Hormonal Treatment Of Prostate Cancer Research Articles

Precarious Bodies and Masculinities: The Experience of Exercise During Hormonal Treatment for Prostate Cancer

This study focuses on ageing men treated for prostate cancer receiving androgen deprivation therapy (ADT) linked to a spectrum of side effects, sometimes understood as emasculating. To understand the consequences of ADT and how to counteract side effects related to masculinity, interviews were conducted with treated men participating in an exercise programme. The aim was to analyse how participants experienced and embodied the exercise programme in relation to ageing, illness and masculinity. Findings show that the men experience their bodies as changing, loosing habituated abilities. The beginning of the programme evoked feelings of precarious bodies, whereas further along these feelings evolved into those of bodily remedy. Participation was seen as opportunity to meet other men in the same situation and created a sense of fellowship.

Gösta Jönsson (1909-1978): A pioneer in the hormonal treatment of prostate cancer in Sweden.

Treatment of castration-resistant prostate cancer is and has been a challenge. In 1957, the chemist Imre Könyves came to Sweden as a refugee from Hungary and started to work at AB Leo, a pharmaceutical company in Helsingborg. In 1961, he started to synthesize compounds where the oestrogens were linked to a mustard group by a carbamate. This resulted in estramustine phosphate, which was initially tested against mammary cancer with disappointing results. He then started a cooperation with urology professor Gösta Jönsson, Head of the Department of Urology at the Lund University Hospital, to test estramustine phosphate against prostate cancer. Jönsson started clinical estramustine phosphate tests in 1966. His studies were one-armed and consecutive, with a "favourable response" in 83% of previously untreated patients. These favourable results could not be reproduced in later randomized controlled studies suggesting that estramustine phosphate as primary treatment was not better than conventional estrogenic treatment. Conclusions: Even if the results of Gösta Jönsson's studies could not be confirmed, the subsequent randomized studies of estramustine phosphate may hide the desired action of estramustine phosphate in a subgroup of patients. It has still not been elucidated whether estramustine phosphate has effects in this subgroup of patients with ostrogen-resistant prostate cancer.

Pretreatment plasma osteopontin level as a marker of response to curative radiotherapy and hormonal treatment for prostate cancer

Background and purposeOsteopontin is a known marker for tumour hypoxia with relevance for the outcome of radiotherapy. We analysed the plasma concentration of OPN in prostate cancer patients receiving RT with or without ADT to evaluate OPN as a potential marker of treatment response. Materials and methodsBetween 2012 and 2014, 274 patients with prostate cancer qualifying for RT were enrolled to the study. SCADT received 34.3 % of patients, LCADT 46.3 %. The median OPN concentration was 83.9 ng/mL. We analysed the groups by OPN level: group A with OPN below and group B with OPN above the median. ResultsThere was a significant difference in OPN between the Gleason score (p = 0.005), the D’Amico risk (p = 0.002), the ADT (p < 0.001) and the RT (p = 0.019) groups. We found a positive correlation between OPN and clinical stage (p = 0.042).There were no significant effect of OPN on bRFS, RFS and MFS. The 10-year OS rate for group A was 81 % and for group B 60 % (p < 0.001). Cox analysis showed that low OPN level (p < 0.001), low age (p = 0.002) and low Gleason score (p = 0.038) were associated with higher OS. The prognostic influence of OPN on survival decreased with duration of ADT with the strongest effect of OPN (HR=3.93) observed when RT alone was used, weakest effect (HR=2.48) for SCADT and the smallest effect (HR=2.09) for LCADT. ConclusionsBased on the obtained results, we assume that the level of OPN measured before the start of radiotherapy may be an independent predictor of OS of patients with prostate cancer treated with radiotherapy with and without ADT.

Остеопороз у чоловіків: стан проблеми, фактори ризику, діагностика, сучасні підходи до лікування

Остеопороз (ОП) у чоловіків — це гетерогенне захворювання, якому сьогодні приділяється мало уваги. Традиційно ОП вважався захворюванням, вражаючим лише жінок. Сформоване ставлення до чоловічого ОП як до рідкісної патології, тому відсутність настороженості призводить до того, що багато пацієнтів залишаються без лікування. Однак під час проведених досліджень установлено, що третина всіх переломів проксимального відділу стегна припадає на частку чоловічого населення, зумовлюючи високий рівень інвалідизації та первинної смертності. Проблема діагностики й лікування ОП останнім часом стає все актуальнішою у зв’язку зі старінням населення та виникненням ускладнень, властивих цій хворобі. Частота ОП-асоційованих переломів у чоловіків аналогічна частоті інфаркту міокарда і перевершує навіть частоту карциноми легенів і раку передміхурової залози. Результати для чоловіків-пацієнтів після перелому стегна виглядають гнітюче: одна третина (32 %) помирає протягом першого року, і тільки 21 % здатні самостійно жити в суспільстві через рік після перелому. Ця проблема найпоширеніша в осіб старше 70 років. Етіологія ОП у чоловіків може бути ідіопатичною або вторинною внаслідок гіпогонадизму, дефіциту вітаміну D і недостатнього вживання кальцію, гормонального лікування раку передміхурової залози, супутньої патології, використання лікарських препаратів, що впливають на метаболізм кісток. У даному огляді на основі сучасних європейських та американських рекомендацій розглянуті питання епідеміології ОП у чоловіків, основні принципи діагностики захворювання, засновані на даних оцінки клінічних проявів, анамнезу, включаючи цілеспрямований скринінг. Використання алгоритму FRAX дозволяє призначити лікування пацієнтам на етапі, коли показники мінеральної щільності кісткової тканини знаходяться в ме­жах остеопенічних значень і наявні додаткові фактори ризику. Детально описані методи інструментального та лабораторного обстеження пацієнтів. Підкреслені основні методи лікування, препаратами першого вибору для лікування ОП у чоловіків є бісфосфонати (алендронат, ризендронат, золедронова кислота) і терипаратид, другої лінії — деносумаб. Незважаючи на те, що доказова база цих препаратів саме в чоловіків є малою, сучасні дані не передбачають наявності гендерної різниці результатів лікування при аналогічних значеннях мінеральної щільності кісткової тканини. Своєчасна діагностика та профілактика ОП у чоловіків сприятимуть більш ранньому його виявленню, дозволять розпочати адекватну терапію та зменшити кількість переломів у таких пацієнтів.

Modeling the synergistic properties of drugs in hormonal treatment for prostate cancer

Prostate cancer is one of the most prevalent cancers in men, with increasing incidence worldwide. This public health concern has inspired considerable effort to study various aspects of prostate cancer treatment using dynamical models, especially in clinical settings. The standard of care for metastatic prostate cancer is hormonal therapy, which reduces the production of androgen that fuels the growth of prostate tumor cells prior to treatment resistance. Existing population models often use patients’ prostate-specific antigen levels as a biomarker for model validation and for finding optimal treatment schedules; however, the synergistic effects of drugs used in hormonal therapy have not been well-examined. This paper describes the first mathematical model that explicitly incorporates the synergistic effects of two drugs used to inhibit androgen production in hormonal therapy. The drugs are cyproterone acetate, representing the drug family of anti-androgens that affect luteinizing hormones, and leuprolide acetate, representing the drug family of gonadotropin-releasing hormone analogs. By fitting the model to clinical data, we show that the proposed model can capture the dynamics of serum androgen levels during intermittent hormonal therapy better than previously published models. Our results highlight the importance of considering the synergistic effects of drugs in cancer treatment, thus suggesting that the dynamics of the drugs should be taken into account in optimal treatment studies, particularly for adaptive therapy. Otherwise, an unrealistic treatment schedule may be prescribed and render the treatment less effective. Furthermore, the drug dynamics allow our model to explain the delay in the relapse of androgen the moment a patient is taken off treatment, which supports that this delay is due to the residual effects of the drugs.

CYP17A1 and Androgen-Receptor Expression in Prostate Carcinoma Tissues and Cancer Cell Lines

Background: CYP17A1 is involved in the steroidogenesis of dehydroepiandrosterone and androstenedione. CYP17A is a target for the hormonal treatment of prostate cancer (PCa). Objectives: To investigate the role of CYP17A1 as a driver of PCa growth. Materials and Methods: We examined the expression of CYP17A1 and of androgen receptors (AR) in PCa specimens and in PCa cell lines. Results: CYP17A1 was strongly expressed in the cytoplasm of PCa cells (median 50% of cancer cells, range 0-100%). The nuclear AR expression in cancer cells was directly related with CYP17A1 (p < 0.0001, r = 0.51). The hormone dependent 22Rv1 cell line expressed the CYP17A1 and AR protein and mRNA, in contrast to the PC3 and DU145 cell lines (p < 0.0001). Testosterone and dexamethasone induced nuclear expression of AR and this effect was abolished by abiraterone. CYP17A1 levels were not affected by the incubation with testosterone, while abiraterone significantly reduced its expression. Abiraterone reduced the growth rate and migration of testosterone stimulated 22Rv1 cells. Conclusions: CYP17A1 is strongly expressed in half about of human prostate carcinomas, implying an intracellular androgen synthesis by cancer cells. Abiraterone effectively blocked nuclear accumulation of AR and suppressed CYP17A1 expression. CYP17A1 may function as a biomarker to select the best hormonal anticancer therapy

Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells-Brief Report.

Androgen deprivation therapy has been associated with increased cardiovascular risk in men. Experimental studies support that testosterone protects against atherosclerosis, but the target cell remains unclear. T cells are important modulators of atherosclerosis, and deficiency of testosterone or its receptor, the AR (androgen receptor), induces a prominent increase in thymus size. Here, we tested the hypothesis that atherosclerosis induced by testosterone deficiency in male mice is T-cell dependent. Further, given the important role of the thymic epithelium for T-cell homeostasis and development, we hypothesized that depletion of the AR in thymic epithelial cells will result in increased atherosclerosis. Prepubertal castration of male atherosclerosis-prone apoE-/- mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD3 antibody abolished castration-induced atherogenesis, demonstrating a role of T cells. Male mice with depletion of the AR specifically in epithelial cells (E-ARKO [epithelial cell-specific AR knockout] mice) showed increased thymus weight, comparable with that of castrated mice. E-ARKO mice on an apoE-/- background displayed significantly increased atherosclerosis and increased infiltration of T cells in the vascular adventitia, supporting a T-cell-driven mechanism. Consistent with a role of the thymus, E-ARKO apoE-/- males subjected to prepubertal thymectomy showed no atherosclerosis phenotype. We show that atherogenesis induced by testosterone/AR deficiency is thymus- and T-cell dependent in male mice and that the thymic epithelial cell is a likely target cell for the antiatherogenic actions of testosterone. These insights may pave the way for new therapeutic strategies for safer endocrine treatment of prostate cancer.

The complex interplay of sex steroids manifested by endocrine treatment of prostate cancer

The complex interplay of sex steroids manifested by endocrine treatment of prostate cancer

Personalized hormonal treatment for prostate cancer: An opportunity for improvement

Not applicable.

Surgery and hormonal treatment for prostate cancer and sexual function.

Prostate cancer (PC) is one of the most common cancers effecting men today. With earlier detection and improvements in available treatment modalities, there still remains significant morbidity associated with the treatment of PC. Male sexual health and erectile function are greatly impacted by these therapies and remain a concern to PC survivors. This article reviews the current literature on male sexual health following radical prostatectomy (RP) or androgen ablation therapy for PC. Each treatment modality affects male sexual function to an appreciable level, although certain patients have better outcomes if they have preoperative potency, are younger, or have nerve-sparing surgery. There is a delayed recovery up to 2 years seen in erectile function following RP. With androgen deprivation therapy (ADT), attempts can be made at different administration strategies and exercise may possibly play a role in maintaining erectile function. Penile rehabilitation protocols attempt to protect erectile function immediately following therapy through different modalities, although no one approach has been agreed upon.

A new protocol for intermittent androgen suppression therapy of prostate cancer with unstable saddle-point dynamics

Intermittent androgen suppression (IAS) therapy is a class of hormonal treatment for prostate cancer, in which a drug-induced androgen deprivation can reduce the population of prostate cancer cells. In IAS therapy, drugs are administrated only in on-treatment periods that are separated intermittently by off-treatment periods. The presence of off-treatment periods may be beneficial for maintaining the sensitivity of the tumor cells to androgen deprivation. Thus, IAS can be superior to continuous androgen suppression (CAS) for delaying or possibly preventing relapse of a tumor. IAS therapy usually monitors the level of serum prostate-specific antigen (PSA), which is related to the population of tumor cells. Each on-treatment period begins when the PSA level is greater than an upper threshold; treatment results in a decrease in the PSA level. The on-treatment period is suspended when the PSA level falls below a lower threshold; the PSA level then rises again until the beginning of the next on-treatment period. To determine the transitions between on- and off-treatment periods, we propose a new IAS protocol that uses a model-based estimate of the state point in the phase space of the tumor dynamics. We show that the proposed protocol is effective if, in each of the on- and off-treatment periods, the tumor dynamics exhibits a saddle-point instability accompanied by a stable manifold. Mathematical analysis reveals that tumor dynamics can be controlled in a more effective and robust manner with the proposed protocol than with conventional IAS. We also discuss the clinical feasibility of the proposed protocol as an alternative to conventional IAS therapy.

Le traitement hormonal du cancer de la prostate

To describe drugs used in the hormonal treatment (hormonotherapy) of prostate cancer. Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. LHRH analogs and the antiandrogens remain the cornerstone in the treatment of locally advanced and metastatic prostate cancer. New therapeutic classes emerged recently (inhibitor of the synthesis of the androgen, the new antiandrogens) and allowed to grow again the limits of the hormone resistance and define the concept castration-resistant prostate cancer. The hormonal treatment of the prostate cancer grew rich of new therapeutic classes which are going to change the medical care of the prostate cancer in the coming years and the urologist must play its full part.

A Man with Breast Cancer Following Hormonal Treatment for Prostate Cancer

Male breast cancer is rare with an annual incidence of less than 1% in Hong Kong. Some postulate the effect of estrogen as an important risk factor for development of male breast cancer. With the increasing use of hormonal therapy for patients with prostatic cancer, it may result in hormonal imbalance with a relative hyper-estrogenic state, which may increase the risk of male breast cancer. However so far there is no clinical evidence of its causal effects. Here we report a case of development of breast cancer in male patient after hormonal treatment (luteinizing hormone releasing hormone analog and anti-androgen) for prostatic cancer, and followed by a review of the literature for the association between them.

Quality of life and results of total androgen blockade alone and with radiotherapy in the treatment of nonmetastatic prostate cancer

Hormonal treatment of prostate cancer (CaP) in the form of total androgen blockade (TAB) with or without radiotherapy is applied in metastatic disease and in patients with nonmetastatic and localized disease as well. The aim of the study was to compare oncological results, residual and newly developed symptoms during treatment and the quality of life in patients with nonmetastatic CaP treated by using TAB and in a group treated both with TAB and radiotherapy (RT+TAB). Retrospective analysis of 126 patients with nonmetastatic CaP was performed. Follow-up was 36 months. Seventy-nine out of 126 patients were treated with TAB alone and 47 with TAB and radiotherapy (TAB+RT). Overall survival, metabolic syndrome appearance and the frequency of nonmalignant complications during treatment were analyzed. Urinary, digestive and sexual symptoms were analyzed, as well as the overall health condition of the patients. Fatal outcome and/or disease progression occurred in 29 out of 126 patients (23%). High risk patients were significantly more frequent in the TAB+RT group (p=0.04). Mortality rate was not different in both groups indicating that better results of treatment were achieved in patients treated with TAB+RT. Metabolic syndrome appeared in 51.6% of TAB patients and in 51.1 of TAB+RT patients, and was significantly more frequent at the end of the follow-up than at the beginning of the treatment (p=0.003 in TAB and p=0.01 in TAB+RT group). Urinary symptoms were more frequent than digestive symptoms in both groups. The quality of life was slightly improved after the beginning of therapy to be followed by the tendency of gradual decrease. Both modalities of treatment were efficient. Therapy TAB+RT was more efficient in high risk patients. Metabolic syndrome was more frequent after a long-term administration of therapy than at the beginning. The quality of life was the most affected in sexually active patients.

Beyond castration-defining future directions in the hormonal treatment of prostate cancer.

It is now almost 70 years since Charles Huggins described the relationship between testosterone and the prostate gland. Arguably defining one of the first targeted therapies, the reduction of testosterone to castrate levels remains unaltered as the standard of care for men with metastatic prostate cancer. The failure of castration to permanently control the growth of prostate cancer leads to a state called castration-resistant prostate cancer (CRPC). Whilst numerous mechanisms have been suggested for the emergence of castration resistance [Scher and Sawyers (J Clin Oncol 23(32):8253-8261, 2005); Chen et al. (Curr Opin Pharmacol 8(4):440-448, 2008), Pienta and Bradley (Clin Cancer Res 12(6):1665-1671, 2006); Feldman and Feldman (Nat Rev Cancer 1(1):34-45, 2001); Mostaghel and Nelson (Best Pract Res Clin Endocrinol Metab 22(2):243-258, 2008)], a greater understanding of prostate cancer biology suggests that many such cancers retain a dependency on androgens and endeavour to increase bioavailable androgens through mechanisms such as AR amplification and intracrine androgen synthesis [Mohler et al. (Clin Cancer Res 10(2):440-448, 2004); Attard et al. (Clin Cancer Res 17(7):1649-1657, 2011); Hu et al. (Expert Rev Endocrinol Metab 5(5):753-764, 2010)]. With the recent approval of abiraterone acetate (Zytiga) and the pending approval of MDV3100, this article previews the future directions in clinical development and issues that will arise with the next generation of androgen-targeted agents.

An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer.

Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.

Ischemic heart disease and stroke before and during endocrine treatment for prostate cancer in PCBaSe Sweden

In observational studies of men with prostate cancer, men on endocrine treatment (ET) have had an increased risk of ischemic heart disease (IHD) and stroke. However, prostate cancer per se may increase risk of IHD and stroke and men on ET may have been at increased risk already prior to initiation of ET. We assessed the incidence of IHD and stroke in men with prostate cancer before and during different endocrine treatments. The hazard ratio (HR) of IHD and stroke in 39,051 men with prostate cancer vs. a matched control population without prostate cancer was assessed by use of Cox proportion hazard models. An increased risk was found among 30,883 men with prostate cancer who did not receive ET, with a HR of 1.08 (95% CI 1.00-1.18) for IHD and 1.10 (95%CI 1.00-1.21) for stroke. In 8,168 men who initiated ET during the observation period, the risk of IHD was significantly higher (p = 0.014), during ET (HR 1.40, 95% CI 1.17-1.67) compared with before initiation of ET (HR of 0.98, 95% CI 0.72-1.33), whereas no such increase was found for stroke. Regardless of treatment, men with prostate cancer had a small increase in risk of IHD and stroke and initiation of ET was associated with a further increase in risk of IHD. Our data underline the importance of a proper indication for ET because many men with low-risk prostate cancer currently receive ET.

Gastrin‐releasing peptide: Predictor of castration‐resistant prostate cancer?

Neuroendocrine (NE) cells of the prostate are known to be androgen-independent and NE peptides like gastrin-releasing peptide (GRP) or neuron-specific enolase (NSE) can stimulate growth in a paracrine manner, and this is thought to be one of the escape mechanisms in castration-resistant prostate cancer (CRPCa). In a longitudinal study, we investigated the development of the NE serum factors GRP, NSE, and chromogranin A and their correlation with prostate-specific androgen (PSA) during hormonal treatment. Thirty two patients, with histology-proven, localized or metastatic prostatic carcinoma (PCa), who were undergoing therapy with LHRH analogue or a combination of LHRH analog and peripheral androgen blockade, took part in the study. In addition, eight healthy volunteers were each tested twice for serum GRP to elicit a "physiological" standard value. Blood samples were taken periodically from each patient within an 18-month time frame. We defined the standard value for GRP in the healthy participants as 0.852 ng/ml (mean + 2 SD) and observed that the GRP values for patients with PCa were significantly higher (P = 0.034). There was a positive correlation between PSA and GRP in patients with biochemical failure. CgA correlated with PSA development in the CRPCa patients. NSE values rose steadily over the study period, but with no correlation to PSA. Our data confirm that NE factors are elevated during hormonal treatment of prostate cancer. GRP is higher in PCa patients undergoing androgen deprivation therapy and is possibly involved in the initiation of hormonal escape in PCa.

Granulomes induits par des injections de leuproréline acétate (Enantone ®)

Gonadorelin analogues (LHRH) are used for the endocrine treatment of prostatic cancer, central early puberty and various gynaecological conditions. Cutaneous adverse events seldom occur. We report a case of injection-site granulomas induced by leuprorelin acetate (Enantone®). A 76-year-old man presented with several subcutaneous nodules on his left arm. The nodules were hard but painless. He had received subcutaneous injections of Enantone® for prostatic cancer. Histological examination of a skin biopsy specimen demonstrated granulomatous inflammation with a necrotic centre; screening for an infectious aetiology was negative. Serial sections showed giant cells containing translucent round microspheres in the subcutaneous tissue. Limitation to the leuprorelin acetate injection sites in the arm and detection at histological analysis of microspheres probably bound to an injected product militated in favour of granulomas caused by injections of Enantone®. Injection-site granulomas caused by Enantone® are rare. Their formation may depend on the mode of administration: the more superficial the injection, the higher the risk of developing granulomas. The formation of these lesions is probably a foreign body reaction to the excipient.

Androgen deprivation therapy for prostate cancer and its complications

AbstractThis article focuses on the hormonal treatment of prostate cancer by the reduction of androgen activity. The authors outline the under‐recognised complications that can be caused by the castration effect of androgen deprivation therapy. Copyright © 2010 Wiley Interface Ltd