抗雄激素撤除综合征

目的　探讨抗雄激素撤除综合征的临床特点及意义。　方法　对 2 4例前列腺癌 (C期10例 ,D期 14例 )采用联合雄激素阻断 (双侧睾丸切除 氟他胺 )治疗。 7～ 3 6个月后 ,因病变进展而停用氟他胺。每 2～ 4周检测血清PSA值并观察临床症状变化。　结果　 8例患者血清PSA值较停药前下降 ,平均下降 75 % ,其中下降 >5 0 %者 6例。 4例临床症状有改善 ,2例前列腺结节较前缩小。平均缓解时间为 4 .3个月。　结论　当联合雄激素阻断治疗的晚期前列腺癌出现激素拮抗性时 ,停用抗雄激素治疗为一可行的治疗选择     

Evaluation of total versus partial androgen blockade in the treatment of advanced prostatic cancer

In order to evaluate the proposed benefit of complete androgen blockade in the treatment of patients with advanced prostatic cancer, we initiated a multicenter prospective and randomized study. At the time of this report 99 patients with newly diagnosed, previously untreated prostatic cancer were randomly distributed to one of the following treatments: group I, orchiectomy plus antiandrogen Flutamide; group II, depot LH-RH analog Zoladex plus Flutamide; group III, orchiectomy alone, and group IV, Zoladex alone. Our preliminary data fail to demonstrate a superiority of total androgen blockade over partial androgen blockade in the treatment of patients with advanced cancer of the prostate.     

Advanced Prostate Cancer: Hormones and Beyond

Bilateral orchiectomy became the “gold standard” treatment option for advanced prostate cancer following the Nobel Prize winning study by Huggins and Hodges in 1941. Almost 40 yr later, the combination of a nonsteroidal antiandrogen with castration-based treatment (combined androgen blockade [CAB]) was proposed to offer superior response and survival compared with castration alone. However, 25 yr and many randomised studies later, the benefit of CAB remains controversial. Here, we present a clinical scenario that describes a patient with advanced prostate cancer and we review the available treatment options. The first part of the article focuses on androgen-dependent disease, comparing castration (surgical or medical) to either Casodex™ (bicalutamide) 150 mg monotherapy or CAB. In the CAB setting, Casodex 50 mg combined with castration-based therapy is calculated to reduce the rate of all-cause mortality by an estimated 20% compared with castration alone. The second part of the article describes treatment options for androgen-independent prostate cancer, including alternative forms of hormonal therapy, such as oestrogen therapy and ketoconazole- and docetaxel-based chemotherapy.     

Interstitial pneumonitis induced by bicalutamide and leuprorelin acetate for prostate cancer

Maximal androgen blockade therapy is the standard endocrine treatment for advanced prostate cancer. We report here an unusual case of interstitial pneumonitis induced by bicalutamide and/or leuprorelin acetate treatment for metastatic prostate cancer.     

Intermittent androgen blockade in prostate cancer: rationale and clinical experience

Cancer of the prostate continues to be one of the most common malignancies in men in Europe, with a large number of patients presenting with advanced disease. The current standard treatment for metastatic cancer of the prostate, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen blockade usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth. Based on experimental and preclinical studies, intermittent androgen blockade appears to be a potential alternative to permanent androgen blockade. Through the cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state. In this paper experimental and preclinical studies concerning intermittent androgen blockade are reviewed. At present several prospective randomized trials are under way to test intermittent androgen blockade as an alternative treatment in various stages of cancer of the prostate. However, until the results of these trials are available, this approach remains experimental.     

Androgen deprivation therapy: a primer on concepts and therapeutic options

Prostate cancer is a cause of significant morbidity and mortality in men. Endogenous levels of androgen, produced by the testis and adrenal gland, have a complex and controversial role in the development and progression of prostate cancer. Androgen deprivation therapy (ADT) is a common treatment for prostate cancer, particularly in metastatic tumor cases and in certain cases of locally advanced disease. This paper reviews the surgical and medical options used to produce androgen blockade. Bilateral orchiectomy is the historic gold standard with fewer side effects than medical castration, although currently less frequently utilized. Gonadotropin releasing hormone (GnRH) agonists are the most commonly used medications for achieving castration. Other medications include estrogens, GnRH antagonists, steroidal and non-steroidal anti-androgens and 5-alpha reductase inhibitors. The advantages and side effects of each type of medication are described. Intermittent therapy and continuous androgen deprivation is discussed. While intermittent ADT is currently experimental, there is accumulating evidence demonstrating satisfactory oncologic outcomes with decreased morbidity compared to continuous treatment.     

Additive effect of zoledronic acid on serum prostate-specific antigen changes for hormone-sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade

Combined androgen blockade is widely used to treat patients with advanced prostate cancer. Recently, zoledronic acid was proven to be effective in preventing skeletal‐related events for prostate cancer patients with bone metastases. Aim of the present study was to assess the effect of adding zoledronic acid to combined androgen blockade in the treatment of hormone‐naïve metastatic prostate cancer patients by analyzing the changes of biomarker levels. Patients were treated with either a combination of combined androgen blockade and zoledronic acid (n = 23) or combined androgen blockade alone (historical control combined androgen blockade group, n = 42). Zoledronic acid was injected intravenously at 4 mg every 4 weeks for 2 years. Prostate‐specific antigen and bone turnover markers (alkaline phosphatase and pyridinoline cross‐linked carboxyterminal telopeptide of type 1 collagen) were examined before treatment and at 3, 6, and 12 months after treatment. Sequential changes of prostate‐specific antigen, alkaline phosphatase and pyridinoline cross‐linked carboxyterminal telopeptide of type 1 collagen for the two groups versus pretreatment levels were compared. Prostate‐specific antigen values in both groups significantly declined at 3, 6 and 12 months compared with pretreatment levels. However, the decline of the prostate‐specific antigen was lower in the combined androgen blockade group. Alkaline phosphatase significantly declined at 6 and 12 months in the combination of combined androgen blockade and zoledronic acid group, with no significant changes seen in the combined androgen blockade group. The addition of zoledronic acid to combined androgen blockade showed prostate‐specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients.     

Overview of enzyme inhibitors and anti-androgens in prostatic cancer.

Surgical castration and estrogen therapy for prostate cancer were developed in 1941, and have been shown to improve both quality of life and survival. Little change in the therapeutics of prostate cancer has occurred over the subsequent three decades. In the 1970s, the progestational anti-androgens, ketoconazole and flutamide, were introduced as androgen-blocking agents, and have been shown to block at least partially both adrenal and testicular androgens. Gonadotropin-releasing hormone (GnRH) agonists were shown in the 1980s to produce medical castration without the cardiac and cerebrovascular risks of standard dose estrogen. In the 1980s, large-scale, multicenter, double-blind studies were done to compare the effect of combined androgen blockade, using multiple drugs, to single-drug blockade of gonadal androgen with regard to time to progression and survival in stage D2 cancer. These studies were done to test theories regarding the role of adrenal androgens and their effects on androgen-sensitive tumor clones in prostate cancer. The theory of clonal heterogeneity, particularly with regard to androgen sensitivity, has led to the continuation of three major controversies about the management of prostate cancer: Is combined blockade of testicular and adrenal androgens in stage D2 prostate cancer more effective than gonadal androgen blockade alone? What is the optimal secondary or tertiary therapy for relapsed prostate cancer? Is there any advantage for combined androgen blockade at the start of therapy in stage D2 prostate cancer as compared to sequential therapy with blockade of testicular androgens first, and then adrenal androgens at the time of relapse?     

Androgen deprivation therapy for prostate cancer: current status and future prospects

Androgens play a major role in promoting the development and progression of prostate cancer. As a result, androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. Different strategies involving this hormonal therapy produce a significant clinical response in most of the patients, but most responders eventually lose dependency, resulting in mortality. Thus, whether hormonal therapy contributes to the improvement of overall survival rates, especially in patients with advanced prostate cancer, remains controversial. However, patients with advanced disease clearly have a benefit from androgen deprivation-based treatment for palliating their symptoms and for improving the quality of their lives. In order to improve overall survival, novel treatment strategies that prolong the androgen-dependent state and that are useful for androgen-independent disease based on specific molecular mechanisms need to be identified.     

Current concepts in androgen deprivation therapy – is there a “best” endocrine treatment?

Androgen deprivation therapy has become the mainstay treatment for locally advanced and metastatic prostate cancer. Castrate testosterone levels can be achieved by a multitude of treatments. We performed a medline literature search to answer the question, is there a “best” endocrine treatment? In conclusion we found that the “best” endocrine therapy for advanced prostate cancer is complete androgen blockade (CAB) with a luteinizing hormone-releasing hormone (LHRH) agonist and a nonsteroidal antiandrogen.     

前列腺电汽化术加雄激素全阻断综合治疗晚期前列腺癌(附36例报告)

目的探讨晚期前列腺癌的综合治疗方法。方法对36例晚期前列腺癌采用经尿道前列腺电汽化术加雄激素全阻断疗法。结果随访4～48个月,所有患者术后近期排尿通畅,转移性骨痛减轻或消失,血清PSA有不同程度的下降,直肠指诊前列腺体积缩小。2例患者后期转移性骨痛症状反复发作,转上级医院放疗。结论应用经尿道前列腺电汽化术加雄激素全阻断疗法。能显著改善晚期前列腺癌患者生活质量,延长生命。     

Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy

PURPOSE: We evaluate the quality of life of asymptomatic men with nonmetastatic prostate cancer who receive androgen deprivation therapy. MATERIALS AND METHODS: Quality of life was longitudinally evaluated in a cohort of 144 men with locally advanced prostate cancer or prostate specific antigen relapse after local therapy who chose to receive (79 patients) or not to receive (65 patients) androgen deprivation therapy. Androgen deprivation therapy consisted of orchiectomy, leuprolide alone or leuprolide plus flutamide. Multivariate analysis of variance was used to test the effect of different treatment regimens on patient quality of life. RESULTS: Men who received androgen suppression had more fatigue, loss of energy, emotional distress and a lower overall quality of life than men who deferred hormone therapy. Combined androgen blockade had a greater adverse effect on quality of life than monotherapy. CONCLUSIONS: Androgen deprivation therapy may significantly impair the physical and emotional health of asymptomatic patients with nonmetastatic prostate cancer.     

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.     

Hormonal therapy of prostate cancer: is there any news?

Androgen ablative therapy was introduced in the early 1940s and, even today, has remained the golden standard for the treatment of advanced prostate cancer. During the past decades, a variety of improvements have been achieved which, however, primarily aimed at a better tolerance or improved acceptance of androgen deprivation. However, after almost six decades of hormonal therapy it is appropriate to ask whether progress was also made in terms of efficacy, particularly as far as prolongation of survival or quality of life is concerned. During the last few years, two therapeutic strategies, maximal androgen blockade and intermittent androgen suppression, have been considered true conceptual advances. However, despite tremendous efforts and a huge number of studies so far, these concepts appear to produce more questions rather than answers. Therefore, it seems appropriate to raise some critical issues of maximal androgen blockade and intermittent androgen suppression. Copyright Copyright 1999 S. Karger AG, Basel     

Current status of endocrine therapy in localized prostate cancer: cure has become a strong possibility

It is clear that all available means should be taken to diagnose prostate cancer early and to use efficient therapy immediately in order to prevent prostate cancer from migrating to the bones where treatment becomes extremely difficult and cure or even long-term control of the disease is an exception. The only means of preventing prostate cancer from migrating to the bones and becoming incurable is efficient treatment at the localized stage of the disease. In fact, since radical prostatectomy, radiotherapy and brachytherapy can achieve cure in about 50% of cases, these approaches are all equally valid choices as first treatment of localized prostate cancer. However, in view of the current knowledge and available data, nowadays, androgen blockade should also be considered as first line treatment. While showing the high efficacy of hormonal therapy in localized prostate cancer, present knowledge clearly indicate that long-term treatment with the best available hormonal drugs, somewhat similar to the 5 years of Tamoxifen in breast cancer, is required for optimal control of prostate cancer. It is also clear from the data analyzed that combined androgen blockage alone could well be an efficient therapy of localized prostate cancer while it has already been recognized as the best therapy for metastatic disease. This paper presents and discusses the current knowledge available on the use and results of endocrine therapy in localized prostate cancer.     

Primary, nonviral, hepatocellular carcinoma in patients with prostate cancer treated by hormone therapy: 2 case reports

We studied two cases of primary, hepatocellular carcinoma (HCC) that occurred following hormone therapy (estrogen therapy in one case and total androgen blockade therapy in another) for stage D2 prostate cancer. Prostate cancer is considered to be hormone-dependent, and androgens appear to be important hormonal factors. However, hepatocellular carcinoma has been shown to have both estrogen and androgen receptors, suggesting that this may be dependent on estrogen or androgen. Reported here are two unique cases of hepatocellular carcinoma in patients with prostate cancer; the pathogenesis of HCC in these patients was suspected to be related to diethylstilbestrol (DES) therapy and antiandrogen therapy for their prostate cancer.     

Prostate cancer following testosterone replacement in Klinefelter syndrome

Klinefelter syndrome is a common cause of hypogonadism. Testosterone replacement therapy has beneficial effects on bone, muscle and psychosexual function. However, it may remove the relative protection from adenocarcinoma of prostate, which is otherwise rare in uncomplicated Klinefelter syndrome. We report the case of a 55-year-old man with Klinefelter syndrome who developed prostate cancer after only 7 years of androgen supplementation. Androgen deprivation therapy was complicated by the presence of testosterone implants. The patient was treated with androgen blockade followed by radiation therapy. We recommend that serum prostate specific antigen (PSA) and digital rectal examinations be carried out during, as well as before androgen replacement.     

Medical versus surgical androgen suppression therapy for prostate cancer: a 10-year longitudinal cost study

PURPOSE: We provide a relative cost comparison of medical versus surgical androgen suppressive therapy for prostate cancer. MATERIALS AND METHODS: Comparison is based on a cohort of 96 patients who began androgen suppressive therapy for prostate cancer between 1988 and 1990. Patients were followed until death or the end point of study in June 2000 at which time 15% were alive. Current Medicare orchiectomy reimbursements were compared to 1999 wholesale drug costs. RESULTS: For an individual patient the cost of luteinizing hormone releasing hormone (LH-RH) agonist treatment surpassed the cost of surgery at less than 4.2 to 5.3 months, and for combined androgen blockade (LH-RH agonists and nonsteroidal antiandrogens) at less than 2.7 to 3.4 months. For 5 (5.2%) patients on combined androgen blockade and 6 (6.3%) on LH-RH agonists alone, medical therapy would have had a cost advantage over bilateral orchiectomy. For the androgen suppression cohort the cost of LH-RH agonist treatment was 10.7 to 13.5 times and combined androgen blockade was 17.3 to 20.9 times the cost of bilateral orchiectomy. Urology resource use comparisons are provided. These findings significantly underestimate the cost advantage of surgery. A seventh of the patients were alive at study end point, and prostate specific antigen induced stage shifting and changes in practice patterns resulted in earlier and more frequent androgen suppressive treatment. CONCLUSIONS: Except for patients with short anticipated survivals current medical androgen suppressive treatment options are more costly than bilateral orchiectomy. There is a need for a cost comparable medical option to orchiectomy.     

Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer

OBJECTIVES: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. METHODS: Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. RESULTS: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. CONCLUSIONS: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.     

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.