前列腺癌内分泌治疗的历史与现状

自1941年Huggins等通过临床研究率先证实应用雌激素或／和手术去势治疗晚期前列腺癌（prostatecancer，PC）有良好的效果以来，Pc的内分泌治疗至今已有68年。PC的内分泌治疗开创了恶性实体肿瘤内分泌治疗的先河。由于对PC内分泌治疗的研究成果，先后有Huggins、Schally和Guillemin3人分别获得1966年、1977年诺贝尔生理学和医学奖。经过60多年的基础与临床研究，对激素敏感型晚期PC的内分泌治疗方案达成了共识，美国临床肿瘤学会制订的《前列腺癌诊治指南》2006年修订版中推荐采用双侧睾丸切除术或促性腺激素释放激素类似物作为初始去势治疗方案。单独应用非甾体类抗雄药物治疗可以作为备选方案，也可采用联合雄激素阻断治疗方案。目前，除用于临床试验研究目的外没有足够的证据支持间歇雄激素阻断治疗方案。雌激素作为二线内分泌治疗方案，09版NCCN制定的《前列腺癌诊治指南》不推荐单独应用抗雄药物治疗作为内分泌治疗方案。     

联合雄激素阻断治疗中晚期前列腺癌

目的 探讨联合雄激素阻断治疗不宜手术根治的前列腺癌的疗效。方法 回顾性分析28例前列腺癌患者采用手术或药物去势联合雄激素阻滞剂氟他胺治疗的临床资料，并结合文献进行讨论。结果 联合雄激素阻断治疗可迅速降低患者血清睾酮及PSA，使前列腺体积缩小，临床症状缓解。结论 联合雄激素阻断治疗晚期前列腺癌更合理，也更有效。     

以肺转移癌为首发表现的前列腺癌长期存活1例报告并文献复习

目的:探讨转移性去势抵抗前列腺癌长期存活的特点及治疗方法。方法:对1例以肺转移为首发表现的前列腺癌长期存活病人的临床资料进行回顾性分析,并复习相关文献。结果:本例发现时即有肺转移的前列腺癌晚期病人,经过手术去势和间断的联合药物激素阻断治疗、化疗和新型抗前列腺癌药物阿比特龙等综合治疗,存活19年,且目前仍病情较平稳。结论:对于转移性前列腺癌应采取个体化的综合治疗,以期达到最佳的治疗效果。     

去势治疗诱导的神经内分泌前列腺癌的研究进展

目前大量临床与实验研究已经证实,去势治疗在神经内分泌前列腺癌（NEPC）发生过程中发挥了重要作用。转移性前列腺癌接受转移性前列腺癌行去势治疗（ADT）后部分患者将逐渐发展为NEPC。NEPC预后极差,多由前列腺癌细胞发生神经内分泌分化（NED）引起。《中国肿瘤临床》2016年第2期“国家基金研究进展综述”栏目刊登了题为“去势治疗诱导的神经内分泌前列腺癌的研究进展”的文章,就NED细胞起源及分子机制的进一步研究进行综述,探索哪些信号通路可以预防或逆转NED ,为研发靶向药物或生物免疫制剂提供理论基础。     

色普龙和氟他胺治疗转移性前列腺癌的比较

抗雄激素疗法是治疗转移性前列腺癌的最主要措施 ,醋酸环丙孕酮 (色普龙 )是类固醇类抗雄激素药物 ,氟他胺是非类固醇类抗雄激素药物 ,本研究对这两种抗雄激素药物单一治疗转移性前列腺癌的疗效和安全性进行了比较。310例转移性前列腺癌患者被随机分为两组 ,分别用氟他胺 (2 5 0ｍｇ ,口服 ,3次 /日 )和色普龙 (10 0ｍｇ ,口服 ,3次 /日 )进行单一的抗雄激素治疗 ,氟他胺组15 4例 ,色普龙组 15 6例。入组条件 :进入本研究前未经其他内分泌治疗、有前列腺外转移、无转移灶的疼痛且没有近期心脏病发作史的前列腺癌患者 ,并且至少满足下列 3个…     

前列腺癌的内分泌治疗

前列腺癌的内分泌治疗是前列腺癌治疗的重要部分,它能使进展期前列腺癌获得明显治疗效果.一般来讲,内分泌治疗仅用于进展期前列腺癌病人.1941年Huggins和Hodges发表了"去势、雌激素和雄激素注射对转移性前列腺癌血清磷酸酶的作用"的论文,他们发现升高的血清酸性磷酸酶在去势后即下降,碱性磷酸酶初始阶段有缓慢上升,后下降保持正常.这些磷酸酶水平变化通常和前列腺癌症状有关.Huggins因为发明了前列腺癌的内分泌治疗,从而获得了诺贝尔奖.     

去势治疗诱导的神经内分泌前列腺癌的研究进展

目前大量临床与实验研究已经证实,去势治疗在神经内分泌前列腺癌（neuroendocrine prostate cancer, NEPC）发生过程中发挥了重要作用。转移性前列腺癌接受转移性前列腺癌行去势治疗（androgen-deprivation therapy,ADT ）后部分患者将逐渐发展为NEPC。NEPC预后极差,多由前列腺癌细胞发生神经内分泌分化（neuroendocrine differentiation,NED）引起。《中国肿瘤临床》2016年第2期“国家基金研究进展综述”栏目刊登了题为“去势治疗诱导的神经内分泌前列腺癌的研究进展”的文章,就NED细胞起源及分子机制的进一步研究进行综述,探索哪些信号通路可以预防或逆转NED ,为研发靶向药物或生物免疫制剂提供理论基础。     

乳腺癌内分泌治疗新进展

乳腺癌的内分泌治疗已有百余年历史。 1 896年Beatson首先报道卵巢切除可使乳腺癌缩小。 2 0世纪 40年代 Higgins应用睾丸切除或雌激素治疗前列腺癌取得成功 ,为肿瘤的内分泌治疗奠定了基础。乳腺癌的发生和发展受内分泌调控 ,目前可以从三方面进行治疗 :抗雌激素、芳香酶抑制剂和垂体LHRH类似物。内分泌药物通过阻断雌激素的产生 (如芳香酶抑制剂 )或雌激素在细胞水平上的作用 (如抗雌激素药 )而发挥作用。内分泌药物的选择取决于绝经情况 ,绝经前妇女 ,卵巢产生高水平的雌激素 ,故需卵巢去势 ,这可通过外科手术、放射治疗或促黄体激素…     

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。     

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。      

Advanced Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men. Screening and advances in the treatment of localized disease may help reduce the burden of this disease. Unfortunately, despite progress in these areas, a significant number of men continue to present with advanced disease or to develop advanced disease at some time after treatment for their local disease. The treatment of advanced or metastatic prostate cancer is systemic therapy. The mainstay of systemic therapy for prostate cancer has been hormonal therapy for many years. Orchiectomy and estrogens were the initial hormonal therapies used. Over the past several years a number of agents have been shown to produce similar rates of disease control with improved tolerability profiles. The luteinizing hormone releasing hormone (LHRH) agonists are the most frequently used hormonal agents in prostate cancer. Antiandrogens have also been used as single agents, or in combination with LHRH agonists. Soon LHRH antagonists may come into clinical practice. When hormone therapy fails to control this disease, chemotherapy is the next line of treatment. Over the past several years, several newer chemotherapy agents have renewed enthusiasm for this avenue of treatment in prostate cancer. Novel agents utilizing a variety of recently identified mechanisms of action are likely to become clinically relevant in the treatment of prostate cancer over the next few years. This review seeks to address the major issues relating to the pharmacological treatment of advanced prostate cancer.     

Management of patients with hormone refractory prostate cancer

Prostate cancer is the second most common cancer in men in the UK, and the incidence of prostate cancer has increased dramatically over the past two decades. Although most men are diagnosed at early stage, more than 50% develop locally advanced or metastatic disease. Androgen ablation with luteinising hormone-releasing hormone (LHRH) agonists alone, or in combination with anti-androgens, is the standard treatment for men with metastatic prostate cancer. Unfortunately, almost all men develop progressive disease after a variable time period, despite the maximal androgen blockade. The management of hormone refractory prostate cancer (HRPC) is challenging, as there is no uniformly accepted strategy. Various treatment options, including second-line hormone therapy, are discussed. Chemotherapy is being increasingly used and, importantly, docetaxel and estramustine may play an important role in the near future. The role of radiotherapy, strontium-89, bisphosphonates, novel agents and future therapies are also outlined.     

Prostate cancer--treatment of hormone independent cancer]

At the present time in Japan, the androgen ablation therapy, such as the surgical castration, estrogen therapy, antiandrogen therapy and LHRH agonist therapy, is mainly used for the treatment of advanced prostate cancer as well as for early prostate cancer. Ten to twenty percent of advanced prostate cancer do not respond to the initial endocrine therapy. The most of advanced prostate cancer relapse to androgen independent state within several years after the initial endocrine therapy. This characteristic of prostate cancers to develop resistance to androgen ablation therapy is the main problem in the treatment of prostate cancer. We surveyed the literatures regarding the treatments of the hormone independent prostate cancer. The results of bilateral adrenalectomy or antiandrogen therapy for patients who had relapsed to standard hormone therapy was disappointing. These data showed that the absence of testes and adrenals is not sufficient to stop the progression of the hormone independent cancer cells. Theoretically, the chemotherapeutic agents will be expected to be active agents for the hormone independent prostatic cancer. However, none of the products available are particularly active and the objective response rate is less than 10%. Therefore, the least toxic agents should be used. The treatment of painful metastasis in the terminal stage patients with hormone independent prostate cancer should be positively achieved. The external beam irradiation is useful for palliation of local bone pain of prostate cancer. Analgesics including morphine should be also positively used for the relief of pain in the terminal stage patients with prostate cancer.     

Management of a hormone dependent cancer with endocrine therapy--prostate cancer

We offer a historical overview of endocrine therapy for prostate cancer. Hormone therapy remains the cornerstone of treatment for patients with locally advanced or metastatic prostate cancer. Although this therapy has been traditionally performed by oral estrogen or bilateral orchiectomy, there are now two most important pharmacological hormonal therapies: LH-RH agonist and antiandrogen therapy. We do not have yet sufficient data to conclude whether maximal androgen blockade from the combined use of an LH-RH agonist and an antiandrogen will prolong the survival in patients with metastatic prostate cancer, nor to conclude whether neoadjuvant androgen ablation therapy improves the disease-free survival of patients after radical prostatectomy. New treatment strategies and modalities such as LH-RH antagonists, intermittent hormonal therapy, and antiandrogen monotherapy are appearing and being tested in clinical trials. However, to date there is still no effective therapy for patients who have hormone refractory disease.     

激素抵抗性前列腺癌的治疗进展

激素抵抗性前列腺癌的治疗是目前前列腺癌治疗中的重点与难点。虽然各种治疗方法层出不穷，从化疗到放疗，从生物治疗到同位素治疗，但真正能延长生存的治疗方法并不多。多西他赛联合强的松方案已经成为治疗前列腺癌的一线化疗方案，可有效延长患者生存期。唑来膦酸能明显减少骨相关事件的发生率，已被广泛应用于前列腺癌骨转移的治疗。而生物靶向治疗在前列腺癌中的研究正热，已有许多初步有效的研究报道，进一步确切的疗效评估有待大样本研究证实。     

Non-hormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care's Genitourinary Cancer Disease Site Group

Background

Prostate cancer that has recurred after local therapy or disseminated distantly is usually treated with androgen deprivation therapy; however, most men will eventually experience disease progression within 12 to 20 months. New data emerging from randomized controlled trials (RCTs) of chemotherapy provided the impetus for a systematic review addressing the following question: which non-hormonal systemic therapies are most beneficial for the treatment of men with hormone-refractory prostate cancer (HRPC) and clinical evidence of metastases?

Methods

A systematic review was performed to identify RCTs or meta-analyses examining first-line non-hormonal systemic (cytotoxic and non-cytotoxic) therapy in patients with HRPC and metastases that reported at least one of the following endpoints: overall survival, disease control, palliative response, quality of life, and toxicity. Excluded were RCTs of second-line hormonal therapies, bisphosphonates or radiopharmaceuticals, or randomized fewer than 50 patients per trial arm. MEDLINE, EMBASE, the Cochrane Library, and the conference proceedings of the American Society of Clinical Oncology were searched for relevant trials. Citations were screened for eligibility by four reviewers and discrepancies were handled by consensus.

Results

Of the 80 RCTs identified, 27 met the eligibility criteria. Two recent, large trials reported improved overall survival with docetaxel-based chemotherapy compared to mitoxantrone-prednisone. Improved progression-free survival and rates of palliative and objective response were also observed. Compared with mitoxantrone, docetaxel treatment was associated with more frequent mild toxicities, similar rates of serious toxicities, and better quality of life. More frequent serious toxicities were observed when docetaxel was combined with estramustine. Three trials reported improved time-to-disease progression, palliative response, and/or quality of life with mitoxatrone plus corticosteroid compared with corticosteroid alone. Single trials reported improved disease control with estramustine-vinblastine, vinorelbine-hydrocortisone, and suramin-hydrocortisone compared to controls. Trials of non-cytotoxic agents have reported equivocal results.

Conclusion

Docetaxel-based chemotherapy modestly improves survival and provides palliation for men with HRPC and metastases. Other than androgen deprivation therapy, this is the only other therapy to have demonstrated improved overall survival in prostate cancer in RCTs. Further investigations to identify more effective therapies for HRPC including the use of systemic therapies earlier in the natural history of prostate cancer are warranted.     

Hormonal therapy for prostate cancer: past,present and future

Prostate cancer is the second leading cause of cancer mortality in men in the USA. For the past six decades, hormonal therapy has been the main treatment of advanced prostate cancer. Hormonal therapy has developed from a surgical procedure to a complex pharmacological treatment. Trials comparing the efficacy of different monotherapies have demonstrated the equivalence of DES, LHRH agonists and orchiectomy. Combined androgen blockade has been compared with monotherapy. However, the results of the different trials have been conflicting. Novel hormonal therapy schedules involving intermittent treatment and peripheral androgen blockade are currently in clinical trials. The role of hormonal therapy in locally advanced disease as part of a multimodality therapy is a new and rapidly developing aspect of hormonal therapy. The mechanism of hormone refractoriness in prostate cancer is an active area of basic science and translational research.     

Hormonal therapy for prostate cancer: past,present and future

Prostate cancer is the second leading cause of cancer mortality in men in the USA. For the past six decades, hormonal therapy has been the main treatment of advanced prostate cancer. Hormonal therapy has developed from a surgical procedure to a complex pharmacological treatment. Trials comparing the efficacy of different monotherapies have demonstrated the equivalence of DES, LHRH agonists and orchiectomy. Combined androgen blockade has been compared with monotherapy. However, the results of the different trials have been conflicting. Novel hormonal therapy schedules involving intermittent treatment and peripheral androgen blockade are currently in clinical trials. The role of hormonal therapy in locally advanced disease as part of a multimodality therapy is a new and rapidly developing aspect of hormonal therapy. The mechanism of hormone refractoriness in prostate cancer is an active area of basic science and translational research.     

Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer

Abarelix, a gonadotropin-releasing hormone antagonist, with its indication for advanced symptomatic prostate cancer, represents the newest category of hormonal therapy introduced in the past 15 years. Results from Phase II and III clinical trials demonstrate the advantages of abarelix over commonly used luteinizing hormone-releasing hormone (LHRH) agonist therapy: abarelix does not cause a surge in serum testosterone that can precipitate a flare phenomenon or worsening of disease, particularly dangerous for patients with metastatic, symptomatic disease, and produces medical castration more quickly. Abarelix was also demonstrated to promptly and substantially reduce follicle-stimulating hormone levels to lower than LHRH agonist. Study results demonstrate effective anticancer responses during extended exposure to abarelix: improvements in pain score and/or analgesic use, improvements in urinary symptoms (including urinary catheter removal) and complete avoidance of bilateral orchiectomy for patients undergoing at least 12 weeks of treatment. In Phase III clinical trials, abarelix demonstrated a similar overall safety profile when compared with LHRH agonist monotherapy, and a superior safety profile when compared with LHRH agonist plus antiandrogen combination therapy. Abarelix patients experienced a greater incidence of immediate-onset systemic allergic reactions as compared with control arms.