联合雄激素阻断治疗转移性前列腺癌

本文就近年来联合雄激素阻断治疗转移性前列腺癌的状况和有关问题辊以综述。     

间歇性与持续性雄激素阻断治疗晚期前列腺癌疗效比较

目的：比较间歇性与持续性雄激素阻断治疗晚期前列腺癌的疗效以及治疗产生的副作用。方法选取我科2012年1月-2013年1月收治的晚期前列腺癌患者76例,分为观察组（38例）及对照组（38例）。观察组38例行间歇性雄激素阻断治疗即药物去势加抗雄激素药物,对照组38例行持续性雄激素阻断治疗即手术去势加抗雄激素药物。比较两组患者的副反应发生率及治疗后的生活质量。结果观察组38例患者发生潮热症状者13例（34.21％）、乳房胀痛者12例（31.58％）。对照组23例患者发生潮热症状者26例（68.42％）、乳房胀痛者25例（65.79％）。比较两组潮热症状及乳房胀痛的发生率差异均有统计学意义（P＜0.05）。两组患者治疗后,观察组患者在肠道症状、性功能、尿路症状、骨痛、治疗相关症状方面都较对照组有明显的改善,生活质量大大提高,两组对比差异有统计学意义（P＜0.01）。结论间歇性联合雄激素阻断治疗可以明显降低患者治疗的副作用并且增加治疗后的生活质量,是晚期前列腺癌患者行雄激素阻断治疗的首选方案。     

雄激素最大限度阻断治疗前列腺癌的现状

早在 1 945年 ,Ｈｕｇｇｉｎｓ等〔1〕就开始在临床中引入雄激素全阻断 (ＴＡＢ)的概念 ,即在去势手术后再行双侧肾上腺切除术 ,以期完全去除雄激素 ,但由于病残率和死亡率较高 ,这一方法未能被广泛采用。 1 979年Ｂｒａｃｃｉ〔2〕首先报道将孕酮作为一线抗雄激素药物用于去势之后的患者 ,以达到雄激素最大限度阻断 (ＭＡＢ)的作用。Ｌａｂｒｉｅ等在 1 985年首先报道将ＬＨ ＲＨ类似物 (Ｌｅｕｐｒｏｌｉｄｅ)与非甾体抗雄激素药物 (Ｆｌｕｔａｍｉｄｅ)合用 ,以达到最大限度阻断雄激素的目的。在ＭＡＢ方案中 ,Ｓｏｌｏｗａｙ等〔3〕将抗…     

晚期前列腺癌的雄激素阻断治疗

目的探讨间歇性雄激素阻断治疗与持续性雄激素阻断治疗晚期前列腺癌的疗效和不良反应。方法65例晚期前列腺癌患者分为两组，A组34例行间歇性雄激素阻断（IAB）治疗，B组31例行持续性雄激素阻断（CAB）治疗，比较两组在疾病进展时间和不良反应方面的差异。结果A组中位随访时间为37．0个月，B组中位随访时间为35．8个月。A、B组疾病进展率分别为29．4％和54．8％，两组比较差异有统计学意义（P=0．038）。A、B组疾病中位进展时间分别为34．9个月、28．4个月，两组比较差异有统计学意义（P=0．0018）。在有骨转移患者中，A、B组疾病中位进展时间分别为33．6个月、27．1个月，两组比较差异有统计学意义（P=0．020）。在无骨转移患者中，A、B组疾病中位进展时间分别为38．7个月、30．3个月，两组比较差异有统计学意义（P=0．0006）。不良反应发生率分别为A组发生潮热症状23．5％、乳腺肿痛17．6％、骨质疏松14．7％。B组发生潮热症状64．5％、乳腺肿痛54．8％、骨质疏松45．2％。两组比较差异有统计学意义：潮热症状P=0．0006，乳腺肿痛P=0．0014，骨质疏松P=0．0065。结论对晚期前列腺癌患者IAB治疗可以延缓病变的进展，减少雄激素阻断导致的不良反应，提高患者的生活质量，应作为晚期前列腺癌患者的首选治疗。     

选择性绿激光汽化术联合全雄激素阻断治疗晚期前列腺癌

目的：探讨经尿道选择性绿激光汽化术（PVP）联合全雄激素阻断治疗晚期前列腺癌伴膀胱颈梗阻患者的临床疗效.方法：回顾性分析15例应用PVP联合全雄激素阻断治疗晚期前列腺癌伴膀胱颈梗阻患者的临床资料,观察患者手术时间、留置导尿管时间、术前后前列腺体积、国际前列腺症状评分（IPSS）、生活质量评分（QOL）、最大尿流率（Qmax）、剩余尿（PVR）及前列腺特异性抗原（PSA）的变化.结果：所有手术均成功,无输血及前列腺电切综合征现象.手术时间40～120 min,术后留置导尿管时间3～5天.术前前列腺体积、IPSS以及QOL分别为（95.13±16.36）ml、（19.87±4.10）分、（3.67±1.23）分.术后1个月分别为（48.47±11.55）ml、（12.27±3.24）分、（2.004±1.25）分（P均〈0.01） 术前Qmax、PVR分别为（8.05±2.51）ml/s、（136.47±32.16）ml,术后1个月分别为（18.40±4.63）ml/s、（33.87±13.44）ml（均P〈0.01） 术前PSA为（78.00±29.11）μg/L,术后1个月、3个月分别为（1.32±0.70）/μg/L、（0.48±0.07）μg/L（均P〈0.01）.结论：PVP联合全雄激素阻断治疗晚期前列腺癌伴膀胱颈梗阻是安全有效的,可以明显缓解患者的症状,抑制肿瘤进展,提高患者的生活质量.     

去势联合雄激素阻断治疗前列腺癌

我们于1997年1月～2002年1月采用去势联合雄激素阻断治疗前列腺癌18例,疗效满意,报告如下。     

间歇性与持续性雄激素阻断治疗晚期前列腺癌疗效比较

目的 比较间歇性与持续性雄激素阻断治疗晚期前列腺癌的疗效和副反应。方法 晚期前列腺癌患者69例，分2组。A组34例行间歇性联合雄激素阻断治疗，B组35例行手术去势加抗雄激素药物即持续性雄激素阻断治疗。比较2组患者的疾病进展时间和副反应发生率。结果 A组中位随访31．5（10～60）个月，B组32．6（12～63）个月。A组患者共行60个周期治疗，平均治疗周期13．7个月，其中治疗期6．4个月、间歇期7．3个月。A、B组中位疾病进展时间分别为31、28个月，差异无统计学意义（P=0．446）；骨转移患者中A组中位疾病进展时间24个月，B组为18个月，2组比较差异有统计学意义（P=0．04）。2组副反应发生率分别为：潮热症状A组20．6％（7／34），B组62．9％（22／35）（P〈0．01）；骨质疏松A组11．8％（4／34），B组31．4％（11／35）（P〈0．05）；乳房肿痛A组14．7％（5／34），B组37．1％（13／35）（P〈0．05）。结论 对晚期前列腺癌患者行雄激素阻断治疗应首选间歇性联合雄激素阻断治疗。     

前列腺癌的间歇雄激素阻断疗法(附编者按)

前列腺癌的发病率在全球范围内呈上升趋势,据美国统计约占男性癌肿的36%和男性癌肿相关死亡率的13%[1]。尽管近年来联合应用直肠指诊、Ｂ超、ＰＳＡ测定和前列腺穿刺活检,使前列腺癌检出率大大提高,但许多患者在出现临床症状就诊时多已发生转移,失去治愈的机会,还有许多病人在原发性局限性病变行前列腺切除和(或)放射治疗后,又发生全身播散和复发。1941年Ｈｕｇｇｉｎｓ等采用去势手术治疗晚期前列腺癌,约70%～80%患者获暂时缓解。肿瘤缩小和癌细胞死亡是由于雄激素减少而使细胞凋亡所引起。50多年来,晚期前列腺癌的标准治疗已包括去雄激素…     

间歇性雄激素阻断治疗晚期前列腺癌效果观察

目的 评价间歇性雄激素阻断治疗晚期前列腺癌的可行性及优点.方法 选取晚期前列腺癌患者59例,随机分为2组.给予间歇性雄激素阻断治疗30例(A组),给予持续雄激素阻断治疗29例(B组),观察两组患者的疾病进展及治疗期间副反应的发生情况,比较两种方法的治疗效果.结果 A组患者平均随访26个月,B组患者平均随访27个月,两组患者疾病进展情况未见明显差异.A组患者副反应低于B组患者且能在治疗间歇期得到缓解.结论 间歇性雄激素阻断治疗方法可行,能够减少患者治疗的副反应,提高患者生活质量.     

经尿道前列腺电汽化切除加雄激素阻断治疗晚期前列腺癌

目的探讨经尿道前列腺电汽化切除加雄激素阻断治疗晚期前列腺癌的临床疗效。方法对31例前列腺癌晚期(D)患者采用经尿道前列腺电汽化切除及睾丸切除术,术后3~5d口服氟他胺做全雄激素阻断以及氟他胺加达菲林的药物去势治疗。结果随访3~42个月,生存者29例,2例患者生存超过5年,20例超过1年。其中7例骨转移病灶减少,6例骨痛患者治疗后疼痛消失。前列腺特异性抗原(PSA)从术前的75.37μg/L降至1.34μg/L(术后1个月),3个月后降为0.27μg/L。B超、胸片、骨扫描未见新的转移灶。结论经尿道前列腺癌电汽化切除加全雄激素阻断治疗晚期前列腺癌具有较好的临床疗效。     

Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

Background

Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa).

Objective

To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB.

Design, setting, and participants

This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa.

Intervention

During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue).

Outcome measurements and statistical analysis

Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded.

Results and limitations

We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p = 0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76–1.07). There was a trend for an interaction between PSA and treatment (p = 0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61–1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy.

Conclusions

Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.     

125I 粒子植入联合最大限度雄激素阻断治疗高危前列腺癌

目的：探讨 ¹²⁵I 放射性粒子植入联合最大限度雄激素阻断治疗高危前列腺癌的临床效果。方法：78 例高危前列腺癌患者,全身麻醉,截石位,经直肠超声勾画前列腺轮廓,计算机制定植入计划,经会阴 ¹²⁵I 放射性粒子依次植入,术后继续全雄激素阻断治疗 18 个月停止内分泌治疗,后每三月复查 PSA, PSA 连续 3 次上升≥ 2 ng/mL 或至原来底限的 2 倍,则重新开始内分泌治疗。结果：所有患者手术均顺利,植入粒子 41 ～ 94 粒,平均 69 粒。术后随访 18 ～ 54 个月,平均 35 月。术后 18 月内分泌治疗结束 56 例患者 PSA 降到 0.02 ng/mL 以下,18 例 PSA 未达到 0.02 ng/mL 以下,4 例患者出现 PSA 反弹;术后 27 月 1 例发生多发骨转移死亡;术后 39 月 3 例出现 PSA 反弹,再次全雄激素阻断内分泌治疗 3 个月 PSA 值下降到治疗时低值,目前随访中 53 例 PSA 在 0.02 ng/mL 以下,继续密切监测 PSA 及全身状况随诊观察。结论： ¹²⁵I 粒子植入联合术后全雄激素阻断内分泌治疗是治疗高危前列腺癌的一种微创、可供高危前列腺癌选择的有效方法。     

全雄激素阻断和全雄激素阻断结合~(125)I放射微粒植入治疗前列腺癌

目的 :探讨全雄激素阻断和全雄激素阻断结合12 5I放射微粒植入治疗前列腺癌的临床疗效。　方法 :收集我院近 10年来中晚期前列腺癌病人 44例 ,其中C期 2 8例 ,D期 16例。双侧睾丸切除 +抗雄激素药物治疗 (A组 )35例 ,双侧睾丸切除 +抗雄激素药物 +12 5I放射微粒植入近距离放射治疗 (B组 ) 9例。比较治疗前后PSA的变化及生存率。　结果 :A组 35例病人PSA平均值由 6 0 .3μg/L降至12 .1μg/L。B组 9例病人PSA平均值由72 .1μg/L降至 3.6 μg/L。 35例A组病人随访 9～ 84(平均39.2 )个月 ,排除非癌性死亡 3例 ,因前列腺癌引起的死亡 6例 ,生存率为 81.3%(2 6 / 32 )。B组 9例病人随访 7～ 2 4(平均 13)个月 ,病人全部存活。　结论 :全雄激素阻断治疗及全雄激素阻断治疗结合12 5I放射微粒植入近距离放射治疗 ,是治疗中晚期前列腺癌的可供选择的有效方法。     

非那雄胺在晚期前列腺癌治疗中的作用

目的：探讨非那雄胺加间歇性雄激素阻断在晚期前列腺癌治疗中的作用。方法：将33例T3。期或T4期前列腺癌患者分为两组,A组18例采用比卡鲁胺加戈舍瑞林,间歇性雄激素阻断治疗;B组15例采用非那雄胺加比卡鲁胺加戈舍瑞林治疗。间歇期内B组继续服用非那雄胺。结果：治疗后9个月,A组13例完全缓解．3例部分缓解,2例无变化,有效率为88．9％。前列腺特异性抗原（PSA）为0．3～37．3ng／ml,平均（7．6±6．5）ng／ml。B组12例完全缓解,2例部分缓解,1例无变化,有效率为93．3％。PSA为0．1～10．5ng／ml,平均（4．2±2．8）ng／ml。B组PSA值低于A组,差异有统计学意义（P〈0．05）。随访61．7（31～82）个月,B组停药间期（25．1±10．1）个月长于A组（15．7±8．6）个月（P〈0．05）。A组5年生存率为55．6％（10／18）,B组为66．7％（10／15）,差异无统计学意义（P〉0．05）。治疗后5年,A组仍有6例有效（33．3％）,B组8例有效（53．3％）,差异无统计学意义（P〉0．05）。结论：非那雄胺加上间歇性雄激素阻断治疗,能使晚期前列腺癌PSA进一步降低,停药间期延长。     

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.     

Combined androgen blockade in the management of advanced prostate cancer: A sensible or ostensible approach

BACKGROUND: To compare the efficacy of orchiectomy alone and orchiectomy plus flutamide in treating patients with advanced carcinoma prostate. MATERIALS AND METHODS: The study was initiated on 1 July 1997 and closed after enrolling 100 patients on 30 June 2000. Patients were prospectively randomized to orchiectomy alone (O) and orchiectomy plus flutamide (OF). A complete response (CR) was defined as the normalization of bone scans and serum prostate-specific antigen (PSA) levels returning to normal (< 4 ng/mL). A partial response (PR) was defined as a 50% reduction in metastasis mass compared to the initial study or a decrease in the PSA level of 50% of the initial value. Progressive disease (PD) was defined as the development of any new hot spot on bone scan or any increase in previously existing PSA level by 25%. RESULTS: A total of 100 patients were entered in the study. The maximum percentage change in PSA levels in both groups was found in the first 3 months after orchiectomy, that is, 95% and 97% for the O and OF groups, respectively. In more than 80% of the patients this decrease in PSA was maintained for 3 years. The mean percentage change at 3 years in the O and OF groups was 70% and 75% (P = 0.95), respectively, and the overall response rate (CR + PR) was 88.50% and 86.53% in the two groups, respectively (P = 0.85). The follow-up period ranged between 3 and 5 years (mean, 3.5 years). The mean time to progression was 27 and 29 months in the O and OF groups, respectively. The overall survival rate at 3 and 5 years in two treatment groups was 45.83% and 48.07%, 20.83% and 23.07% in the O and OF groups, respectively (P = 0.75). CONCLUSIONS: Maximum percentage decrease in PSA is seen within the first 3 months of therapy. Orchiectomy alone is as effective as combination therapy in decreasing serum PSA. Overall survival at 3 and 5 years in the orchiectomy only group was as good as that of combination therapy. These data suggest that the routine addition of flutamide to orchiectomy is not advisable.     

前列腺癌雄激素依赖转化后细胞内雄激素受体表达变化的研究

目的：探讨雄激素受体（AR）在前列腺癌雄激素依赖特性转化过程中的作用。方法：对33例晚期前列腺癌患者进行雄激素阻断治疗并作长时间随访,其间有18例发生了雄激素依赖转化．15例未发生雄激素依赖转化。采用免疫组织化学及RT—PCR法测定18例患者雄激素依赖转化前后及15例患者雄激素阻断治疗前后癌细胞内AR蛋白及AR基因的表达情况。结果：18例患者雄激素依赖转化前后AR蛋白及AR基因的表达分别为（1．33±0．97VS3．11±0．76）和（28．41±3．38Ct vs 36．73±1．81Ct）,两者之间差异有统计学意义（P〈0．01）;15例患者雄激素阻断治疗前后AR蛋白及AR基因的表达分别为（1．47±0．83 vs 1．40±0．99）和（29．50±3．08Ct vs29．14±3．23Ct）,两者之间差异无统计学意义（P〉0．05）。结论：AR基因及AR蛋白表达增强是前列腺癌雄激素依赖转化的原因之一。     

雄激素受体在前列腺癌中的抗凋亡效应研究进展

前列腺癌(PCa)是中老年男性多发癌症之一,目前针对晚期转移性患者的主要治疗手段是去雄激素治疗,但是绝大部分患者最终都进展为侵袭性更强的激素非依赖型PCa,而对此类患者尚无有效治疗方法。雄激素受体(AR)是前列腺上皮细胞分化与增生的基本调节因子,在调控PCa细胞存活机制方面具有非常重要作用。目前的研究结果已经表明在激素非依赖型PCa进展过程中,AR的非正常激活是关键性因素。现简要综述AR调控的PCa细胞存活机制以及针对它而设计的RNA干扰技术对PCa的治疗运用方面的进展。