Medication utilization evaluation of androgen deprivation therapy for prostate cancer in Taiwan

Prostate cancer is one of the most common cancer in males. Both the incidence and the mortality rates of prostate cancer show an increasing trend. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. The aim of our study was to show the epidemiology of prostate cancer and the proportion of patients utilizing ADT.This study used Taiwan''s National Health Insurance Research Database (NHIRD) and identified the patients who had been diagnosed with prostate cancer (International Classification of Disease (ICD)-10: C61) and followed up between Jan 1, 2008 and Dec 31, 2015. The ADT drugs used by prostate cancer patients were recorded: Gonadotropin-releasing hormone (GnRH) agonists; GnRH antagonist; estrogen analogs and androgen receptor antagonist.A total of 25,233 patients with newly diagnosed prostate cancer in 2008–2014 were enrolled. The utilization of ADT increased from more than 7,000 person-time in 2008 to more than 50,000 person-time in 2014. Cyproterone acetate was the most commonly used drug in 2008–2015, but its proportion of utilization, which was the highest in stage 2 cancer, dropped from 43% in 2008 to 15% in 2015. Bicalutamide was the second most used drug from 2008 to 2015, but its utilization was not different for different stages.The incidence rate of prostate cancer increased in the study period and medical expenditure also increased in ADT treatment. Health insurance benefits for various ADT drugs should be further evaluated.     

Quality of life in prostate cancer patients taking androgen deprivation therapy

OBJECTIVES: To examine the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL), self-reported HRQOL was compared in prostate cancer patients receiving short- (< 6 months) or long-term (> or = 6 months) ADT and healthy controls. DESIGN: Cross-sectional study. SETTING: Academic medical center in Pittsburgh, Pennsylvania. PARTICIPANTS: Ninety-six men, including those with prostate cancer receiving short-term, long-term, and no ADT and healthy controls. Men taking medications or having diseases known to affect bone mineral metabolism were excluded. MEASUREMENTS: The 36-item Short Form Medical Outcomes Study Health Survey (an HRQOL assessment) and a comorbidity index were administered to each participant. Characteristics, including body composition (assessed using dual-energy x-ray absorptiometry) and gonadal status (serum total and free testosterone) were measured approximately 3 months or less before the HRQOL assessment. RESULTS: As expected, men receiving ADT had significantly lower levels of testosterone, free testosterone, and lean body mass, as well as greater body fat and comorbidity index (all P<.01) than men not receiving ADT (i.e., men with prostate cancer and healthy controls). Participants receiving ADT reported significantly poorer QOL in the areas of physical function (P<.001), general health (P<.001), and physical health component summary (P<.001) than men not receiving ADT. There were no significant differences in HRQOL outcomes between participants receiving short- or long-term ADT. Comorbidity and testosterone levels were associated with several QOL scales. After controlling for the significant joint predictors of comorbidity and total testosterone using hierarchical regression analysis, ADT was no longer a significant predictor, and only comorbidity and total testosterone contributed to the explanation of the variance of the physical health component summary. Comorbidity alone contributed to the explanation of the variance in physical function, bodily pain, general health, and vitality. CONCLUSION: Patients with prostate cancer who were receiving ADT experience worse HRQOL than those not receiving ADT, but duration of ADT was not a contributing factor. After controlling for comorbidity, total testosterone level rather than ADT accounted for a small yet statistically significant percentage of the total variance of the physical health component summary. These findings have important clinical implications regarding the decision to treat prostate cancer patients with ADT.     

Androgen deprivation therapy for precancerous lesions of the prostate

Androgen deprivation therapy has become well-established in the treatment of prostate cancer. Luteinizing-hormone-releasing hormone (LHRH) agonists, anti-androgens, orchiectomy, and combination hormonal therapy are treatment options offered to select patients. The prospect of intervention prior to the development of adenocarcinoma is appealing, and high-grade prostate intra-epithelial neoplasia (PIN), the only known precursor, is the best possible target. There is a decrease in the incidence of high-grade PIN in patients treated with combination androgen deprivation therapy (LHRH agonist and anti-androgen). Changes include increased apoptosis, decreased mitotic activity, less conspicuous nucleoli, and basal-layer prominence. Treatment with the 5alpha-reductase inhibitor finasteride results in a significant decrease in the incidence of high-grade PIN. The effect of 5alpha-reductase inhibitors and selective estrogen receptor modulators on histopathologic evaluation remains unclear, as the number of cases evaluated is small, but new data will be forthcoming with completion of multiple clinical trials.     

‘First,do no harm’: managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer

Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non‐metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long‐term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival‐prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.     

Current status and prospects of androgen depletion therapy for prostate cancer

The old concept of androgen depletion therapy (ADT) for prostate cancer, which had been established on the basis of clinical experiences essentially on the far advanced disease, should be changed. The recent major increase in the diagnosis of localized and locally advanced prostate cancer due to prostate-specific antigen (PSA) screening prompts us to make clear the role of ADT for such an early stage of prostate cancer. Recent literature has proved that combination therapy of castration (medical or surgical) and non-steroidal anti-androgens (maximal androgen blockade, MAB, or combined androgen blockade, CAB) is markedly effective on non-metastatic prostate cancer. It is important to promote basic and clinical research based on the understanding that cure of prostate cancer is almost always possible with ADT if progression to the hormone-independent prostate cancer which accompanies metastatic disease can be avoided.     

雄激素受体对前列腺癌PC3细胞株增殖能力的影响

目的研究雄激素受体（AR）对雄激素非依赖性前列腺癌细胞株PC3增殖能力的影响。方法将含有AR的质粒（Pbabe-AR）稳定转染到PC3细胞,建立起新的细胞系PC3-AR,并用实时逆转录聚合酶链反应（Q—PCR）、蛋白免疫印迹试验（Western blot）和荧光素酶法确认AR的表达水平和功能;用MTT法、软琼脂糖凝胶实验检测AR对体外培养PC3细胞增殖的影响。结果PC3-AR细胞能够稳定表达有功能的AR;MTT实验显示PC3-AR细胞体外生长慢于PC3-v细胞,加入DHT以后效果更加明显。相对于PC3-v,PC3-AR在软琼脂糖凝胶中形成的克隆明显减少。结论AR能够降低PC3-AR细胞在体外的增殖能力。     

Mechanisms of prostate cancer progression to androgen independence

Prostate cancer is a major health problem in the United States and worldwide. In 2007, more than 27,000 men were estimated to have died from prostate cancer in the United States alone. Although important advances have been made in the diagnosis and treatment of prostate cancer, therapies focused on the removal or inhibition of androgen action remain the most important components of therapy for individuals with metastatic disease. Despite the application of such modalities, the vast majority of patients with metastatic disease progress with a median survival of less than 2 years. A number of different mechanisms have been identified that may potentially contribute to the progression of prostate cancer. These insights suggest that signaling via the androgen receptor (AR) -- either via alternate signaling pathways impinging on the AR or through the in situ formation of androgens within progressive tumors -- is an important contributor to such progressive disease. It is anticipated that such mechanistic insights will lead to the development of useful new therapies in the future.     

Morphological changes induced by androgen blockade in normal prostate and prostatic carcinoma

Maximal androgen blockade (MAB), combining a luteinizing hormone releasing hormone (LHRH) agonist and a pure or non-steroidal anti-androgen, induces significant morphologic changes in the prostate. The tumor volume, density, capsular penetration, and surgical margin involvement are strongly reduced following such treatment. On histology, normal prostate tissue and tumor undergo marked atrophy and shrinkage. Although residual cancer cells are readily identifiable in most cases, they may often be sparse and easily overlooked. The increased Gleason score apparent after MAB is most likely related to fragmentation of acinar structures, and grading is not recommended following MAB. Residual cancer cells show features of lower activity and increased apoptosis. Such therapy-induced changes may be reversible, although occasional clones of cancer cells are apparently not affected and have probably developed resistance. Finally, MAB leads to marked but reversible morphologic changes and reduction in prevalence and extent of prostatic intra-epithelial neoplasia (PIN). Monotherapy using a variety of agents causes comparable but often less extensive changes.     

Primary combined androgen blockade in localized disease and its mechanism

In spite of clinical practice guidelines such as NCI-PDQ - in which primary androgen deprivation therapy (PADT) is not recommended as the primary treatment for localized prostate cancer - many patients have been treated with PADT. One of the reasons is that urologists themselves permit patients' desire because they know the effectiveness of PADT for some patients in their experiences. In this review we demonstrate basic mechanisms and the clinical efficacy of primary combined androgen blockade (PCAB) for localized or locally advanced prostate cancer. Then we discuss which patients are candidates for PCAB, and show that more than 30% of low- or intermediate-risk localized prostate cancers could be controlled in the long term with only PCAB. Short-term or intermittent PADT could not be recommended because of the possibilities of changing the character of the cancer cells by incomplete androgen ablation. We propose algorithms for the treatment of localized prostate cancer not only in low- and intermediate-risk groups but also in the high-risk group.     

75岁及以上的老年前列腺癌患者雄激素剥夺治疗后的长期认知障碍风险分析

目的:观察75岁及以上老年前列腺癌患者雄激素剥夺治疗(ADT)后的长期认知障碍风险,并分析ADT应用和认知障碍的相关性。方法:回顾性队列研究,纳入1996—2003年在美国国立癌症数据库(SEER)中75岁及以上老年前列腺癌患者,根据是否行ADT分为ADT组(82514例)和对照组(121 856例)。比较两组的基线临...     

Targeting the stromal androgen receptor in primary prostate tumors at earlier stages

To differentiate roles of androgen receptor (AR) in prostate stromal and epithelial cells, we have generated inducible-(ind)ARKO-TRAMP and prostate epithelial-specific ARKO TRAMP (pes-ARKO-TRAMP) mouse models, in which the AR was knocked down in both prostate epithelium and stroma or was knocked out in the prostate epithelium, respectively. We found that loss of AR in both mouse models resulted in poorly differentiated primary tumors with expanded intermediate cell populations. Interestingly, knockdown of both epithelial and stromal AR in ind-ARKO-TRAMP mice at earlier stages resulted in smaller primary prostate tumors with lower proliferation rates, and knockout of AR in pes-ARKO-TRAMP mice resulted in larger primary prostate tumors with higher proliferation rates. The differential proliferation rates, yet with similarly expanded intermediate cell populations, indicated that the prostate stromal AR might play a more dominant role than the epithelial AR to promote primary tumor proliferation at an early stage of tumor. Tissue recombination of human prostate stromal cell lines (WPMY1-v or WPMY1-ARsi) with human prostate cancer epithelial cell lines (PC3-v or PC3-AR9) further demonstrated that the AR might function as a suppressor in epithelial cells and a proliferator in stromal cells in the primary prostate tumors. The dual roles of the AR in prostate epithelium and stroma may require us to reevaluate the target and timing of androgen-deprivation therapy for prostate cancer patients and may suggest a need to develop new drugs to selectively target stromal AR in the primary prostate tumors at earlier stages.     

Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications

Residual tissue androgens are consistently detected within the prostate tumors of castrate individuals and are thought to play a critical role in facilitating the androgen receptor-mediated signaling pathways leading to disease progression. The source of residual tumor androgens is attributed in part to the uptake and conversion of circulating adrenal androgens. Whether the de novo biosynthesis of androgens from cholesterol or earlier precursors occurs within prostatic tumors is not known, but it has significant implications for treatment strategies targeting sources of androgens exogenous to the prostate versus 'intracrine' sources within the prostatic tumor. Moreover, increased expression of androgen-metabolizing genes within castration-resistant metastases suggests that up-regulated activity of endogenous steroidogenic pathways may contribute to the outgrowth of 'castration-adapted' tumors. These observations suggest that a multi-targeted treatment approach designed to simultaneously ablate testicular, adrenal and intracrine contributions to the tumor androgen signaling axis will be required to achieve optimal therapeutic efficacy.     

Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review

Increasing numbers of men with non-metastatic disease are receiving androgen deprivation therapy (ADT) for a variety of indications, some of which are supported by evidence from randomized trials. Balanced against possible survival benefits and better disease control are data that ADT adversely affects quality of life, particularly in the areas of sexual function, physical function, and energy. There is some evidence of worsening upper extremity physical strength but no clear evidence of decline in daily function with ADT. The impact of ADT on cognitive function is not clear at this time. ADT is associated with declines in bone mineral density within 6–12 months of commencing treatment, with increased fracture rates within 5 years of treatment. ADT use is also associated with a 10–15 g/L decline in hemoglobin, although the clinical significance of this drop appears to be limited for most patients. It is reasonable for physicians who are about to start men on ADT to obtain a baseline bone mineral density, to counsel them about the impact on sexual function and possible treatments for sexual dysfunction, and to encourage regular exercise. Further insight into adverse effects of ADT and strategies to minimize these adverse effects await data from ongoing studies.     

Androgen receptor is a tumor suppressor and proliferator in prostate cancer

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo. Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.