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医药导报
医药导报, 2017, 36(12): 1404-1410
doi: 10.3870/j.issn.1004-0781.2017.12.019
联合89锶治疗前列腺癌骨相关事件有效性及安全性Meta分析
Efficacy and Safety of Combined Therapy with 89Sr in Skeletal-Related Events of Prostate Cancer:A Meta-analysis
李亮亮1,, 任小强1, 徐自然2, 辛士永1, 张建国1,
1.河南科技大学第一附属医院泌尿外科,洛阳 471003
2.河南科技大学临床医学院,洛阳 471003
LI Liangliang1,, REN Xiaoqiang1, XU Ziran2, XIN Shiyong1, ZHANG Jianguo1,
1.Department of Urology,the First Affiliated Hospital,Henan University of Science and Technoloy,Luoyang 471003,China
2.College of Clinical Medicine,Henan University of Science and Technoloy,Luoyang 471003,China
通信作者 张建国(1965-),男,教授,硕士生导师,博士,研究方向:泌尿生殖系统肿瘤。电话:0379-69823270,E-mail:jgzhang03@126.com。

作者简介 李亮亮(1988-),男,河南许昌人,硕士,研究方向:泌尿生殖系统肿瘤。电话:0379-69823269,E-mail：461709568@qq.com。
中图分类号: R969.3     文献标识码: B     文章编号: 1004-0781(2017)12-1404-07
摘要:

目的 系统评价联合放射性核素89锶(Sr)治疗前列腺癌骨相关事件的有效性及安全性。方法 计算机检索PubMed、MEDLINE、EMBASE、Cochrane图书馆、CNKI、CBM及万方数据库等,检索时间从1976年89Sr首次报道应用至2015年9月,语种限制为中文、英语。纳入联合89Sr治疗(试验组)对比非联合(对照组)治疗前列腺癌的随机对照试验,对符合纳入标准的临床研究进行资料提取和质量评价后,采用RevMan5.2版统计软件进行Meta分析。结果 最终纳入18项RCT研究,共计1 280例患者。Meta分析结果显示:两组患者在疼痛缓解率[OR=4.71,95%CI(3.34,6.62),P<0.000 1]、骨转移灶减少率[OR=3.63,95%CI(2.60,5.09),P<0.000 1]和生活质量改善率[OR=2.16,95%CI(1.16,4.02),P<0.05]方面差异有统计学意义。试验组患者的无进展生存期显著长于对照组,差异有统计学意义 [HR=0.84,95%CI(0.73,0.97),P=0.02],总生存期[HR=0.82,95%CI(0.65,1.02),P=0.07]与对照组比较,差异无统计学意义。两组患者不良反应差异无统计学意义[OR=1.46,95%CI(0.98,2.17),P>0.05]。结论 联合放射性核素89Sr治疗前列腺癌骨相关事件的效果优于非联合治疗组,在患者不良反应发生率方面无明显差异,安全性较好。但本研究受纳入研究质量和样本量限制,该结论尚需更多高质量、长期随访的大样本RCT加以验证。
关键词: 89锶 ; 癌 ; 前列腺 ; 骨相关事件 ; 系统评价 ; 对照试验 ; 随机

Abstract:

Objective To evaluate the efficacy and safety of combined therapy with 89Sr for treating skeletal-related events of prostate cancer. Methods Databases including PubMed,MEDLINE,EMBASE,the Cochrane library,CNKI,CBM and Wanfang were systematically searched since 89Sr was first reported in 1976 to September 2015 to include the randomized controlled trials (RCTs) of the combined therapy with 89Sr for skeletal-related events of prostate cancer.The statistical analysis was performed using Review Manager Version 5.2. Results A total of 18 RCTs involving 1 280 patients were analyzed.The results of meta-analysis indicated:there were statistically significant differences in the pain relief rate [OR=4.71,95%CI(3.34,6.62),P<0.000 1],decrement rate of bone metastasis [OR=3.63,95%CI(2.60,5.09),P<0.000 1] and improvement rate of life quality [OR=2.16,95%CI(1.16,4.02),P<0.05].Progression-free survival of patients in experimental group was significantly longer than that in control group [HR=0.84,95%CI(0.73,0.97),P=0.02].No significant difference was found in overall survival [HR=0.82,95%CI(0.65,1.02),P=0.07].There were no significant differences in the incidence of adverse events [OR=1.46,95%CI(0.98,2.17),P>0.05]. Conclusion Combined therapy with 89Sr has better efficacy and comparable safety profile compared with standard therapy.However,the quality and sample size of the included studies are limited,so more high-quality and large-sample RCTs are needed to verify the validity.
Key words: 89Sr ; Cancer ; prostate ; Skeletal-related events ; Systematic review ; Controlled trial ; randomized

世界范围内,前列腺癌的发生率逐年增高,在欧美国家男性中位居前二位[1]。我国前列腺癌的患病率虽低于欧美国家,但其进展却更为迅速。根据国家癌症中心最新数据,自2008年起,前列腺癌的发病率已经在我国男性恶性肿瘤中位居第6位,成为泌尿生殖系统中进展最快的肿瘤[2]。在前列腺癌的肿瘤进程中,骨骼是其最容易发生转移的部位,约70%以上的患者可能出现肿瘤骨转移灶,并继发病理性骨折、骨痛、脊髓受压等骨相关事件(skeletal-related events,SREs)[3]。因此,减轻患者疼痛,预防SREs发生,改善患者的生活质量,延长生存期,已成为晚期前列腺癌临床治疗的主要目的。现今,89锶(Sr)已在临床广泛应用,国内外联合89Sr治疗的相关研究也时有报道,但是,检索相关文献却未见到多中心、大样本的循证研究,各临床指南也未就这类终末期患者的治疗达成共识。笔者希望通过Meta分析方法对目前联合89Sr治疗前列腺癌SREs的有效性及安全性进行系统评价,为临床医师在治疗方案的选择上提供依据,也给我国指南及标准的制定提供相关循证支持。

1 资料与方法
1.1 纳入标准

1.1.1 研究对象 经临床及病理诊断确诊的前列腺癌SREs患者。

1.1.2 患者纳入标准 经确诊的前列腺癌伴骨相关事件患者,病例诊断标准为:①前列腺癌骨相关事件的诊断准则:经手术和(或)通过前列腺系统性穿刺活检的组织病理学诊断;②骨相关事件诊断准则:全身骨扫描、CT、MRI等影像检查证实的骨转移;③临床及病理确诊的骨质破坏、关节畸形及病理性骨折;④有明确远端转移灶,并表现为骨痛、病理性骨折、脊髓受压及严重的功能障碍等骨相关事件。

1.1.3 患者排除标准 严重的心脑血管、呼吸系统疾病者,严重的肝、肾功能不全者及造血功能异常等伴有严重的基础性疾病患者。

1.1.4 干预措施 试验组:间断或连续应用核素89Sr联合内分泌药物、双膦酸盐、放疗、化疗、手术等基础治疗,包括使用各种治疗方式,药物剂量及治疗时间。对照组:非联合89Sr的治疗。

1.1.5 结局指标 有效性指标:疼痛缓解率、骨转移灶减少率、生活质量(quality of life,QOL)改善率、无进展生存期(progression free survival,PFS)及总生存期(overall survival,OS);安全性指标:不良反应发生率。

1.1.6 研究类型 国内外发表的联合89Sr治疗前列腺癌SREs与非联合治疗的随机对照研究。语种中、英文,无论是否采用盲法及隐藏分配方案。

1.2 排除标准

①诊断标准不明确;②暴露的界定和大部分文献差别较大;③资料收集方法不科学;④数据分析方法不详、错误或未提供;⑤历史性回顾,经验总结、综述、个案报道等。

1.3 检索策略

计算机及手工检索国内外关于联合89Sr治疗前列腺癌SREs的RCT的相关文献及文献后的参考文献,外文检索The Cochrane Library、PubMed、MEDLINE、EMBASE;中文检索CBM、CNKI、中文科技期刊数据库和万方数据库。检索时间为1976年89Sr首次报道应用至2015年9月。检索词为:89锶;氯化锶-89;美他特龙;Sr-89;89Sr;89SrCl2;前列腺癌;前列腺肿瘤;随机对照试验对应英文检索词。检索采用主题词与非主题词(同义词)相结合的方式,检索策略均经多次预检索后确定。根据不同数据库的要求,遵照检索词调整检索策略,以MEDLINE为例,检索联合89Sr治疗前列腺癌的RCT的策略见检索式。检索式:MEDLINE检索策略;#1 randomized controlled trial;#2 randomized controlled trials;#3 Randomized .Controlled .Trials;#4 RCT;#5 controlled clinical trial;#6 random allocation;#7 double blind method;#8 single blind method;#9(single or double)AND(blind or mask clinical trial);#10 randomization;#11 OR/1-10;#12 strontium-89 chloride;#13 strontium chloride,89Sr-labeled;#14 strontium chloride Sr-89;#15 Metastron;#16 strontium-89;#17 89Srcl2;#18 Sr-89;#19 89Sr;#20 Sr89;#21 OR/12-20;#22 MeSH descriptor prostate cancer;#23 carcinoma of prostate;#24 prostate AND(cancer or carcinoma or neoplasm);#25 #22 OR #23 OR #24;#26 #11 AND #21 AND #25;#27 limit to year“1976-2015”。

1.4 文献筛选与资料提取

获得文献检索结果后,通过阅读检索文献题名、摘要,必要时通过阅读全文等,进行逐一筛选,采用事先制定的数据提取表提取数据。由2名评价人员独立进行提取资料、并交叉核对,意见不一致时通过讨论或向专家咨询解决。提取主要内容包括:①一般资料:题名、作者、发表时间、地区;②研究特征:研究对象、病例数、干预措施及质量控制;③研究设计:方法学部分,包括随机分组方案、隐藏方法、是否盲法、意向性分析等;④观察指标:疼痛缓解率、QOL、骨转移灶减少数、PFS、OS、血常规、肝肾功能、不良反应等。

1.5 质量评价

所纳入的文献均采用Cochrane Handbook 5.0.1评价标准,对其随机方法、分配隐藏、盲法、不完整结果数据、选择性报告、其他偏倚来源等6方面进行质量评价。

1.6 统计学方法

采用Cochrane协作网提供的Review Manager 5.2(RevMan5.2)对纳入文献进行数据的处理。首先进行异质性检验,各纳入研究结果之间的异质性采用卡方检验(Chi-square test,Chi2)分析,当各项研究之间无明显统计学异质性(P>0.1,I2<50%)时,采用固定效应模型进行分析;当各研究间统计学异质性较大(P<0.1,I2>50%)时,用随机效应模型进行分析;分析其异质性来源,对可能导致异质性的因素进行亚组分析,剔除异质性较大的研究再分析等。计数资料:采用比值比(odds radio,OR)及95%可信区间(confidence interval,CI)为效应量。计量资料:采用加权均数差(weighted mean difference,WMD)及95%CI作为效应量,Revman统计软件5.0版以上版本中表示加权均数差WMD的符号为“MD”。各效应量均以95%CI表示,各纳入研究结果之间的异质性采用卡方检验,当各项研究之间无统计学差异性,同时还需准确分析结果是否具有统计学意义。

2 结果
2.1 检索结果

初检文献305篇,根据排除标准,阅读题名、摘要,排除经验总结、综述、个案报道等267篇;经阅读全文,因观察指标不一致,缺乏原始数据、非随机对照实验等,排除18篇,最终共纳入RCT研究18篇,包括国内11篇,欧美等7篇。其中,89Sr联合抗雄激素治疗11篇,联合化疗2项,联合放疗2项,联合双膦酸盐2项,联合止痛药研究1项,共计1 280例患者,其中联合89Sr治疗组585例,对照组531例。失访56例。研究对象一般情况基线比较一致,纳入研究基本特征见表1。

表1 纳入文献的基本特征
Tab.1 Basic characteristics of the included studies
第一作者及年份 例数 年龄/岁 干预措施 药物剂量 结局
指标
试验组 对照组 试验组 对照组 试验组 对照组
王林辉等[4](2001) 15 29 68.5 氟他胺 氟他胺 250 mg 250 mg ①②
89SrCl2 148 MBq
常江平等[5](2005) 21 19 69.3±6.5 氟他胺 氟他胺 250 mg 250 mg ①②
89SrCl2 148 MBq
邓智勇等[6](2006) 24 17 72.6 抗雄激素 抗雄激素 250 mg 250 mg ②③
89SrCl2 2.12 MBq·kg-1
郭德明[7](2009) 23 22 71.3±1.5 氟他胺 氟他胺 250 mg 250 mg ②
89SrCl2 55 μCi·kg-1
李焕斌等[8](2009) 32 20 69.4±16.7 抗雄激素 抗雄激素 不详 不详 ①
89SrCl2 不详
杨燮樵等[9](2009) 34 34 68.5 氟他胺 氟他胺 250 mg 250 mg ①②③
89SrCl2 2.12 MBq·kg-1
张建国等[10](2010) 21 18 67.8 唑来膦酸 唑来膦酸 4 mg 4 mg ①②
89SrCl2 2.12 MBq·kg-1
黄越[11](2011) 42 26 71.5±2.7 氟他胺 氟他胺 250 mg 250 mg ①②
89SrCl2 40 μCi·kg-1
赵益华等[12](2013) 14 15 66.7±5.9 帕米膦酸 帕米膦酸 90 mg 90 mg ①③⑥
89SrCl2 1.48 MBq·kg-1
刘鹏杰等[13](2013) 70 22 63.0 抗雄激素 抗雄激素 不详 不详 ①②
89SrCl2 不详
胡迎宾等[14](2014) 30 30 62~67 比卡鲁胺 比卡鲁胺 250 mg 250 mg ①②⑥
89SrCl2 2.12 MBq·kg-1
LEWINGTON等[15](1991) 16 16 71.3 抗雄激素 抗雄激素 250 mg 250 mg ①
89SrCl2 安慰药 150 MBq
PORTER等[16](1993) 61 63 75.2±1.9 抗雄激素 抗雄激素 不详 250 mg ①③④
89SrCl2 250 mg ⑥
MALMBERG等[17](1997) 36 35 69.5 放疗 放疗 不详 不详 ③④⑤
89SrCl2 1.4 MeV
TU等[18](2001) 36 36 71.5 化疗 化疗 不详 不详 ①②④
89SrCl2 安慰药 2.03 MBq·kg-1 安慰药 ⑤⑥
SMELAND等[19](2003) 46 49 70.6 放疗 放疗 不详 不详 ①②③
89SrCl2 0.9%氯化钠注射液 150 MBq 0.9%氯化钠注射液 ④⑥
PAPATHEOFANIS等[20] 25 40 69.7±1.6 止痛药 止痛药 不详 不详 ③⑤
(2009) 89SrCl2 安慰药 2.12 MBq·kg-1 安慰药
BILEN等[21](2015) 39 40 63.0 化疗 化疗 不详 不详 ④⑤⑥
89SrCl2 40 mCi

Outcome indicators:①pain relief rate;②decrement rate of bone metastasis;③improvement rate of life quality;④overall survival;⑤progression-free survival;⑥incidence of adverse reaction

结局指标:①疼痛缓解率;②骨转移灶减少率;③生活质量改善率;④总生存期;⑤无进展生存期(PFS);⑥不良反应发生率

表1 纳入文献的基本特征

Tab.1 Basic characteristics of the included studies

2.2 方法学质量评价

纳入的18篇RCT,其中13篇在文中提及“随机”,8篇描述了具体随机方法,9篇提及是否实施分配隐藏和盲法,4篇对分配隐藏方案进行了描述;15篇RCT数据报告完整,结果缺失研究中对缺失数据和原因进行了描述;2篇报道了失访或退出病例数,文献质量评价详见图1。


图1 Percentage chart of bias risk

2.3 疼痛缓解率

纳入13个研究合并分析其OR值,可知不存在显著异质性(χ2=10.06,P=0.61,df=12,I2=0%),应用固定效应模型,合并OR值为4.71,95%CI(3.34,6.62)。结果表明:联合89Sr试验组可以有效提高疼痛缓解率,两组差异有统计学意义(Z=8.95,P<0.000 01)。见图2。


图2 联合89Sr治疗组和非联合治疗组的疼痛缓解率比较的Meta分析

Fig.2 Meta-analysis on the comparison of pain relief rate between the combined treatment with 89Sr and non-combined treatment

2.4 骨转移灶减少率

纳入11个研究合并分析其OR值,各研究间同质性较好(χ2=13.60,P=0.19,df=10,I2=26%<50%),使用固定效应模型计算,最小OR值1.02,95%CI(0.29,3.60);最大OR值9.40,95%CI(3.19,27.68);合并OR值3.63,95%CI(2.60,5.09)。结果说明:试验组可以有效抑制患者骨转移灶进展,两组检验差异有统计学意义(Z=7.53,P<0.000 01)。见图3。


图3 联合89Sr治疗组和非联合治疗组的骨转移灶减少率比较的Meta分析

Fig.3 Meta-analysis on the comparison of decrement rate of bone metastasis between the combined treatment with 89Sr and non-combined treatment

2.5 QOL改善率

纳入7个研究分析其OR值,各研究间无显著异质,(χ2=13.84,P=0.03,df=6,I2=50%),使用随机效应模型计算,合并OR值为2.16,95%CI(1.16,4.02)。结果表明:试验组可以有效改善患者的生活质量,与对照组比差异有统计学意义(Z=2.42,P=0.02)。见图4。


图4 联合89Sr治疗组和非联合治疗组的生活质量改善率比较的Meta分析

Fig.4 Meta-analysis on the comparison of improvement rate of life quality between the combined treatment with 89Sr and non-combined treatment

2.6 OS

共纳入的5项研究中,各研究间同质性较好,(χ2=4.15,P=0.39,df=4,I2<50%),使用方差倒数权重法(inverse variance,IV)、及固定效应模型分析所纳文献总生存期的logHR值,结果显示:试验组的总生存期与对照组相比,差异无统计学意义[HR=0.82,95%CI(0.65,1.02),P>0.05]。见图5。


图5 联合89Sr治疗组和非联合治疗组总生存期比较的Meta分析

Fig.5 Meta-analysis on the comparison of overall survival between the combined treatment with 89Sr and non-combined treatment

2.7 PFS

共纳入4项研究报告了无进展生存期值,各研究间无显著异质,(χ2=3.49,P=0.32,df=3,I2=14%),使用IV法及固定效应模型分析,结果显示:试验组的PFS显著长于对照组,差异有统计学意义[HR=0.84,95%CI(0.73,0.97),P=0.02]。见图6。


图6 联合89Sr治疗组和非联合治疗组无进展生存期比较的Meta分析

Fig.6 Meta-analysis on the comparison of progression free survival between the combined treatment with 89Sr and non-combined treatment

2.8 不良反应发生率

纳入的7个研究合并分析其OR值,各研究间同质性较好,(χ2=1.47,P=0.96,df=6,I2<50%),使用固定效应模型计算,结果显示:最小OR值为0.81[95%CI(0.19,3.43)];最大OR值为2.23,95%CI(0.73,6.78);合并OR值为1.46,95%CI(0.98,2.17)。结果表明:试验组与对照组相比,两组间不良反应差异无统计学意义(P>0.05)。见图7。


图7 联合89Sr治疗组和非联合治疗组不良反应发生率比较的Meta分析

Fig.7 Meta-analysis on the comparison of adverse reaction rate between the combined treatment with 89Sr and non-combined treatment

3 讨论

骨相关事件是晚期前列腺癌常见表现。核素89Sr是一种具有趋骨性、能够发射β射线的放射类药物,最大射线量为1.46 MeV,放射线程(即骨穿透距离)0.8 cm,半衰期为50.5 d。在元素周期表中Sr与钙(Ca)同族,其化学特性也相类似,容易被成骨细胞增高的肿瘤骨转移灶所吸收富集,经静脉用药后,可以全身多靶点治疗,具有镇痛时间长、简便经济等优点,结合我国国情,在晚期前列腺癌SREs中应用前景广阔。SMELAND等[19]报道,联合89Sr能够有效抑制骨转移灶的进展,使患者在远期治疗中获益。MALMBERG等[17]研究,也证实了在临床应用中联合89Sr能够有效减轻患者疼痛,提高其生活质量,但是对患者的生存期及安全性无深入报道。据BILEN等[21]的报道,联合89Sr治疗未能取得患者OS的明显改善。尽管,目前多数研究报道更倾向于联合89Sr治疗可使患者远期获益,但是,对于联合核素治疗的有效性,长期治疗不良反应的评估等问题仍存在不同见解。本研究基于临床应用争议进行研究设计,荟萃结果显示:联合89Sr可以有效降低疼痛,抑制肿瘤骨转移灶进展,改善患者的生活质量,但在改善患者OS方面,联合组和对照组差异无统计学意义。治疗中,两组患者在不良反应发生率的差异无统计学意义(P>0.05),虽然联合89Sr治疗组中骨髓抑制的并发症出现较常见,但据较多报道的后续观察显示,血液学的毒性反应(轻度白细胞、血小板下降)多为一过性反应,大多在治疗后2~4个月逐渐恢复到正常范围,且对肝肾功能没有明显损伤。只要掌握其适应证和合适的剂量,一般不会发生严重骨髓抑制,这也与FURUBAYASHI等[22]的报道一致。表明在定期监测临床血常规及生化指标下,联合89Sr治疗安全性可靠。

本次系统评价所纳入文献的刊物权威性较低,纳入研究样本量较少,部分证据来自于单个研究,影响了证据的可靠性。另外,所纳入研究对骨髓抑制、不良反应等描述不够详细,研究结论潜在偏倚性较高,随着今后相关临床研究的开展,有进一步更新的必要。另一方面,本次Meta分析,模糊了联合89Sr治疗的具体方案,仅从联合核素治疗的有效性与安全性的方面进行系统评价,研究存在一定局限性。

The authors have declared that no competing interests exist.
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目的 探讨我国前列腺癌发病现状及流行趋势.方法 收集整理全国肿瘤登记中心1998年至2008年登记的前列腺癌数据,包括前列腺癌粗发病率、0 ～ 74岁男性发病累积率、发病构成和年龄发病率.分城乡统计,分析城市及农村男性的前列腺癌发病现状和趋势.结果 2008年中国男性前列腺癌发病率为11.00/10万,世界人口标化发病率(世标率)为6.73/10万,0～ 74岁中国男性前列腺癌发病累积率为0.70％,占中国男性恶性肿瘤发病构成的3.33％.城市男性前列腺癌发病率约为农村的3.7倍.年龄组发病率结果 显示,70岁以上中国男性的前列腺癌居男性泌尿生殖系肿瘤发病率第1位.1998年至2008年中国男性前列腺癌发病率的年均增加比例为12.07％.中 国城市男性前列腺癌发病率增加幅度高于农村,分别为8.53/10万和2.53/10万,但城市男性前列腺癌发病年均增加比例低于农村男性,分别为 11.25％和13.28％.随时间推移,在前列腺癌发病的年龄构成中,高年龄组的比重明显上升.结论 近年来,我国前列腺癌的发病率呈现明显持续增长趋势,前列腺癌正成为严重影响我国男性健康的泌尿系恶性肿瘤.
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Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions. Methods A femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2-/-;??c-/- mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT). Results PCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2-/-;??c-/- mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture. Conclusions PCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.
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目的:研究核素内照射改善前列腺癌骨转移引起的疼痛及对骨转移治 疗的疗效,并与内分泌治疗进行比较.方法:对52例前列腺癌骨转移患者均采用双侧睾丸切除加氟他胺(250 mg,3次/d)治疗.所有患者均于术前不同时间出现明显的疼痛症状,其中15例接受89锶内照射治疗(1 48 MBq静脉注射),8例接受153Sm-EDT-MP内照射治疗(37 MBq/kg静脉注射.1次/月);29例未接受内照射治疗者作为对照组.结果:89锶治疗组有14例患者疼痛明显缓解,占93.3%(14/1 5);153Sm EDTMP治疗组有6例疼痛明显缓解,占75.O%(6/8);单纯内分泌治疗组经调整药物剂量或结构后,疼痛明显缓解者仅9例,占31.o%(9 /29).99Tcm-MDP全身骨显像示骨转移病灶出现不同程度的好转,其中89锶治疗组有11例,占73.3%(11/15);153Sm- EDTMP治疗组有5例,占62.5%(5/8),而单纯内分泌组有7例,占24.1%(7/29).89锶治疗组3例、153Sm-EDTMP治疗组有 2例出现血白细胞和血小板明显下降,经对症治疗后恢复.结论:核素内照射治疗能改善前列腺癌骨转移引起的疼痛,并可不同程度地抑制肿瘤骨转移灶的生长,但 必须密切观察血红蛋白、白细胞及血小板的变化.
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多发性骨转移是晚期前列腺癌(prostate cancer,PCa)最常见的并发症之一.近年来国内外学者纷纷报道氯化锶-89(89SrCl2)治疗转移性骨肿瘤安全、有效,特别是治疗PCa骨转 移疗效高.本研究采用内分泌联合89SrCl2治疗PCa骨转移患者,通过放射性核素骨显像以了解其骨转移灶变化情况,探讨其疗效.现将结果报告如下.
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目的:探讨89锶(89Sr) 联合内分泌疗法治疗前列腺癌骨转移性疼痛的疗效。方法:将45例确诊为前列腺癌且具有骨转移病灶并伴有疼痛的患者随机分为两组:89Sr联合内分泌疗法治 疗的治疗组23例,单纯采用内分泌治疗的对照组22例,观察治疗后两组的止痛疗效、血清PSA水平的变化、血象及生化指标的变化。结果:治疗前两组患者的 疼痛级数间差异无显著性意义(P0.05)。治疗后治疗组患者疼痛级数及血清PSA水平较对照组显著降低(P0.01;P0.05);治疗后治疗组患者骨 转移病灶治疗有效率较对照组显著升高(P0.01)。结论:89Sr联合内分泌疗法能迅速有效地缓解前列腺癌骨转移疼痛,使骨转移病灶缩小或消失,副作用 小,其疗效明显优于单纯内分泌疗法。
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目的 探讨89SrCl2联合内分泌治疗对晚期前列腺癌疼痛及骨转移瘤的疗效.方法 将68例骨扫描呈单发或多发转移灶的晚期前列腺癌患者分为联合组和内分泌治疗组,各34例.联合组采用89SrCl2联合内分泌治疗,内分泌治疗组行单纯 内分泌治疗,治疗3个月后骨扫描检查,了解转移灶情况,测定前列腺素E2(PGE2)浓度.结果 联合组骨痛缓解的总有效率高于内分泌治疗组(88.2% vs 58.8%,P＜0.05).联合纰PGE2明显下降,与内分泌治疗组比较差异有显著性意义(P＜0.05).两组患者骨转移病灶出现不同程度的好转,其 中联合组67.6%患者骨转移灶不同程度缩小,密度变淡或者消失,内分泌治疗组为41.2%(P＜0.05).结论 89SrCl2联合内分泌治疗能改善前列腺癌骨转移引起的疼痛,而且可以破坏骨肿瘤,使转移灶缩小或消失,疗效优于单纯内分泌治疗.
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目的 评价唑来磷酸联合89 Sr治疗前列腺癌骨转移的临床疗效及不良反应.方法 将去势治疗后的前列腺癌骨转移伴不同程度骨痛的39例患者随机分为两组,唑来磷酸组(A组,n=18):唑来磷酸4 mg加生理盐水100 ml,静脉滴注30 min以上,每28 d 1次,2～3次;唑来磷酸联合89Sr组(B组,n=21):唑来磷酸4 mg(方法同上),89 Sr 148～222 MBq/kg体重.分别观察镇痛效果、骨转移灶的变化、前列腺特异性抗原(PSA)及不良反应等.结果 治疗前后A组疼痛评分分别为6.05±3.55和3.61±1.97,tPSA分别为(66.32±24.21)和 (24.53±9.94)μg/L(P<0.001);B组疼痛评分分别为5.93±3.71和1.66±0.91,tPSA分别为 (67.41±23.85)和(20.56±8.64)μg/L(P<0.001).两组骨转移灶消失或减少率分别为55.56%和71.43%. 均未出现严重的不良反应.B组止痛和减少骨转移灶效果优于A组(P<0.05).结论 唑来磷酸联合89Sr对去势治疗后的前列腺癌骨转移骨痛的止痛效果明显,可显著减少骨转移灶,较单独应用唑来磷酸效果好,是一种治疗晚期前列腺癌的有效方 法.
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[12] 赵益华,蒋旭敏,陈浩,等.帕米膦酸二钠联合89Sr治疗激素非依赖型前列腺癌骨转移疗效观察[J].临床泌尿外科杂志,2013,28(11):826-828.
目的:观察帕米膦酸二钠与89Sr联合应用对激素非依赖型前列腺癌(PCa)伴骨转移的治疗效果。方法:将我院收治的29例激素非依赖型PCa伴骨转移患者随机分成A、B两组,A组采用帕米膦酸二钠90mg溶于5%葡萄糖500ml,缓慢滴注4周1次,共2次;B组静脉注射89SrCl21.48mBq/kg,1周后与A组治疗方法相同。采用疼痛视觉模拟法(VAS)评定患者主观骨痛,生活质量(QOL)评分来判定疗效。结果:在疼痛评分方面B组治疗后评分显著低于A组,生活质量评分有效率的差异无统计学意义。结论:帕米膦酸二钠联合89 Sr治疗激素非依赖型PCa伴骨转移在疼痛缓解有效率上高于单独使用帕米膦酸二钠,同时表明帕米膦酸二钠与89Sr具有协同作用,其在不良反应方面无明显增加。
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[13] 刘鹏杰,唐铭,马世兴,等.内分泌治疗在89SrCl2治疗前列腺癌骨转移中的作用[J].昆明医科大学学报,2013,34(4):122-124.
目的 分析内分泌治疗在与89SRCl2联合治疗前列腺癌骨转移过程中所起到的作用.方法 127例确诊前列腺癌骨转移伴有疼痛且接受过睾丸切除术治疗的患者被分为3组:其中A组的70例患者接受了内分泌联合89SrCl2治疗；B组的35例只 接受了89锶治疗；C组的22例患者只接受了内分泌治疗.比较治疗前和治疗3个月后的VAS评分、骨转移灶的变化情况、PSA变化情况.结果 各组之间在治疗前的VAS评分3组之间无统计学差异(P＞0.05),治疗后A、B组疼痛较治疗前减轻明显(P＜0.05),C组疼痛缓解不明显 (P＞0.05)；A组与B组间的疼痛缓解程度无差异(P＞0.05),而A、B组与C组之间有差异(P＜0.05).骨扫描显示骨转移灶好转率A组效果 较B、C组好(P＜0.05),B组与C组无差异(P＞0.05).PSA减低幅度,A组与C组减低不明显(P)0.05),B组减低程度要大于A、C组 (P＜0.05).结论 单独利用89SrCl2或内分泌治疗前列腺癌骨转移不能同时有效的控制疼痛和骨转移灶的发展.同时配合两种治疗可提高疼痛缓解效果并能更好的治疗骨转移 灶.
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[17] MALMBERG I,PERSSON U,ASK A,et al.Painful bone metastases in hormone-refractory prostate cancer:economic costs of strontium-89 and/or external radiotherapy[J].Urology,1997,50(5):747-753.
In a prospective randomized Canadian trial, addition of radionuclide strontium (89Sr) to external radiotherapy (ER) was found to prolong the time to further ER by 15 weeks (35 versus 20, P = 0.006) compared to ER alone in patients with hormone-refractory metastatic prostate cancer (HRMPC). The total direct lifetime costs within the Swedish health care system for the following two treatment strategies was estimated as follows: (a) ER initially and in the event of relapse and (b) ER + 89Sr initially and ER in the event of relapse.Calculation of lifetime costs was based on the initial total treatment cost and the probability of future treatment costs. In a retrospective analysis, the average cost of a relapse treated with ER alone was calculated from the actual care consumption of 79 consecutive patients from the south of Sweden who received ER because of skeletal pain due to HRMPC. The costs related to ER included skeletal scintigraphy, ER, outpatient visits, inpatients days, and travel to the treatment center. When 89Sr was added, the cost also included the radionuclide and its administration. Costs in Swedish currency (SEK) were based on the regional tariff for 1993 (U.S. $1 = SEK 8.30).The initial cost for one relapse treated with ER alone was estimated to be SEK 31,011 (U.S. $3736) per patient resident within county (close to hospital) and SEK 48,585 (U.S. $5854) per patient resident out of county (far from hospital). The corresponding figure for initial addition of 89Sr to ER was SEK 43,426 (U.S. $5232) and 61,000 (U.S. $7349), respectively. However, comparison between estimated lifetime cost for the two treatment strategies indicated potential cost savings with initial addition of 89Sr to 3% SEK 2720 (U.S. $328) and 7% SEK 11,290 (U.S. $1360), respectively.Strontium-89 as initial supplement to ER for palliation of pain in HRMPC is beneficial both from the patient and lifetime health service costs perspectives.
DOI:10.1016/S0090-4295(97)00326-9      PMID:9372886      URL    
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[18] TU S M,MILLIKAN R E,MENGISTU B,et al.Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate:a randomised phase Ⅱ trial[J].Lancet,2001,357(9253):336-341.
Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate.103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks.Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29).Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.
DOI:10.1016/S0140-6736(00)03639-4      PMID:11210994      URL    
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[19] SMELAND S,ERIKSTEIN B,AAS M,et al.Role of stronti-um 2589 as adjuvant to palliative external beam radiotherapy is questionable:results of a double-blind randomized study[J].Int J Radiat Oncol Biol Phys,2003,56(5):1397-1404.
Abstract PURPOSE: To explore the efficacy of adjuvant (89)Sr applied with external beam radiotherapy (EBRT) to treat bone metastases. METHODS AND MATERIALS: Ninety-five patients were randomized to (89)Sr (Arm A) or saline (Arm B) on Day 1 of EBRT to demonstrate a reduction in 3-month physician-assessed subjective progression from 70% to 45%. RESULTS: At 3 and 6 months, no difference between treatment arms was observed in the progression rate. At 3 months, the physician-assessed response rate for all patients was 25%, with 46% of the patients progressing. The pretreatment use of opiates was independently associated with short progression-free survival. On the basis of the quality-of-life assessments, pain relief occurred in 50% of patients and 32% experienced improvement in global quality of life, without impact from (89)Sr. Differences were observed between the physician evaluation of radiotherapy efficacy and the patient assessment. In Arm A, serum alkaline phosphatase, but not serum prostate-specific antigen, decreased during the first 3 months after treatment. CONCLUSION: (89)Sr, adjuvant to ERBT, does not seem to reduce the number of patients with subjective progression at 3 months. Patients should be referred for palliative RT before their bone pain requires high doses of opiates. In radiotherapy trials, the evaluation of pain and pain relief remains problematic because of the confounding use of analgesics.
DOI:10.1016/S0360-3016(03)00274-8      PMID:12873686      URL    
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[20] PAPATHEOFANIS F J,SMITH C,NAJIB M.Improvement in sensory pain rating after palliative systemic radionuclide therapy in patients with advanced prostate cancer[J].Am J Ther,2009,16(2):127-132.
Abstract This study assessed whether baseline and short-term patient-reported quality of life (QOL) differs in patients with symptomatic metastatic prostate cancer undergoing palliative management using opioids, nonsteroidal anti-inflammatory agents (NSAIDs), (89)strontium chloride ((89)Sr), and samarium-lexidronam ((153)Sm). Males were grouped according to primary palliative intervention: opioids (n = 40), NSAIDs (n = 40), (89)Sr chloride (n = 25), and (153)Sm (n = 25). The short form of the self-administered McGill Pain Questionnaire was used to measure QOL at baseline, 4 and 8 weeks after initiation of treatment. Clinical data were collected from patients' medical records. Statistical analyses were conducted using descriptive methods and the Student t test. A significant increase in the sensory pain rating was observed in the patients treated by NSAIDs ([upward arrow]21%) and (89)Sr ([upward arrow]46%), whereas those treated by opioids ([downward arrow]27%) and (153)Sm ([downward arrow]27%) demonstrated a significant (P < 0.05) decrease in this subscore. There was a longitudinal decrease in QOL over time in patients treated by NSAIDs and (89)Sr as measured by the total pain rating score, whereas those treated with the other agents experienced improved QOL. This study demonstrates improvement in QOL achieved using (153)Sm, which is comparable to that achieved with the use of opioids during this observation interval.
DOI:10.1016/S1098-3015(10)64668-2      PMID:19300039      URL    
[本文引用:1]
[21] BILEN M A,JOHNSON M M,MATHEW P,et al.Randomi-zed phase 2 study of bone-targeted therapy containing strontium-89 in advanced castrate-sensitive prostate cancer[J].Cancer,2015,121(1):69-76.
Abstract BACKGROUND: Radiopharmaceutical use may improve the survival time of patients with castrate-resistant prostate cancer and bone metastases. Whether androgen-deprivation therapy (ADT) combined with bone-targeted therapy provides a clinical benefit to patients with advanced castrate-sensitive prostate cancer has not been investigated. METHODS: Eighty male patients were enrolled, and 79 were randomized: 40 to the control arm and 39 to the strontium-89 (Sr-89) arm. After randomization, patients in both study arms received ADT, doxorubicin, and zoledronic acid. Kaplan-Meier methodology was used to evaluate the progression-free survival (PFS) time. Multivariate Cox proportional hazards regression was used to evaluate the effects of Sr-89 after controlling for the number of bone metastases. RESULTS: The median follow-up time for the 29 patients alive at the last follow-up was 76.9 months (range, 0.07-103.4 months). The median PFS time was 18.5 months (95% confidence interval, 9.7-49.4 months) for the control arm and 12.9 months (95% confidence interval, 8.9-72.5 months) for the Sr-89 arm (P65=65.86). No patient developed myelodysplastic syndrome or a hematologic malignancy. An unplanned subgroup analysis suggested increased efficacy of bone-targeted therapy with a greater extent of bone involvement (ie, >6 bone metastases vs ≤6 bone metastases on the bone scan). CONCLUSIONS: The data showed that bone-targeted therapy using 1 dose of Sr-89 combined with chemohormonal ablation therapy did not favorably affect the PFS of patients with castrate-sensitive prostate cancer. The combined therapy was feasible and safe. Whether such bone-targeted therapy provides a favorable outcome for those patients with a greater tumor burden in the bone warrants further investigation. Cancer 2015;121:69-76. 08 2014 American Cancer Society. 08 2014 American Cancer Society.
DOI:10.1002/cncr.28971      PMID:25155428      URL    
[本文引用:2]
[22] FURUBAYASHI N,NEGISHI T,URA S,et al.Palliative effects and adverse events of strontium-89 for prostate cancer patients with bone metastasis[J].Mol Clin Oncol,2015,3(1):257-263.
The aim of the present study was to evaluate the palliative effects and adverse events of strontium89 (Sr89) in patients with bone metastasis from prostate cancer. A total of 18 patients with prostate cancer and painful bone metastases, as diagnosed on bone scintigraphy, who were treated with Sr89 at the National Kyushu Cancer Center between February, 2008 and April, 2014 were reviewed. Of the 18 subjects, 13 (72.2%) achieved a pain response, whereas 5 were classified as pain nonresponders (27.8%). According to a logistic regression analysis, the preadministration characteristics, including age, prostatespecific antigen (PSA), alkaline phosphatase (ALP), history of bonemodifying agent administration, opioid use or palliative radiation therapy, time after the combined androgen blockade nadir and time since the pain onset, were not found to be significant predictors of the pain response. Similarly, the postadministration characteristics, including pain flares and the PSA and ALP response, were not found to be significant predictors of the pain response. Although no patients exhibited leukocyte toxicities, 2 patients experienced myelosuppression, involving anemia and thrombocytopenia, requiring transfusion of red cell or platelet concentrate following Sr89 treatment. of the 18 patients, 5 (27.8%) reported pain flares, all of whom were successfully treated with rescue drugs alone. According to the logistic regression analysis, of the preadministration characteristics, only ALP was identified as a significant predictor of bone marrow suppression in the univariate and multivariate analyses (P=0.006). Therefore, Sr89 treatment was found to be effective in ameliorating bone pain associated with metastasis from prostate cancer. Although it is difficult to identify the patients who will receive pain relief prior to Sr89 administration, this drug should be administered during the early stages due to the potential for bone marrow suppression in patients with high ALP levels.
DOI:10.3892/mco.2014.449      PMID:4251176      URL    
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关键词（key words）
89锶
癌
前列腺
骨相关事件
系统评价
对照试验
随机
89Sr
Cancer
prostate
Skeletal-related events
Systematic review
Controlled trial
randomized
作者
李亮亮
任小强
徐自然
辛士永
张建国
LI Liangliang
REN Xiaoqiang
XU Ziran
XIN Shiyong
ZHANG Jianguo