化疗的疗效George等联合Sunitinib及多西他赛治疗mHRPC的II期临床研究表明,PSA有效率为50%,PR为39%(5/13),SD为54%(7/13),George DJ ,et al.

33、ASCO 2008,5131a,Bcl-2反义寡核苷酸,Bcl-2是细胞内调节细胞凋亡的蛋白,在细胞凋亡过程中具有负性调节作用 临床研究证实Bcl-2的反义寡核苷酸G3139联合多西他赛治疗HRPC显示一定疗效 13顺势维甲酸、干扰素并联合紫杉类药物可降低Bcl-2的表达,并克服Bcl-2介导的激素抵抗。,小结,靶向治疗是目前CRPC研究的热点,但需大规模临床研究。,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,生物免疫治疗,PSA异常 瘤负荷小的群体 免疫治疗,介素-2或干扰素细胞因子基因的转染前列腺特异性膜抗原的单抗标记同位素肿瘤疫苗酸性磷酸酶体外刺激

34、的自体树突状细胞,FDA批准sipuleucel-T(Provenge)治疗转移性前列腺癌,sipuleucel-T是一种疫苗,属自体源性细胞免疫疗法。首先提取患者的外周单核细胞,体外通过结合型重组蛋白的激活,然后将激活细胞和抗原递呈细胞的复合物注射回患者体内。结合型重组蛋白质是前列腺酸性磷酸酶和人粒细胞-巨噬细胞集落刺激因子重组形成。,Sipuleucel-T: cellular immunotherapy produced by exposing a patients leukapheresed cells to recombinant fusion protein consisting

35、of prostatic acid phosphatase antigen and GM-CSFPrimary endpoint: OS,IMPACT: Phase III Sipuleucel-T in mCRPC,Kantoff P, et al. ASCO GU 2010. Abstract 8.,Sipuleucel-T q2w x 3(n = 341),Placebo q2w x 3(n = 171),Patients with asymptomatic or minimally symptomatic mCRPC (N = 512),Treat at physician discr

36、etion and/or salvage protocol,Treat at physician discretion,*Stratified by primary Gleason score, number of bone metastases, and bisphosphonate use,Randomized 2:1*,PROGRESSION,IMPACT: Baseline Characteristics,Kantoff P, et al. ASCO GU 2010. Abstract 8.,IMPACT: Overall Survival,Median follow-up: 36.5

37、 mos (349 events),Kantoff P, et al. ASCO GU 2010. Abstract 8.,Sipuleucel-T,Placebo,HR: 0.759 (95% CI: 0.606-0.951)P = .017 (Cox model),Median OS25.8 mos21.7 mos,36-Month OS32.1%23.0%,Sipuleucel-T was approved by the FDA on April 30, 2010, for the treatment of metastatic prostate cancer,100,80,60,40,

38、20,0,Survival (%),0,12,Time From Randomization (Mos),24,36,48,60,72,341,274,142,56,18,3,171,123,59,22,5,2,Sipuleucel-T,Placebo,Pts at Risk, n,IMPACT: Safety,Overall AEs more frequent with sipuleucel-T vs placeboIncidence of any serious AE similar between arms: 24.3% vs 23.8%, respectively,*Occurring

39、 in 5% of patients receiving sipuleucel-T with 2-fold increase in incidence relative to placebo.,Kantoff P, et al. ASCO GU 2010. Abstract 8.,Predictors of outcome and subgroup results from the integrated analysis of sipuleucel-T trials in metastatic castration-resistant prostate cancer,J Clin Oncol

40、28:7s, 2010 (suppl; abstr 4550),Methods: OS for 3 randomized, double blind, placebo controlled trials was analyzed using a Cox regression model with treatment, adjusted for baseline PSA (ln) and LDH (ln), stratified by study. Results: The integrated analysis included 737 randomized patients (488 sip

41、uleucel-T: 249 placebo) with median follow-up of 36 months. There was a significant sipuleucel-T treatment effect (HR=0.735, 95% CI:0.613, 0.882, P 0.001), which was found to be homogeneous across the 3 trials (study by treatment interaction P=0.66). A positive treatment effect (HR1) was observed in

42、 all subgroups representing 10% of patients, including those defined by age, race, ECOG performance status, number of bone metastases, and previous chemotherapy use. Conclusions: The integrated analysis of 3 sipuleucel-T trials revealed consistent results across trials and within subgroups. The iden

43、tification of ECOG status, PSA, LDH, and hemoglobin as significant predictors of OS in this population is consistent with those identified previously (Halabi 2003, Armstrong 2007) ; however, the identification of number of bone metastases, age, weight, nodal disease, and time from diagnosis to rando

44、mization represent new findings.,Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in mCRPC,PROSTVACPROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-ba

45、sed vector was used for priming followed by six planned fowlpox-based vector boosts.,Kantoff PW,et al. J Clin Oncol 2010,28(7 )(March 1):1099-1105,Kantoff, P. W. et al. J Clin Oncol; 28:1099-1105 2010,Primary end point is progression-free survival,Kantoff, P. W. et al. J Clin Oncol; 28:1099-1105 201

46、0,Overall survival,Kantoff, P. W. et al. J Clin Oncol; 28:1099-1105 2010,Effect modifier analysis,生物免疫治疗小结,由于其明显延长总生存,FDA批准sipuleucel-T(Provenge)治疗转移性前列腺癌,ECOG评分、PSA、LDH、Hb水平可预测总生存。II期研究表明, PROSTVAC可明显延长mCRPC的生存,需要进一步III期研究。,目录,概况内分泌治疗化疗靶向治疗生物免疫治疗骨转移的治疗间断性雄激素剥夺问题和展望,骨转移的分子机制,uNTx,尿NTx(urinary N-telo

47、peptide ,uNTx)作为骨吸收的标志,可预测骨相关事件(skeletal-related events, SRE)的发生Rajpar等研究发现,uNTx是CRPC骨转移患者总生存的独立预后因素,uNTx 20nmol/mmol Cr 和uNTx 20nmol/mmol Cr的患者中位总生存分别为12月和25月。,Rajpar S ,et al.ASCO 2008,5138a,安慰剂 ,1次/3周+口服维生素D 400 IU和钙500 mg/天,唑来膦酸 4 mg,1次/3周 + 口服维生素D 400 IU和钙500 mg/天,0,15 月核心分析,24 月最终分析,n = 214,n

48、= 208,根据诊断前列腺癌时是否出现远处转移对患者进行分层,唑来膦酸 8 mg,1次/3周 +口服维生素D 400 IU和钙500 mg/天,n = 221,唑来膦酸用于晚期前列腺癌-039研究,前列腺癌疗效总结,产生SRE的产生SRE的 平均骨并发症多事件分析 患者比例, % 中位时间, 天 发病率危险比唑来膦酸4 mg 38488 0.77 0.640 n = 214安慰剂493211.47n = 208P 值 .028.009.005.002,唑来膦酸可以显著减少前列腺癌骨转移患者的骨并发症,前列腺癌生存分析,0,20,40,60,80,100,0,120,240,360,480,60

49、0,720,840,960,天*,生存患者比例,,中位数, 天P 值唑来膦酸 4 mg 546 .103安慰剂469,*开始研究药物治疗后的时间.,唑来膦酸 4 mg214 1621135610 安慰剂 20814894405,前列腺癌患者的骨折与生存情况呈负相关,Oefelein M, et al. J Urol. 2002;168:1005-1007.,1.00.90.80.70.60.50.40.30.20.1,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+

50、,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,+,有骨折史24 .04无骨折史171,020406080100120140160180200时间, 月,累积生存患者比例,P 值,n,A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer,RANKL-mediated osteoclast a

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