雄激素剥夺疗法和免疫疗法在前列腺癌治疗中的研究进展

前列腺癌在美国成年男性中发病率位居第一,癌症相关致死率位居第二。雄激素剥夺治疗是最常用的前列腺癌治疗方法,而且通常伴随患者的终身治疗。雄激素和雄激素剥夺疗法对免疫系统有着重要的影响,在目前免疫治疗受到持续关注的情况下这一发现显得尤为重要。研究表明,雄激素剥夺治疗可能对免疫治疗起到促进或者抑制的作用。本文综述了不同类型雄激素剥夺治疗药物的作用机制,探讨了其对前列腺癌细胞及患者免疫系统的影响,以及联合使用雄激素剥夺药物和免疫治疗的前景,为前列腺癌的治疗提供了新的视野和思路。     

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。     

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。      

可变剪接事件结合剪接因子预测雄激素剥夺疗法治疗前列腺癌患者预后模型的建立

目的:探讨可变剪接事件及剪接因子对雄激素剥夺疗法（ADT）治疗的前列腺癌患者预后的预测作用。方法:从TCGA数据库下载60例进行ADT治疗的前列腺癌患者相关临床、转录组信息,并获得可变剪接事件信息。通过R语言程序包,使用LASSO、Cox回归模型筛选相关可变剪接事件及剪接因子,建立相关模型,进行独立预后分析及相关调控网...     

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。     

前列腺癌雄激素依赖转化后雄激素受体基因表达变化的研究

背景与目的:前列腺癌雄激素依赖性转化的机制目前尚不完全清楚,多数认为雄激素受体(androgen receptor,AR)基因的变化可能起重要作用,本研究主要探讨AR基因表达变化在前列腺癌雄激素依赖转化过程中的作用.方法:通过对33例晚期前列腺癌患者进行雄激素阻断治疗并长时间的随访,期间有18例患者发生了雄激素依赖转化,15例患者未发生雄激素依赖转化.采用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基因的表达情况.结果:18例患者雄激素依赖转化前后AR基因的表达分别为[(28.4±3.4) Ct vs (36.7±1.8)Ct],两者之间差异有统计学意义(t=14.43,P<0.001),15例患者雄激素阻断治疗前后AR基因的表达分别为[(29.5±3.1)Ct vs (29.1±3.2)Ct],两者之间差异无统计学意义(t=0.409,P>0.05).结论:AR基因表达增强是前列腺癌雄激素依赖转化的原因之一.     

多西他赛联合雄激素剥夺治疗高肿瘤负荷移性激素敏感性前列腺癌的疗效及不良反应

目的 比较多西他赛联合雄激素剥夺治疗(ADT)高肿瘤负荷移性激素敏感性前列腺癌(mHSPC)的疗效及不良反应.方法 依据治疗方式不同将154例高肿瘤负荷mHSPC患者分为联合组(n=101)和对照组(n=53),联合组患者给予多西他赛+ADT治疗,对照组患者给予单纯ADT治疗.随访4.0～85.0个月,观察记录两组患者前列腺特异性抗原(PSA)-无进展生存期(PFS)、影像学无进展生存期(rPFS)、总生存期(OS)、不良反应发生情况.结果 接受多西他赛+ADT治疗的联合组高肿瘤负荷mHSPC患者的中位PSA-PFS、中位OS分别为19个月、未到达,均明显长于对照组患者的9个月、30个月(P﹤0.01);联合组患者的中位rPFS为20个月,与对照组患者的17个月无明显差异.治疗7个月时,联合组PSA水平降至0.2 ng/ml的患者比例为49.50％(50/101),明显高于对照组患者的15.09％(8/53)(P﹤0.01).101例联合组患者中,2例患者的不良反应信息缺失,其余99例患者发生中性粒细胞减少和胃肠反应较为常见,发生率分别为34.34％和24.24％,总3～4级化疗相关不良反应发生率为14.14％(14/99),整体不良反应较轻,经对症治疗容易控制,无相关死亡不良事件.结论 多西他赛联合ADT治疗高肿瘤负荷mHSPC的疗效明显优于单独ADT治疗,7个月时PSA更易降至0.2 ng/ml,安全性良好.     

六例雄激素非依赖性前列腺癌的治疗

雄激素非依赖性前列腺癌 (ＡＩＰＣ)目前尚无统一有效的治疗方法 ,我们试用综合化疗加安宫黄体酮治疗取得了良好疗效 ,现报告如下。一、临床资料本组 6例 ,男性 ,平均年龄 74岁 ,前列腺特异性抗原(ＰＳＡ)均 >2 0ｎｇ/ｍｌ。病理类型 :低分化腺癌 3例 ,中分化腺癌 3例。ＥＣＴ检查均有骨转移 ,3例伴有肺转移。指肛检查前列腺均质地坚硬 ,有结节 ,有排尿困难或尿潴留 ,并有贫血、乏力、腰腿痛等。其中 3例是经双侧睾丸切除加缓退瘤治疗有效 ,ＰＳＡ降至 <2ｎｇ/ｍｌ,临床症状好转 ,但一段时间后(平均 2 4个月 ) ,ＰＳＡ再次升高至 >2 0ｎｇ/…     

抗雄激素药物治疗去势抵抗型前列腺癌的机制研究进展

去势抵抗型前列腺癌（castration-resistant prostate cancer ,CRPC）是指经内分泌治疗产生耐药并继续发展的致命性前列腺癌,雄激素受体（androgen receptor,AR）激活途径仍是这一阶段前列腺癌发展的驱动机制,因此抗雄激素治疗仍然是重要的治疗手段之一。虽然许多新型抗雄激素治疗药物在临床治疗中显示了显著的疗效,但同时耐药也频繁出现。本文就近年来几种主要抗雄激素治疗药物的作用及相应的耐药机制进行综述。     

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。     

前列腺癌伴贫血与外照射合并内分泌治疗疗效的关系

背景与目的：贫血是恶性肿瘤诊断及治疗过程中常见的并发症。我们主要观察联合雄激素阻断治疗（androgen-deprivation therapy,ADT）对前列腺癌患者血色素的影响及血色素与疗效的关系。方法：分析自2000年5月至2002年4月间有血色素记录的46名前列腺癌患者的资料,所有患者均接受了根治性放射治疗及联合雄激素阻断治疗（双侧睾丸去势术及氟他胺250 mg,每日三次,口服）,观察去势手术前、放射治疗前、放射治疗过程中及放射治疗结束时患者Hb的变化。根据放疗前血色素的水平将患者分为贫血组（Hb〈12 g/dl）和正常血色素组（Hb≥12 g/dl）,采用Paired-T检验来检验放射治疗前、后及新辅助雄激素阻断治疗前至放射治疗前血色素的变化;用Cox回归模型进行无疾病进展生存率的多因素分析来了解放疗前Hb,放疗过程中最低Hb、Gleason score、T分期和治疗前PSA是否为影响无疾病进展生存率的预后因素。结果：46名患者中,新辅助雄激素阻断治疗开始至放疗前,28%的患者Hb下降≤1 g/dl,33%的患者Hb下降介于1-2 g/dl,30%的患者Hb下降超过2 g/dl;放疗期间,37%的患者Hb下降≤1 g/dl,30%的患者Hb下降介于1-2 g/dl;放射治疗前Hb〈12 g/dl和Hb≥12 g/dl患者的3年无疾病进展生存率分别为65%和69%,Log-rank检验显示两者统计学差异无显著性（P=0.567）;多因素分析显示治疗前PSA值,T分期和肿瘤Gleason分级是影响前列腺癌无疾病进展生存率的预后因素,放疗前Hb水平和放疗过程中的最低Hb水平与无疾病进展生存率无显著相关性。结论：联合雄激素阻断治疗导致患者血色素下降,放射治疗前及放射治疗过程中贫血对前列腺癌患者的无疾病进展生存率无显著影响。     

Secondary bladder cancer after anticancer therapy for prostate cancer: reduced comorbidity after androgen-deprivation therapy

Radiotherapy for prostate cancer is associated with an increased incidence of secondary bladder cancer (BC). We investigated the incidence, clinicopathological characteristics, and prognosis of BC after radiotherapy, surgical therapy, and primary androgen-deprivation therapy (ADT) for prostate cancer. This study included 1,334 Japanese patients with prostate cancer treated with radiotherapy (n=631), surgical therapy (n=437), and primary ADT (n=266). During the median follow-up period of 51.2, 44.8, and 45.5 months, secondary BC occurred in 14 (2.2%), 5 (1.1%), and 0 (0%) of patients with prostate cancer treated with radiotherapy, surgical therapy, and primary ADT, respectively. The 10-year BC-free survival rate was 91.3% in the radiotherapy group, 97.4% in the surgical therapy group, and 100% in the primary ADT group. The rates of intravesical recurrence, progression to muscle-invasive BC, and BC-specific death might be higher in secondary BC after radiotherapy compared with after surgical therapy. There was a significant difference in the incidence of secondary BC among different therapeutic modalities for prostate cancer in Japanese men, indicating significantly lower comorbidity rates of secondary BC after primary ADT for prostate cancer compared with radiotherapy.     

A practical guide for assessing and managing cardiovascular risk during androgen-deprivation therapy in patients with prostate cancer

Prostate cancer is the most common malignancy among men worldwide, and androgen-deprivation therapy (ADT) is a mainstay of treatment. There are observational data demonstrating an increased risk of cardiovascular events in patients who receive ADT, particularly those who have an elevated baseline cardiovascular risk. Because, for most patients with prostate cancer, death is predominantly from noncancer-related causes, cardiovascular disease and its risk factors should be optimized during cancer treatment. This review provides an overview of the landscape of ADT treatment and serves as a guide for appropriate cardiovascular screening and risk-mitigation strategies. The authors emphasize the importance of shared communication between the multidisciplinary cancer team and primary care to improve baseline cardiovascular screening and treatment of modifiable risk factors within this higher risk population.     

Influencing factors and prognostic values of hemoglobin changes in prostate cancer patient during radiotherapy combined with androgen-deprivation therapy

Objective To analyze the influencing factors of hemoglobin changes in prostate cancer patients during radiotherapy combined with androgen-deprivation therapy (ADT) and analyze the relationship between the hemoglobin changes and long-term prognosis. Methods The changes of hemoglobin levels in 145 prostate cancer patients treated with radiotherapy combined with ADT in Department of Radiation Oncology of Peking University First Hospital from November 2011 to May 2015 were retrospectively analyzed. Intensity-modulated radiotherapy (IMRT) was employed for conventionally fractionated radiotherapy. Luteinizing hormone-releasing hormone agonist was utilized for endocrine therapy. Results The median hemoglobin reduction during radiotherapy combined with ADT was 8 g/L. The higher the baseline level of hemoglobin, pelvic irradiation and GS score before radiotherapy, the more obvious the decrease of hemoglobin during treatment (all P<0.001). Pelvic radiotherapy significantly increased the decline tendency of hemoglobin throughout the combined treatment (86.8% vs. 72.8%, P=0.05). The duration of endocrine therapy before radiotherapy and the hemoglobin changes during endocrine therapy alone were not significantly correlated with the degree of hemoglobin decline during subsequent radiotherapy (P=0.53 and 0.837). The biochemical failure-free survival did not significantly differ between patients with significant and mild hemoglobin reduction (P=0.686). Conclusions The baseline level of hemoglobin before radiotherapy is negatively correlated with the decrease of hemoglobin during combined therapy. Pelvic radiotherapy is positively correlated with hemoglobin reduction during combined therapy. Hemoglobin reduction during combined therapy is not associated with the long-term biochemical failure-free survival of patients.     

Significant associations of prostate cancer susceptibility variants with survival in patients treated with androgen-deprivation therapy

Androgen-deprivation therapy (ADT) is the most common therapy for advanced prostate cancer, but the prognosis significantly differs among individuals. In this study, we evaluated recently identified 19 prostate cancer susceptibility variants as prognostic predictors for the survival after ADT. A total of 601 prostate cancer patients treated with ADT were enrolled in this study cohort. The prognostic significance of the prostate cancer risk variants on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Two polymorphisms, rs16901979 and rs7931342, were significantly associated with PCSM (p = 0.005 for rs16901979 and p = 0.038 for rs7931342), and rs16901979 was also associated with ACM (p = 0.003) following ADT. Although the effect of rs7931342 was attenuated after controlling for other known clinical prognostic factors, rs16901979 remained a significant predictor for PCSM and ACM after ADT (p = 0.002). Moreover, the addition of the rs16901979 status in current clinical staging system further enhanced the risk prediction on PCSM and ACM particularly for the high-risk patients with distant metastasis (p < 0.017). In conclusion, this is the first study showing that prostate cancer risk variants, such as rs16901979, might improve outcome prediction following ADT, thus allowing identification of high-risk patients who might benefit from appropriate adjuvant therapy.     

Neoadjuvant therapy preceding prostatectomy for prostate cancer: rationale and current trials

Neoadjuvant therapy improves outcomes for a number of malignancies and provides intermediate pathologic outcomes, which correlate with long-term outcomes. Neoadjuvant androgen-deprivation therapy, alone or with docetaxel chemotherapy, preceding prostatectomy for localized prostate cancer is feasible and demonstrates pathologic activity, but evidence for improved long-term outcomes is lacking. Data in support of the further exploration of neoadjuvant therapy for localized prostate cancer preceding prostatectomy are reviewed. Ongoing randomized trials are elucidating the impact of neoadjuvant androgen deprivation combined with docetaxel chemotherapy on pathologic and long-term outcomes. The correlation of pathologic and biologic outcomes with long-term outcomes in this setting is unknown. The neoadjuvant therapy approach followed by prostatectomy is feasible with a wide array of agents and provides a paradigm for evaluating the activity, and mechanism of action and resistance to new treatments. This promising modality may aid the rapid development of novel therapeutic agents. A multidisciplinary approach involving oncologists, urologists and pathologists is critical to the success of this model.     

Differential prognostic factors in low- and high-burden de novo metastatic hormone-sensitive prostate cancer patients

Metastatic burden is a critical factor for therapy decision-making in metastatic hormone-sensitive prostate cancer. The present study aimed to identify prognostic factors in men with high- or low-metastatic burden treated with primary androgen-deprivation therapy. The study included 2450 men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We investigated the prognostic value of various clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) in patients stratified by low- or high-metastatic burden. Among the 2450 men, 841 (34.3%) and 1609 (65.7%) were classified as having low- and high-metastatic burden, respectively. Median PFS of the low- and high-burden groups were 44.5 and 16.1 months, respectively, and the median OS was 103.2 and 62.7 months, respectively. Percentage of biopsy-positive core, biopsy Gleason grade group, T-stage, and N-stage were identified to be differentially prognostic. M1a was associated with worse PFS than was M1b in the low-burden group, whereas lung metastasis was associated with better PFS and OS than was M1b in the high-burden group. Differential prognostic factors were identified for patients with low- and high-burden metastatic prostate cancer. These results may assist in decision-making to select the optimal therapeutic strategies for patients with different metastatic burdens.     

SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy

AimDe novo androgen synthesis is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). During androgen synthesis, 5α-reductase encoded by SRD5A catalyses testosterone into more active dihydrotestosterone and may be involved in the progression to CRPC. Then, this study aimed to reveal the association between genetic variations in SRD5A and the prognosis in metastatic prostate cancer.MethodsWe studied the polymorphisms rs518673 and rs166050 in SRD5A1, and rs12470143, rs523349, rs676033 and rs2208532 in SRD5A2 as well as the time to CRPC progression and overall survival in 104 patients with metastatic prostate cancer that had undergone primary ADT. The association between the polymorphisms and the progression to CRPC as well as overall survival was examined.ResultsPatients carrying the more active GG genotype in SRD5A2 rs523349 exhibited a higher risk of the progression (hazard ration [95% confidence interval], 1.93 [1.14–3.14], p = 0.016) and death (hazard ration [95% confidence interval], 2.14 [1.16–3.76], p = 0.016), compared with less active GC/CC genotypes in SRD5A2 rs523349.ConclusionsHigh 5α-reductase activity due to the polymorphism in SRD5A2 may contribute to resistance to ADT. Furthermore, SRD5A2 rs523349 polymorphism may be a promising biomarker for metastatic prostate cancer patients treated with primary ADT and a molecular target for advanced prostate cancer.     

Toxicity profile characteristics of novel androgen-deprivation therapy agents in patients with prostate cancer: a meta-analysis

Background: To investigate the toxicity profile characteristics of abiraterone acetate and enzalutamide to see if they are of critical clinical value.

Methods: Prospective studies were identified by searching the PubMed, EMBASE, Cochrane Library, and American Society of Clinical Oncology Meeting abstracts. Randomized clinical trials that evaluate abiraterone acetate or enzalutamide in patients with prostate cancer were included. The risk ratio (RR) of adverse events (AEs) was calculated for each trial along with appropriate 95% CI using fixed- or random-effects methods.

Results: Ten studies (5 abiraterone acetate, and 5 enzalutamide studies) were included in the meta-analysis. Use of abiraterone acetate was associated with an increased risk of all-grade adverse effects (RR = 1.01, 95% CI: 1.01–1.02) and high-grade adverse effects (RR = 1.29, 95% CI: 1.15–1.45). Also, there was a significantly higher incidence of some individual adverse effects (e.g. liver-function test abnormalities, arthralgia, cardiac adverse effects, diarrhea, oedema, hypertension and hypokalemia). Treatment with enzalutamide did not increase the risk of all-grade adverse effects and high-grade adverse effects, but there was a significantly higher incidence of some individual adverse effects (e.g. back pain, fatigue, hot flush and hypertension).

Conclusions: Both abiraterone acetate and enzalutamide have toxicity profile characteristics that need to be recognized. Understanding the toxicity profile characteristics of both drugs could promote decision making in clinical use.