雄激素拮抗与前列腺癌预防

前列腺癌是西方发达国家男性最常见的恶性肿瘤，雄激素是其发病的重要因素，采用雄激素拮抗降低前列腺癌发病危险成为近年研究的重点。5α-还原酶抑制剂是前列腺癌预防研究的首选药物，前列腺癌预防试验(PCPT)是全球第一个大样本的前列腺癌预防试验研究。结论表明通过雄激素拮抗降低前列腺癌发病率是可行的。     

雄激素拮抗与前列腺癌预防

前列腺癌是西方发达国家男性最常见的恶性肿瘤 ,雄激素是其发病的重要因素 ,采用雄激素拮抗降低前列腺癌发病危险成为近年研究的重点。 5α -还原酶抑制剂是前列腺癌预防研究的首选药物 ,前列腺癌预防试验 (PCPT)是全球第一个大样本的前列腺癌预防试验研究。结论表明通过雄激素拮抗降低前列腺癌发病率是可行的     

雄激素受体在晚期前列腺癌治疗中的作用

对34例晚期前列腺癌患者在接受抗雄激素治疗前作前列腺雄激素受体（AR）定量测定，以了解AR值在抗雌激素治疗中的作用。结果发现，前列腺癌细胞浆AR（cAR）和细胞核AR（nAR）的平均值分别为71．4±65．7fmol／mg和299．4±371．8fmol／mg；nAR值在100fmol／mg以上者为58．8％，多于cAR的26．5％。随访27例患者，在激素治疗有反应的17例中，nAR＞100fmol／mg者占76.5％，与cAR的17.6％有显著性差异。而在nAR≤100fmol／mg的患者中，60％于治疗8～24个月内反应性消火。认为nAR值的变化能较准确地预测前列腺癌患者对抗雄激素治疗的反应性。     

雄激素非依赖性前列腺癌和雄激素受体的研究进展

晚期前列腺癌可发生雄激素依赖性改变,对抗雄激素治疗不再有效.前列腺癌对雄激素依赖性发生转变的分子机制目前尚未完全阐明,近年来的大量研究显示前列腺癌雄激素非依赖性与雄激素受体(androgen receptor,AR)的反常激活有关,与雄激素受体(AR)表达增加和突变、AR调节因子表达改变、AR信号途径改变有关,但AR在雄激素非依赖性前列腺癌中的作用仍不清楚,本文就这些方面的研究进展作一综述.     

雄激素受体与前列腺癌关系的研究进展

目前前列腺癌还缺乏能较好地预示其预后和内分泌的治疗反应的指标。雄激素受体在这方面的作用已受到人们的重视，为此本文对近年来雄激素受体与前列腺癌发生发主内分泌治疗之间关系的研究进行综述。雄     

间断性雄激素阻断治疗前列腺癌的研究进展

前列腺癌是男性泌尿生殖系统常见肿瘤之一。内分泌治疗是前列腺癌主要治疗手段。但疗效并未达到人们预期的程度，且长期治疗副作用多，间断性雄激素阻断治疗是最近前列腺癌治疗研究热点之一。本文就近几年前列腺癌间断性雄激素阻断治疗原理，基础和临床研究，临床应用原则及有关问题作一综述。     

雄激素非依赖性前列腺癌的治疗进展

前列腺癌是男性泌尿生殖系统常见的恶性肿瘤。在前列腺癌的治疗中,部分患者可行根治性前列腺切除手术,但其余患者需要内分泌及其他非手术治疗。经抗雄激素治疗后部分患者病情好转,但部分患者在治疗12～18个月后逐渐对抗雄激素治疗失去反应,逐步发展为雄激素非依赖性前列腺癌,非依赖性状态的出现是前列腺癌患者死亡的原因也是治疗的难点。近年来,对雄激素非依赖性前列腺癌的治疗有了许多新的认识和进展。本文作一综述。     

间歇性雄激素阻断治疗前列腺癌的研究进展

间歇性雄激素阻断(intermittent androgen deprivation,IAD)治疗是雄激素阻断治疗前列腺癌(即内分泌治疗)的一种新策略。目前的研究表明间歇性雄激素阻断治疗可行并具有其独特的优势。本文就间歇性雄激素阻断治疗前列腺癌的原理、近年来的基础和临床研究及应用原则等问题作一综述。     

间歇性雄激素阻断治疗前列腺癌的研究进展

间歇性雄激素阻断(intermittentandrogendeprivation,IAD)治疗是一种新的前列腺癌激素治疗方式。初步研究表明IAD治疗可以延缓激素抵抗的发生,改善患者的生活质量、降低不良反应,并可能可以延长患者的生存期,减少治疗费用,是一种可行的前列腺癌治疗方式。本文结合国内外文献,对IAD治疗前列腺癌的研究进展作一综述。     

雄激素受体在晚期前列腺癌治疗中的作用

３４例晚期前列腺癌病人在接受抗雄激素治疗前作前列腺雄激素受体（ＡＲ）定量测定，以了解ＡＲ值在抗雄激素治疗中的作用。结果发现：前列腺癌细胞浆ＡＲ（ｃＡＲ）和细胞核ＡＲ（ｎＡＲ）的平均值（ｆｍｏｌ／ｍｇＤＮＡ）分别为７１．４±６５．７和２９９．４±３７１．８；ｎＡＲ值在１００以上的例数为５８．８％，多于ｃＡＲ的２６．５％。随访２７例病人，对激素治疗有反应的１７例中，ｎＡＲ＞１００的例数占７６．５％，与ｃＡＲ的１７．６％差异有显著性。而在ｎＡＲ≤１００ｆｍｏｌ的病人中，６０％于治疗８～２４个月内反应性消失。认为ｎＡＲ值的变化能较准确地预测前列腺癌病人对抗雄激素治疗的反应性。     

间歇性雄激素阻断治疗晚期前列腺癌效果观察

目的 评价间歇性雄激素阻断治疗晚期前列腺癌的可行性及优点.方法 选取晚期前列腺癌患者59例,随机分为2组.给予间歇性雄激素阻断治疗30例(A组),给予持续雄激素阻断治疗29例(B组),观察两组患者的疾病进展及治疗期间副反应的发生情况,比较两种方法的治疗效果.结果 A组患者平均随访26个月,B组患者平均随访27个月,两组患者疾病进展情况未见明显差异.A组患者副反应低于B组患者且能在治疗间歇期得到缓解.结论 间歇性雄激素阻断治疗方法可行,能够减少患者治疗的副反应,提高患者生活质量.     

A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Men with prostate cancer have higher rates of non‐cancer mortality and CV morbidity and some of that excess risk has been attributed to the treatment they receive. ADT is an established treatment option for men with locally‐advanced and metastatic prostate cancer and, although it has been shown to confer a disease‐free survival advantage, it has also been associated with an increased incidence of CV disease and the metabolic syndrome (characterized by a cluster of CV risk factors, including insulin resistance). The benefits of the insulin sensitizer metformin and lifestyle intervention for reducing the incidence of metabolic syndrome have been shown in patients with impaired glucose tolerance. At the time of writing, the present study is the first to use metformin and lifestyle intervention in men with prostate cancer with the aim of reducing the risk of developing ADT‐related CV morbidity and the metabolic syndrome. The study shows that lifestyle changes and metformin may indeed reduce the complications of androgen suppression in these men. Although further investigations are needed to establish which of the two interventions may be most beneficial, the favourable effects of a combination of these interventions on patients' quality of life and the potential for improved overall survival are of clinical significance.

OBJECTIVE

• ? To investigate the effects of metformin and lifestyle changes on the development of androgen deprivation therapy (ADT)‐related metabolic syndrome.

PATIENTS AND METHODS

• ? Men with prostate cancer due to receive ADT were recruited and randomized.
• ? Controls received ADT alone.
• ? Men in the intervention arm received ADT with 6 months of metformin, a low glycaemic index diet and an exercise programme.
• ? All patients were investigated pretreatment and at 6 months for the metabolic syndrome, as well as for related biochemical and physical parameters.

RESULTS

• ? In total, 40 men were recruited and randomized (20 to each arm).
• ? After 6 months, significant improvements in abdominal girth (P= 0.05), weight (P < 0.001), body mass index (P < 0.001) and systolic blood pressure (P= 0.01) were seen in the intervention arm compared to controls.
• ? Biochemical markers of insulin resistance did not differ significantly.

CONCLUSIONS

• ? The present study shows the potential benefits of metformin and lifestyle changes in ADT‐treated men.
• ? Further studies will aim to determine which intervention is most important, and may show that overall survival can be improved.

     

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.     

Androgen and prostate cancer: the role of primary androgen deprivation therapy in localized prostate cancer

BackgroundThe basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT.MethodsA retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out.ResultsIt was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation.ConclusionAlgorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated.     

Use of androgen deprivation therapy for metastatic prostate cancer in older men

OBJECTIVE

To assess factors associated with early or delayed androgen deprivation therapy (ADT) among men diagnosed with metastatic prostate cancer, and to assess the relationship between ADT and overall survival, as there is uncertainty about the ideal timing for initiating ADT in men with metastatic prostate cancer.

PATIENTS AND METHODS

We studied a population‐based cohort of American men aged ≥66 years diagnosed with metastatic prostate cancer during 1992–2002 and followed to 2003. We assessed the receipt of ADT early (≤4 months from diagnosis), delayed (>4 months), or not at all, using multinomial logistic regression to identify factors associated with treatment, and Cox proportional‐hazard models to assess whether treatment was associated with survival.

RESULTS

Overall, 69.5% of men received early ADT and 7.3% delayed. Adjusted rates of early ADT were lower for black than white men (58.3% vs 71.0%), and of delayed ADT were higher for black than white men (12.7% vs 6.2%). Receipt of ADT was associated with improved survival (adjusted hazard ratio 0.69, 95% confidence interval 0.66–0.73). The benefit of early treatment did not differ from delayed treatment (P = 0.58).

CONCLUSIONS

A large minority of men with metastatic prostate cancer, particularly black men, receive delayed or no ADT. Early or delayed ADT was associated with similarly prolonged survival. After controlling for patient and tumour characteristics, survival did not differ by race, and receipt of ADT did not contribute to racial differences in survival.     

Bone health in men receiving androgen deprivation therapy for prostate cancer

PURPOSE: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. MATERIALS AND METHODS: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. RESULTS: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. CONCLUSIONS: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential.     

Management of decreased bone mineral density in men starting androgen‐deprivation therapy for prostate cancer

OBJECTIVE

To determine whether clinicians discuss bone‐specific side‐effects with patients on androgen‐deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side‐effect of ADT, leading to increased risk of fracture.

PATIENTS AND METHODS

Sixty‐six men (mean age 70.6 years) with non‐metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual X‐ray absorptiometry (DXA) at baseline. Patients were interviewed to obtain their medical histories, and charts were reviewed to determine whether clinicians documented potential bone side‐effects in clinic notes, and made lifestyle and/or medication recommendations. Both were done at the start of ADT, and 3 and 6 months later. Patients were classified based on DXA T‐score as having normal BMD, as osteopenic, or osteoporotic.

RESULTS

At baseline, 53% of patients had osteopenia and 5% had osteoporosis. Within 6 months of starting ADT, general side‐effects and bone‐specific side‐effects of ADT were documented as being discussed with 26% and 15%, respectively. Clinicians recommended lifestyle interventions to 11% of patients. Pharmacological interventions (calcium, vitamin D, and/or bisphosphonates) were recommended to 18% of all patients within 6 months of starting ADT, and to 26% and 67% of osteopenic and osteoporotic patients, respectively.

CONCLUSIONS

A minority of patients is being informed of bone‐specific side‐effects of ADT. Lifestyle and drug interventions to prevent declines in BMD were recommended uncommonly. Practices around bone health for men starting ADT are suboptimal.     

Kinetics of testosterone recovery in clinically localized prostate cancer patients treated with radical prostatectomy and subsequent short-term adjuvant androgen deprivation therapy

Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230–905) ng dl⁻¹. All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥300 ng dl⁻¹) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.     

Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the androgen receptor, but there has been conflicting data from small retrospective studies evaluating the effect of CAG repeat polymorphisms on response to ADT. This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR‐CAG repeat lengths do not predict response to ADT.

OBJECTIVES

? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the AR. ? The purpose of the present study was to determine if AR‐CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT).

PATIENTS AND METHODS

? Germline AR‐CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival.

RESULTS

? There was no significant correlation between differences in the AR‐CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ? AR‐CAG repeat lengths did not significantly correlate with age, prostate‐specific antigen (PSA), Gleason score or clinical stage at diagnosis. ? In patients with metastatic disease, longer AR‐CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P= 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54–1.09).

CONCLUSIONS

? This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. ? Germline AR‐CAG repeat lengths do not predict response to ADT.