前列腺癌患者雄激素剥夺治疗后的代谢营养问题

前列腺癌是男性最常见的恶性肿瘤之一，雄激素剥夺治疗是前列腺癌一线治疗方案。长时间雄激素剥夺治疗前列腺癌患者持续处于雄激素低下状态会出现一系列代谢和营养问题，比如肥胖、糖尿病、脂肪代谢异常、代谢综合征、心血管疾病风险增加等，严重影响患者生活质量、肿瘤序列治疗的进行和预后。但相关针对性研究较少，本文对长时间雄激素剥夺治疗前列腺癌患者的代谢和营养问题，就肥胖、糖尿病、血脂异常以及代谢综合征几个方面，进行深入讨论并对相关研究进行展望。     

30例前列腺癌雄激素剥夺治疗对骨密度和骨代谢的影响分析

摘 要:［目的］ 探讨前列腺癌雄激素剥夺治疗对患者骨密度及骨代谢的影响。［方法］ 前列腺癌及前列腺增生患者,每组各30例:前列腺癌患者予以雄激素剥夺治疗,前列腺增生患者予以前列腺切除或相应药物治疗。观察两组患者治疗前及治疗1年后骨密度和骨代谢相关指标的变化。［结果］ 两组患者治疗前骨密度及骨代谢指标无差异(P>0.05);治疗1年后,前列腺癌组患者骨量减少,骨源性碱性磷酸酶及骨钙素N端片段明显降低,而Ⅰ型胶原羧基末端肽明显升高（P<0.05）。［结论］ 前列腺癌患者予以雄激素剥夺治疗会增加骨量丢失,影响骨代谢,导致骨质疏松。     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标北大核心CSCD

0引言雄激素和雄激素受体（androgen receptor,AR）通路激活在前列腺癌的发生、发展中具有重要作用。因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法（androgen deprivation therapy,ADT）一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80%的患者不可避免的发展为去势抵抗性前列腺癌.     

PD-1及PD-L1抑制剂在前列腺癌治疗中的研究现状

前列腺癌是男性常见的恶性肿瘤,目前主要的治疗手段是根治性前列腺切除术（RP）以及雄激素剥夺疗法（ADT）,但两者均有其各自的局限性。近年来免疫治疗发展迅速,其中细胞程序性死亡受体-1（PD-1）及细胞程序性死亡配体-1（PD-L1）作为免疫治疗的理想靶点,其抑制剂在治疗肺癌、结肠癌等多种癌症中发挥了越来越重要的作用。而随着PD-1/PD-L1在前列腺癌方面的研究进展及深入,其在前列腺癌中的作用机制也逐渐明了,PD-1/PD-L1抑制剂在前列腺癌治疗上也将具有广阔的前景。本文将就PD-1及PD-L1在前列腺癌中的表达、作用机制及其抑制剂治疗前列腺癌的相关研究进展作一综述。     

前列腺癌雄激素剥夺治疗的新思路——睾酮最大控制临床研究新进展

前列腺癌是常见的男性恶性肿瘤之一,其发病率位居男性恶性肿瘤第二位。前列腺癌的发病率居于所有男性恶性肿瘤首位。中国男性的前列腺癌发病率低于欧美国家,但随着生活方式、饮食习惯的西化以及人均寿命延长,前列腺癌的发病率也呈现逐年升高的趋势。雄激素受体（androgen receptor,AR）在前列腺癌的发生、发展过程中扮演着重要角色,抑制AR信号转导通路是前列腺癌治疗的基础,比如在去势抵抗性前列腺癌（castration-resistant prostate cancer,CRPC）治疗中,使用AR拮抗剂能够竞争性结合AR并阻断内源性雄激素的结合,从而干扰雄激素依赖的细胞下游反应,阻止前列腺癌的进展。雄激素剥夺治疗（androgen deprivation therapy,ADT）是前列腺癌治疗的基石,国内专家共识中前列腺癌去势治疗有效定义的睾酮（testosterone,T）水平为低于50 ng/dL。随着研究的深入,越来越多的研究表明T低于20 ng/dL的患者临床预后更佳：T ＜ 20 ng/dL时可以诱导包括雄激素敏感和部分雄激素不敏感亚群细胞的死亡,在治疗间隙细胞增殖时可以获得雄激素高度敏感的细胞群,从而延长了去势抵抗的时间。如果不能达到T ＜ 20 ng/dL,可能会导致部分雄激素不敏感的亚群持续存在,这些亚群在再次治疗后会快速增殖,加速肿瘤向去势抵抗发展。目前控制T水平的促性腺激素释放激素激动剂（gonadotropin-releasing hormone agonist,GnRHa）的有效性和安全性在研究中和临床上均得到了明确的验证,在药物层面上提供了控制T ＜ 20 ng/dL的临床可行性。通过总结T水平与ADT新进展,探讨最大限度控制T水平与前列腺癌治疗中患者受益、药物疗效及安全性的关系。     

转移性前列腺癌的内分泌治疗

雄激素与正常前列腺细胞与前列腺癌细胞的生长存在密切关系。目前，内分泌治疗目前仍是转移性前列腺的最有效治疗手段，其目的在于减少或消除雄激素对前列腺生长的促进作用，从而缓解转移性前列腺癌的症状。转移性前列腺癌的内分泌治疗通常包括手术去势与药物去势。药物去势通过使用雌激素类药物、抗雄激素类药物或黄体素释放激素类似物等药物以阻断雄激素与雄激素受体的结合或减少体内雄激素的产生。以非甾体类抗雄激素药物联合手术去势或LHRH类似物为方案的雄激素完全阻断治疗可阻断睾丸和肾上腺分泌的所有睾酮对前列腺的作用，但其效果是否优于单一药物去势治疗尚无定论。二线内分泌治疗，包括抗雄激素药物撤停、抗雄激素药物治疗、雌激素药物治疗、P450酶抑制剂治疗及皮质类固醇类药物治疗对初始内分泌治疗失效后的“激素非依赖性”前列腺癌仍具一定疗效，且因其毒副作用较少，应于全身化疗前优先采用。     

什么样的前列腺癌患者要进行化疗？

晚期前列腺癌经内分泌治疗后，多数在经历不同的缓解期（一般为2年左右）后将转为雄激素非依赖性前列腺癌，此时对各种内分泌治疗药物的治疗均无效。抗肿瘤化疗药物治疗前列腺癌，近几年发展迅速。全身化疗主要适用于晚期转移性前列腺癌，经内分泌治疗或放射治疗失败后，肿瘤进入了雄激素非依赖阶段的患者。     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标

0 引言 雄激素和雄激素受体(androgen receptor,AR)通路激活在前列腺癌的发生、发展中具有重要作用.因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法(androgen deprivation therapy,ADT)一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80％的患者不可避免的发展为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC),生存期不超过2年[1-2].最近研究表明,前列腺癌细胞自身获得经由胆固醇从头合成雄激素的能力以及肿瘤利用肾上腺来源的激素前体转化为雄激素是前列腺癌进展为CRPC的关键因素[3-6].     

比卡鲁胺治疗雄激素非依赖性前列腺癌

雄激素非依赖性前列腺癌（androgen-independent prostate cancer，AIPCa）是前列腺癌治疗中的难点之一，在临床上AIPCa根据疾病发展的不同阶段可以再分为：雄激素非依赖性、激素敏感型前列腺癌，和雄激素非依赖性、激素不敏感型前列腺癌或称激素抵抗性前列腺癌。激素敏感型雄激素非依赖性前列腺癌对改变激素治疗方式仍敏感，因此，二线内分泌治疗是主要的治疗选择。比卡鲁胺（bicalutamide，康士德，casodex）是欧美常用的二线内分泌治疗药物之一，在临床上取得了一定的疗效。而国内报道极少。为观察比卡鲁胺的疗效，我们于2000年1月-2004年12月，用比卡鲁胺作为二线内分泌治疗药物，治疗AIPCa患者20例，对部分患者有效。     

去势抵抗性前列腺癌的治疗进展*

去势抵抗性前列腺癌是一种致死性疾病,进展快,常伴随着转移,预后极差,死亡率接近100% ,患者中位生存时间少于20个月,是前列腺癌治疗的热点和难题,其发生发展机制尚不明确。近些年来涌现出许多治疗去势抵抗性前列腺癌的新方法,包括新型雄激素受体拮抗剂、免疫治疗、紫杉烷类化疗药物、抗血管生成药物、放射性核素、骨靶向药物以及各疗法联合应用等,改善了患者的生存期。本文就去势抵抗性前列腺癌的治疗进展进行综述。      

雄激素受体在前列腺癌细胞中作用及其靶向治疗的研究进展

雄激素受体(androgen receptor, AR)在前列腺癌的发生发展中扮演重要角色。雄激素剥夺疗法(androgen deprivationtherapy, ADT)早期可成功抑制肿瘤的生长, 但最终导致肿瘤复发并进入激素抵抗阶段。AR对前列腺癌基质细胞起促进肿瘤增殖和转移作用, 是上皮腔样细胞的存活因子, 而对肿瘤干细胞样细胞及上皮基底细胞的增殖起抑制作用, AR在不同类型细胞中的不同作用向当前ADT传统的疗法提出挑战, 为发展新的治疗策略提供理论依据。目前以AR为靶点的靶向治疗药物研发也取得一些进展。本文就AR在前列腺癌不同类型细胞中的作用及靶向治疗方面的进展加以综述。      

Complications of androgen deprivation therapy in men with prostate cancer

Androgen deprivation therapy (ADT) is indicated for the treatment of metastatic prostate cancer and locally advanced disease. In addition to sexual side effects, long-term ADT results in several other changes, including hot flashes; gynecomastia; changes in body composition, metabolism, and the cardiovascular system; osteoporosis; anemia; psychiatric and cognitive problems; and fatigue and diminished quality of life. This review discusses these complications of ADT and treatments aimed at reducing them. It is important for clinicians to anticipate these effects and to initiate measures to prevent or minimize them in order to maintain quality of life in prostate cancer survivors.     

雄激素受体在去势抵抗性前列腺癌进展中的作用及研究进展

雄激素受体是前列腺癌发生发展的重要因素。雄激素去势疗法是目前治疗前列腺癌的标准疗法,在早期可以有效的抑制肿瘤生长。但2～3年内,肿瘤会复发或进展,形成去势抵抗性前列腺癌。目前关于雄激素去势疗法治疗后去势抵抗性前列腺癌发生发展机制研究的文献较多（其中包括类固醇激素代谢的变化、雄激素受体基因的扩增或过表达、雄激素受体辅助调节因子、雄激素受体剪接变异体、生长因子和／或细胞因子、雄激素受体突变等等机制）,但还没有对具体机制完全了解并形成共识。目前普遍认为在去势抵抗性前列腺癌中,雄激素和雄激素受体在其发生发展中起到了关键的作用。本文就雄激素受体在前列腺癌进展为去势抵抗性前列腺癌的机制中的作用加以综述。     

The genetics of castration-resistant prostate cancer: what can the germline tell us?

Androgen deprivation therapy (ADT) is the cornerstone treatment for advanced prostate cancer. Despite frequent responses, the majority of metastatic tumors will progress to castration-resistant prostate cancer. Numerous molecular and genetic perturbations have been described in castration-resistant prostate cancer, which are attributable for gain-of-function changes in the androgen receptor, allowing for cell survival and proliferation with castrate levels of testosterone. The utility of these somatic perturbations, which are selected for in the tumor after ADT, for prognostication of response and response duration in metastatic prostate cancer, is problematic. Here, we discuss recent studies that describe germline polymorphisms that determine the response to ADT. Coding and noncoding germline polymorphisms in genes involved in the androgen pathway affect the response to ADT. These polymorphisms require further study and validation. However, they have the potential to be useful for prognosticating the response to ADT, designing clinical trials for patients who have poor germline prognostic features and designing novel therapies targeted against genes that influence the response to ADT.     

去势抵抗性前列腺癌的药物治疗现状

雄激素剥夺疗法(ADT)一直是晚期前列腺癌的代表性疗法。当前列腺癌进展为去势抵抗性前列腺癌(CRPC)时,ADT的抗性也随之出现。目前,多西他赛是首个被美国食品药品监督管理局(FDA)批准用于CRPC的细胞毒性化疗药物。另外,还有阿比特龙、恩杂鲁胺等药物也获得FDA批准,且这些药物都显示出良好的生存获益。本文对这些疗法的临床试验和生存获益进行了回顾,并对这一领域的新兴药物进行了讨论。本综述将对CRPC的药物治疗现状进行陈述,并为临床用药提供参考。     

Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients: Comparing between high- and middle-income Asian countries

The number of newly diagnosed prostate cancer cases varies across Asia, with higher mortality-to-incidence ratio reported in developing nations. Androgen deprivation therapy (ADT), alone or in combination, remains the mainstay of first-line treatment for advanced prostate cancer. Key findings of extensive research and randomized controlled trials have shaped current clinical practice and influenced clinical guideline recommendations. We describe here the recent trend of ADT in newly diagnosed prostate cancer for Asia focusing on Japan (high-income country) and Malaysia (middle-income country) based on the Asian Prostate Cancer (A-CaP) Study. The combination of radiotherapy and ADT or ADT alone was common in patients with intermediate-to-high risk localized and locally advanced disease. For metastatic prostate cancer, maximum androgen blockade (gonadotrophin-releasing hormone [GnRH] agonist/antagonist plus antiandrogen) was prevalent among the Japanese patients while primary ADT alone with GnRH agonist/antagonist was widely practiced in the Malaysian cohort. Upfront combined therapy (ADT plus docetaxel or androgen receptor pathway inhibitor) has significantly improved the outcomes of patients with metastatic castration-naïve prostate cancer. Its application, however, remains low in our cohorts due to patients’ financial capacity and national health insurance coverage. Early detection remains the cornerstone in prostate cancer control to improve treatment outcome and patient survival.     

Androgen deprivation therapy in nonmetastatic prostate cancer patients: Indications,treatment effects,and new predictive biomarkers

Men with prostate cancer with positive margins, extraprostatic extension, positive lymph nodes, high prostate‐specific antigen, or high Gleason Score are at high risk of recurrence following primary therapy. Androgen deprivation therapy (ADT), which includes medical/surgical castration, antiandrogen therapy, and combined androgen blockade, can be combined with primary therapy to shrink the tumor, reduce margin positivity, and reduce the risk of recurrence. However, many problems still remain, such as optimizing the application of ADT in the treatment of prostate cancer, for example, ideal patient population and optimal timing and duration of therapy. To investigate these problems, we searched PubMed for relevant publications on clinical studies of deprivation therapy for nonmetastatic prostate cancer. In this review, we discuss our findings on the role of ADT in the treatment of castrate‐sensitive nonmetastatic prostate cancer and the adverse effects associated with ADT. We also examine the recent advances in new predictive biomarkers for ADT, many of which are currently in the exploratory phase. Overall, the addition of ADT to primary therapy improves outcomes for patients with intermediate‐ or high‐risk prostate cancer.     

Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review

Prostate cancer is the most frequently diagnosed malignancy among UK men and accounts for 12% of male deaths. Androgen deprivation therapy (ADT) is commonly used as part of the treatment for prostate cancer. It is effective at suppressing prostate-specific antigen, stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival. However ADT, presumably at least in part owing to low testosterone levels is associated with insulin resistance, the development of metabolic syndrome plus increased overall and cardiovascular disease mortality. We have reviewed the relationship between prostate cancer, ADT, metabolic syndrome, type 2 diabetes, and cardiovascular disease. We have not reviewed other potential medical problems such as osteoporosis. We suggest that there should be a baseline assessment of patients' risk for cardiovascular disease before starting ADT. Consideration should be given to starting appropriate therapies including lifestyle advice, antihypertensive and lipid-lowering agents, insulin sensitizer, plus possibly aspirin. Having started ADT, the patients should have a regular (possibly annual) assessment of their cardiovascular risk factors.