去势抵抗性前列腺癌的治疗进展

临床上去势抵抗性前列腺癌（castrationresistant prostate cancer,CRPC）是前列腺癌死亡的重要原因,近年来美国FDA批准了多种新药用于CRPC的治疗,如新型雄激素合成抑制剂（阿比特龙,TAK-700）、雄激素受体拮抗剂（MDV3100）以及新的免疫疗法（Sipuleucel-T）等.本文就CRPC治疗进展作一综述.     

镭-223治疗骨转移性去势抵抗性前列腺癌的研究进展

世界范围内,前列腺癌(prostate cancer,PCa)是男性第二大常见癌症,2012年新诊断的PCa患者为110万,约占新增癌症病例总数的15%[1].在我国,随着生活方式、饮食结构的逐渐西化和人口老龄化的加剧,Pca的发病率近年来呈持续快速增长趋势[2].10%~20%的Pca发生远处转移,其中以骨转移最多见[3].大多数转移性Pca患者最初对雄激素去势疗法或手术去势治疗有效[4],10%~20%的患者最终发展为去势抵抗性Pca(castration-resistant prostate cancer, CRPC)[5].一旦发展为CRPC,很难治愈,中位生存期不到2年[6].且超过90%的CRPC患者存在骨转移,骨转移可导致骨相关事件((skeletal related events,SREs),如病理性骨折、脊髓压迫、肿瘤相关的外科手术干预及外放射治疗等,不仅降低了生活质量和总生存期(overall survival,OS),还增加了治疗负担[3,7-8].针对转移性CRPC,一些新的治疗方法和手段逐步进入临床验证或使用,镭-223是唯一对有骨转移症状但无已知内脏转移的CRPC患者能带来生存获益的新药.美国FDA于2013年5月批准拜耳公司研发的二氯化镭(通用名:镭-223;商品名:Xofigo)注射液上市.本文对镭-223治疗骨转移性CRPC的进展及安全性和有效性进行了评述.     

去势抵抗性前列腺癌药物治疗的新策略

大部分进展性前列腺癌患者初始对内分泌治疗敏感,最终会对内分泌治疗产生抵抗.近几年来治疗去势抵抗性前列腺癌取得了很大的进展,本文就药物阻断雄激素的合成、免疫治疗、靶向治疗、二线化疗药物及化疗药物耐药机制研究方面进行综述.     

177Lu-PSMA放射性配体治疗在转移性去势抵抗性前列腺癌的应用初探

目的:评估¹⁷⁷Lu-PSMA放射性配体治疗在转移性去势抵抗性前列腺癌的安全性及初步疗效。方法:收集2017—2020年空军军医大学西京医院收治并接受¹⁷⁷Lu-PSMA放射性配体治疗的转移性去势抵抗性前列腺癌患者,对其中3例典型患者的临床资料进行回顾性分析。结果:病例1确诊前列腺癌后,分别先后予以前列腺癌根治术、双侧睾丸切除术、放疗、转移灶切除+粒子植入术,PSA有效控制10余年后持续上升,⁶⁸Ga-PSMA PET/CT提示多发淋巴结及骨转移,行2个周期¹⁷⁷Lu-PSMA放射性配体治疗后,PSA由2092 ng/mL下降至920 ng/mL,治疗前后血红蛋白、白细胞、肝肾功无明显变化。病例2术前行⁶⁸Ga-PSMA PET/CT发现2处骨转移灶,新辅助内分泌治疗6个月后行前列腺癌根治术,术后PSA逐渐升高,影像学检查发现转移灶增加,行3个周期¹⁷⁷Lu-PSMA放射性配体治疗,复查⁶⁸Ga-PSMA PET/CT转移灶缩小,病灶...     

镭-223治疗转移性去势抵抗性前列腺癌的有效性与安全性初步分析

目的探讨镭-223治疗转移性去势抵抗性前列腺癌(mCRPC)患者的有效性和安全性。方法回顾性分析2021年1月至2022年1月重庆大学附属肿瘤医院采用镭-223治疗的22例mCRPC患者的临床资料。年龄(70.7±1.3)岁;美国东部肿瘤协作组(ECOG)评分1分7例, 2分15例;骨转移分级Ⅱ级7例, Ⅲ级15例。针对mCRPC, 既往行一线治疗1例(4.6%), 二线治疗4例(18.2%), 三线治疗10例(45.5%), 四线治疗4例(18.2%), 五线治疗3例(13.6%);平均经历三线治疗。从诊断mCRPC至开始镭-223治疗的中位时间为29(20, 34)个月。治疗前中位碱性磷酸酶(ALP)为147.0(101.8, 212.5)U/L, 中位前列腺特异性抗原(PSA)为44.7(20.2, 99.1)ng/ml;6例(27.27%)合并1～2级贫血, 血红蛋白中位值115.0(103.8, 122.5)g/L, 中性粒细胞计数(3.0±0.3)× 109/L, 血小板计数(169.8±17.0) ×109/L。患者每4周静脉注射镭-223(剂量为55kBq/kg), 最...     

转移性去势难治性前列腺癌的治疗进展

两种新颖的药物cabazitaxel(卡巴他赛)和sipuleucel-T已被增加到治疗CRPC当中增加疗效.Cabazitaxel是一种新颖的紫杉烷类抗癌药物,能有效延长常规多西他赛治疗转移性去势难治性前列腺癌(CRPC)患者的总生存周期.而sipuleucel-T是一种以自体树突细胞为基础的疫苗,能延长未出现器官转移的去势难治性前列腺癌(CRPC)患者的存活周期.第三种药物,醋酸阿比特龙是一种CYP17抑制剂,能抑制雄激素合成,对于既往接受多西他赛治疗的患者能明显延长其存活.此外,有数据显示一种RANK-ligand抑制剂狄诺赛麦(denosumab)比唑来膦酸(zoledronic acid)更有效预防男性骨转移并发症.Cabazitaxel,sipuleucel-T和denosumab已于2010年在美国被相关机构批准用于转移性CRPC,而醋酸阿比特龙也在Ⅲ期试验结果的基础上获得批准.其临床效果仍需要大量验证,而对循环肿瘤细胞的评估有助于判断预后情况.本文将描述去势难治性前列腺癌(CRPC)的多种最新研究进展.     

卡巴他赛治疗去势抵抗性前列腺癌的研究进展

对于去势抵抗性前列腺癌(castration -resistant prostate cancer,CRPC),化疗是重要的一种治疗方法.目前常用的一线化疗药物是多西紫杉醇,但对于多西紫杉醇耐药的进展期CRPC患者尚缺少明确的化疗药物.卡巴多赛,由于在此前的临床试验中显示出对改善多西紫杉醇耐药CRPC患者生存方面的疗效,而于2010年获得FDA批准上市.本文拟对本药的最新研究进展作一综述.     

非转移性去势抵抗性前列腺癌抗雄药物治疗新进展

前列腺癌是威胁男性健康的恶性肿瘤之一。我国前列腺癌发病率呈逐年上升趋势。非转移性去势抵抗性阶段是前列腺癌进展过程中的特殊疾病阶段,尽早识别非转移性去势抵抗性前列腺癌(nmCRPC)并及时干预,有助于延缓疾病进展并延长患者生存时间。近年来阿帕他胺等新型抗雄药物的使用显著延长了nmCRPC患者的无转移生存时间,延缓了患者症...     

去势抵抗性前列腺癌骨转移治疗的研究进展

目前对于去势抵抗性前列腺癌(CRPC)骨转移的治疗,不再局限于单一使用多西他赛化疗;目前有很多新疗法出现,其中镭-233、177镥-前列腺特异膜抗原-617(177Lu-PSMA-617)、骨靶向治疗(BTT)+醋酸阿比特龙(AA)+泼尼松(P)可延长患者总生存期(OS);多西他赛+锶-89可延长患者临床无疾病进展生存...     

Androgens and prostate cancer risk: a prospective study

BACKGROUND: Androgens have been implicated in prostate tumorigenesis, but prospective studies have overall reported no association between circulating levels of androgens and risk of prostate cancer. However, some recent studies have shown that a high level of testosterone increase the risk of non-aggressive tumors but is associated with a decreased risk of aggressive tumors. METHODS: We prospectively measured plasma levels of total testosterone, androstanediol glucuronide (A-diol-g) and sex hormone binding globuline (SHBG) and calculated estimated levels of free testosterone, in a nested case-control study of 392 cases and 392 matched controls. RESULTS: None of the studied hormones were significantly associated with prostate cancer risk in the full study group or in subgroups according to tumor aggressiveness. Odds ratios in the full study group, for top versus bottom quartile, was for total testosterone 1.25 (95% CI = 0.79-2.00; P(trend) = 0.51); free testosterone, 1.31 (95% CI = 0.82-2.07; P(trend) = 0.35); A-diol-g, 0.88 (95% CI = 0.59-1.33; P(trend) = 0.77); and for SHBG, 1.01 (95% CI = 0.64-1.58; P(trend) = 0.94). CONCLUSIONS: We found no significant associations between androgen levels and risk of prostate cancer in this population-based, non-screened cohort.     

Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline

PURPOSE: We evaluated the incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease. We also assessed the predictive role of bone turnover markers determined at baseline. MATERIALS AND METHODS: A total of 112 patients were consecutively enrolled in our study from July 1990 to July 1998 and followed until death or the last followup. Bone pain, disease extent in bone, serum prostate specific antigen, hemoglobin, and a panel of bone formation and resorption markers were assessed at baseline before any second line treatment. RESULTS: Skeletal complications in 34 patients (30.3%, estimated yearly incidence 12.3%) involved vertebral deformity or collapse requiring spinal orthosis in 20 (17.9%), spinal cord compression in 7 (6.2%), pathological bone fracture in 10 (8.9%), symptomatic hypercalcemia in 1 (0.9%) and symptomatic hypocalcemia in 1 (0.9%). Median time to the evidence of the initial skeletal complication was 9.5 months. These adverse events did not influence overall survival. At baseline patients with eventual skeletal complications had greater bone pain (p = 0.02), a heavier tumor load in bone (p = 0.005), lower performance status (p = 0.05), and higher serum alkaline phosphatase (p <0.02) and urinary deoxypyridoline (p <0.05) than their counterparts. Multivariate analysis revealed that only urinary deoxypyridinoline was independently associated with the onset of these events (p <0.02). The scatterplot of urinary deoxypyridinoline values in patients with and without skeletal complications enabled us to detect a cutoff of 38 pM./mM. for predicting 51% of skeletal events with only an 8% false-positive rate. CONCLUSIONS: Skeletal complications are common in patients with prostate cancer and hormone refractory disease. Bone loss is the major cause of onset. Baseline deoxypyridinoline at the cutoff point noted had moderate sensitivity but high specificity for predicting these adverse skeletal events.     

In vivo models of prostate cancer metastasis to bone

Purpose

The metastasis of prostate cancer to bone is the most significant cause of morbidity and mortality in this disease. An estimated 28,900 men die annually secondary to prostate cancer bone metastasis. Current treatments increase survival for 2 months and only bisphosphonates offer any palliative benefit. This shortcoming is due in part to inadequate models in which to study the molecular biology of the disease and evaluate therapeutic regimens. We examined the breadth of models available that recapitulate the process of prostate cancer metastasis to bone.

Materials and Methods

A PubMed search was done for publications concerning prostate cancer metastasis to bone and the imaging of bone metastases. Only studies focusing on model systems of disease progression and imaging of the process were included. Additional studies were found by cross-reference searching.

Results

Prostate cancer metastasis to bone is a lengthy, complex process characterized by multiple stages. This has made it difficult to find adequate laboratory models in which to recreate the disease process. Each available model has characteristics of particular phases of disease progression to bone. The most widely used models are transgenic mice, variations of SCID mice, and the traditional orthotopic and xenotransplantation models. Furthermore, investigators have started to adapt their models to incorporate imaging modalities for following the progression of prostate cancer to bone.

Conclusions

The development of models of prostate cancer metastasis to bone is an evolving discipline. A deeper understanding of the metastatic process has served to improve current models and it will continue to do so in the future.     

Impact of previous local treatment for prostate cancer on subsequent metastatic disease

PURPOSE: Metastatic prostate cancer, which is the precursor of most deaths from the disease, is treated most commonly with hormonal therapy. Generally the primary tumor is never treated. Due to evidence that controlling other primary neoplasms affects patient survival we examined the impact of radical prostatectomy and radiotherapy on the outcome in patients with metastatic prostate cancer in the context of a randomized clinical trial. MATERIALS AND METHODS: Southwest Oncology Group Study 8894 randomized 1,286 men with metastatic prostate cancer to orchiectomy and placebo or orchiectomy and flutamide. We performed proportional hazards analysis of variables previously identified to have a significant impact on survival. In this analysis we determined the impact of previous radical prostatectomy or radiotherapy on survival. RESULTS: Previous radical prostatectomy in patients with metastatic prostate cancer was associated with a statistically significant decrease in the risk of death (hazard ratio 0.77, 95% confidence interval 0.53 to 0.89) relative to those who did not undergo earlier prostatectomy. Conversely previous radiotherapy was associated with a greater risk of death in those who had previously undergone prostatectomy and those who received no definitive earlier therapy. CONCLUSIONS: It must be stressed that this intriguing observation was a secondary analysis of a phase III study. Nevertheless, it raises the question of whether control of the primary tumor impacts the ultimate outcome in patients with advanced prostate cancer. The suggestion of the role of radical prostatectomy in locally advanced prostate cancer, the now established role of extirpative therapy for renal cell carcinoma and the suggestion of this phenomenon in ovarian carcinoma should prompt further evaluation of this finding in other data sets. It may provide new opportunities for clinical trials.     

雄激素非依赖性晚期转移性前列腺癌生存预后分析

目的 分析雄激素非依赖性晚期转移性前列腺癌的预后相关因素.方法 1996年12月至2008年3月250例晚期转移性前列腺癌患者在内分泌治疗期间进展为雄激素非依赖性前列腺癌,对其进行随访,末次随访时间为2008年3月31日,中位随访时间为24个月(3～135个月).末次随访时131例生存,105例死亡,14例失访.利用统计学软件进行生存预后分析.结果 中位生存时间为30个月.1年牛存率79%,2年生存率59%,3年生存率41%.单因素分析及多因素分析显示:内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时PSA速率、内分泌治疗有效时间为独立预后冈素.结论 内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时的PSA速率和内分泌治疗有效时间为雄激素非依赖性晚期转移性前列腺癌生存时间的独立预后因素.     

Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies.     

转移性去势抵抗性前列腺癌骨转移患者精准随访方案的构建及应用

目的制定精准随访方案,并探讨其在转移性去势抵抗性前列腺癌(mCRPC)患者中的应用效果。方法将64例mCRPC骨转移患者随机分为干预组和对照组,各32例。对照组采用常规随访,干预组组建多学科协作随访团队,构建骨转移精准随访方案并实施。干预6个月后评价效果。结果干预组骨相关事件发生率与对照组比较,差异无统计学意义(P0.05);干预组生活质量各维度得分(除外社会/家庭状况)、疼痛控制满意度显著高于对照组,疼痛强度、疼痛影响及疼痛信念得分显著低于对照组(P0.05,P0.01)。结论对mCRPC骨转移患者实施精准随访能显著降低疼痛强度,相对减少骨相关事件发生率,提高患者生活质量。     

对比T2WI与T2*WI用于前列腺癌放射治疗计划的效果

目的 对比观察T2WI与T2^*WI在基于黄金基准标志物（GFM）放射治疗（简称放疗）前列腺癌（PCa）中融合CT-MR图像和勾画靶区的效果。方法 针对线性测试假体（LTB）采集T2WI与T2^*WI,评估图像质量。将3枚GFM置入凝胶中,采集CT、T2WI及T2^*WI,评价T2WI与T2^*WI的匹配度。对10例经病理确诊的PCa患者行经直肠超声引导下细针抽吸术,将3枚GFM置入前列腺靶区不同层面后采集盆腔CT、T2WI及T2^*WI。分别由3名放疗医师（RTP）于各种图像上勾画PCa靶区,以软件自动测量两两之间于各种图像内的放疗等中心处同层面勾画靶区的豪斯多夫距离、戴斯相似系数（DSC）和Cohen''s Kappa系数,并计算其平均值,评价3种图像的形变匹配度。结果 针对LTB,T2^*WI存在轻微几何失真,T2WI与T2^*WI三维重建图像中LTB中心的空间位移为0.11 mm。T2WI与T2^*WI识别凝胶中的GFM的准确率均为100%（6/6）。T2WI三维重建图像中,GFM中心相对CT三维重建的空间位移平均值为0.26 mm;T2^*WI重建图像则为0.20 mm。临床试验结果显示,基于T2WI识别GFM的准确率为10.00%（3/30）,基于T2^*WI则为96.67%（29/30）。3名RTP基于CT、T2WI与T2^*WI勾画靶区的豪斯多夫距离、DSC、Cohen''s Kappa系数平均值差异均有统计学意义（F=12.365、3.398、4.109,P均<0.001）,两两比较差异均有统计学意义（P均<0.05）。结论 制定PCa放疗计划时,相比T2WI,T2^*WI更适用于融合CT-MR图像和勾画靶区。