Hormone Therapy For Prostate Cancer Research Articles

A nonlinear model with competition between prostate tumor cells and its application to intermittent androgen suppression therapy of prostate cancer

The recurrence of a tumor is a crucial problem in hormonal therapy of prostate cancer. Recent studies suggest that intermittent androgen suppression administration may prolong or hopefully prevent the progression to the recurrence. It was shown that a simple mathematical model is useful to understand how and why intermittent administration can be effective and to seek a better medication scheme. In this paper, we propose a new model for the intermittent androgen suppression therapy. What is central in the new model is that the competitive effect between androgen-dependent and independent cancer cells is assumed to be essential for the decrease of androgen-independent cells under a normal androgen level. In the newly proposed model, the separatrix in the phase space for a normal androgen level plays an important role. There is crucial difference between the previous model and the new one in the phase diagram of success and failure of the permanent tumor control by intermittent androgen suppression administration. That means that the suggestions from the models for clinical problems can be different. We also consider the combined model of the previous and newly proposed models, which can smoothly bridge two models.

Radiation Therapy With or Without Hormonal Therapy for Prostate Cancer

In several randomized trials, researchers have demonstrated improvement in both disease-specific and overall survival among prostate cancer patients

Die plastische chirurgische Therapie der Gynäkomastie nach antihormoneller Therapie bei Prostatakarzinom

Gynecomastia is a potential side effect of hormone therapy for prostate cancer. In large, randomized, placebo controlled studies approximately 50% or more of patients with prostate cancer experienced gynecomastia attributable to various mechanisms. Although it is mostly reported as mild to moderate, gynecomastia is one of the reasons most frequently cited for premature discontinuation of such treatment. Prophylactic radiotherapy and prophylactic tamoxifen have been shown to decrease the incidence of hormone-induced gynecomastia; nevertheless, there are still cases of refractory gynecomastia, and in these plastic surgery is needed for correction. Gynecomastia is a benign enlargement of the male breast, requiring no treatment unless it is a source of embarrassment and/or distress for the adolescent or man affected. The indications for surgical treatment of gynecomastia are founded on two main objectives: restoration of the male chest shape and diagnostic evaluation of suspected breast lesions. The authors believe that the complete circumareolar technique with no further scarring creates the best aesthetic results with fewer complications. When this is used in combination with liposuction very pleasing aesthetic results can be achieved.

Évolution de la testostéronémie chez les patients traités par hormonothérapie pour un cancer prostatique

To assess the time-course of plasma testosterone in patients with prostate cancer treated by endocrine therapy. A PubMed review of the literature on plasma testosterone and the various endocrine therapies for prostate cancer was performed. The time-course of plasma testosterone varies according to the type of endocrine therapy. The effective castration level, classically considered to be 50 ng/dl, is currently tending to be replaced by 20 ng/dl. Following surgical castration, plasma testosterone reaches effective castration levels within several hours, while with LH-RH agonist therapy, plasma testosterone reaches its trough value after three to four weeks, and remains low for six months after stopping treatment. However, about 15% of patients treated with LH-RH agonists do not achieve effective castration levels. Plasma testosterone remains unchanged or even increases in response to anti-androgens. Plasma testosterone assay is of limited value in routine clinical practice in patients receiving endocrine therapy for prostate cancer, but should be performed in the case of elevation of PSA to ensure that the patient has achieved effective castration levels. The correlation between plasma testosterone and progression of prostate cancer is unclear. Other studies are therefore necessary to define the value of plasma testosterone assay in patients treated for prostate cancer.

Aspirin and Hormone Therapy for Prostate Cancer

To the Editor: Abnormal liver-function tests have been reported in 5% of patients taking high-dose aspirin for rheumatoid arthritis or osteoarthritis.1 A study of castrated rabbits revealed that se...

Prediction of Survival of Metastatic Prostate Cancer Based on Early Serial Measurements of Prostate Specific Antigen and Alkaline Phosphatase

We determined how serial measurements of prostate specific antigen and alkaline phosphatase can be used to predict survival early in the course of hormone treated metastatic prostate cancer. The study was based on a prospective randomized trial of 915 patients with metastatic prostate carcinoma designed to compare parenteral estrogen (polyestradiol phosphate) vs total androgen blockade. We included 697 men who survived at least 6 months and had complete serial measurements of prostate specific antigen and alkaline phosphatase. Six models were constructed based on prostate specific antigen and alkaline phosphatase at start, and after 6 months of treatment, alkaline phosphatase flare and relative prostate specific antigen velocity. We constructed time dependent receiver operating characteristic curves with corresponding area under the curve to predict death from prostate cancer within 3 years. The best variables to predict outcome were alkaline phosphatase at 6 months (AUC 0.79 for polyestradiol phosphate and 0.72 for total androgen blockade), alkaline phosphatase at baseline (AUC 0.70 for polyestradiol phosphate and total androgen blockade) and prostate specific antigen at 6 months (AUC 0.70 for polyestradiol phosphate and total androgen blockade). Prostate specific antigen and alkaline phosphatase levels 6 months after start of treatment give better prediction of survival than baseline levels. Alkaline phosphatase at start of treatment and alkaline phosphatase and prostate specific antigen after 6 months can be used to predict survival of hormone treated metastatic prostate cancer.

Current Status of Endocrine Therapy for Prostate Cancer in Japan Analysis of Primary Androgen Deprivation Therapy on the Basis of Data Collected by J-CaP

Based on the data of current status of endocrine therapy for prostate cancer registered in the Japan Study Group of Prostate Cancer (J-CaP), we conducted an analysis of primary androgen deprivation therapy (PADT) and an interim analysis of the prognosis. Of the 26 272 cases registered in the server of J-CaP, the 19 409 cases initially receiving PADT were included in this study. The initial therapy was divided into eight categories according to its features. Of the 19 409 patients, 1513 (7.8%) were given anti-androgen monotherapy, 955 patients (4.9%) surgical castration only, 1001 patients (5.2%) surgical castration + anti-androgen, 3015 patients (15.5%) LHRH monotherapy, 1658 patients (8.5%) LH-RH + short-term anti-androgen, 10 434 patients (53.8%) LH-RH + anti-androgen, 37 patients (0.2%) watchful waiting and 796 patients (4.1%) other therapy. In progression-free survival, the prognosis was slightly better following maximum androgen blockade (MAB) in each stage. The pattern of PADT is more typical in Japan compared with that in the United States. Patients who received MAB accounted for 59.0% of all the patients. MAB tends to be more often selected for patients who are rated as being at high risk on the basis of high Gleason score or PSA level upon diagnosis in each clinical stage of the disease. Investigations of the outcome are on-going and they will make clear the significance of this trend in Japan.

Phase II Study of Ketoconazole Plus Granulocyte-Macrophage Colony-Stimulating Factor for Prostate Cancer: Effect of Extent of Disease on Outcome

The efficacy of ketoconazole plus the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor was prospectively evaluated in patients with castration resistant prostate cancer with and without metastases. Eligible patients had progressive castration resistant prostate cancer by consensus criteria and had received no prior immunotherapy, chemotherapy or ketoconazole. Patients received 400 mg ketoconazole orally 3 times daily, and 20 mg hydrocortisone orally each morning and 10 mg hydrocortisone orally each evening. Granulocyte-macrophage colony-stimulating factor (250 microg/m2) was administered subcutaneously on days 15 to 28 of each 28-day cycle. Progression was defined as disease progression or toxicity. A total of 49 patients were enrolled, including 37 with radiographically evident metastases and 12 with prostate specific antigen only disease. Median patient age was 68 years (range 52 to 84) and median prostate specific antigen was 23.1 ng/ml (range 5.4 to 306.5). Time to progression, which was the primary study end point, was 9.7 months for all patients. Ten of the 30 treatment failures showed radiographic progression and 6 were due to toxicity, while treatment failure in 14 of 30 patients (47%) consisted only of increasing prostate specific antigen. Median time to progression was 6.9 and 15.4 months in patients with and without metastases, respectively (p = 0.01). Of 48 patients 36 (75%, 95% CI 60-86) experienced a 50% or greater decrease in prostate specific antigen. Four grade 4 events occurred that were unrelated to the study drug. Grade 3 events related to study therapy in more than 1 patient consisted of fatigue in 7 (14%). Combined ketoconazole and granulocyte-macrophage colony-stimulating factor yields a high response rate and it is an option for patients with castration resistant prostate cancer. Time to progression in patients without metastases is significantly longer than in those without metastases.

Secondary hormonal therapy for prostate cancer: what lies on the horizon?

Androgen deprivation therapy with medical or surgical castration is generally the first-line treatment against advanced prostate cancer. Almost invariably, metastatic prostate cancer overcomes testosterone depletion and grows, despite castrate levels of testosterone. Despite advances in cytotoxic chemotherapy, secondary hormonal therapies are often used after the development of castrate-resistant prostate cancer. Secondary hormonal therapies either lower the androgen levels further or directly antagonize the androgen receptor in prostate cancer cells. We discuss novel secondary hormonal agents that are under development, which work by either inhibiting androgen synthesis or directly targeting the androgen receptor.

Hormone therapy for prostate cancer

Hormone therapy for prostate cancer

The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy

Hormone therapy for prostate cancer eventually fails leading to a stage called hormone-resistant (HR) disease. To investigate the issue about the characteristics and the radiation response in HR prostate cancer, we established HR cell sub-lines, 22RV1-F and 22RV1-DF, from 22RV1 cells with androgen deprivation for 16 weeks, and obtained LNCaP-HR from LNCaP with long-term bicalutamide treatment. We examined their sensitivities to radiation therapy and the underlying mechanisms. In vitro and in vivo faster tumor growth rate was noted in the HR prostate cancer cells when compared with control. Moreover, HR prostate cancer cells had greater capacity to scavenge reactive oxygen species, and suffered less apoptosis and senescence, and subsequently were more likely to survive from irradiation as measured by clonogenic assay in vitro and growth delay in vivo. The decreased p53 and increased mouse double minute 2 oncogene (MDM2) might be the potential underlying mechanisms for the more aggressive growth and more radioresistance in HR prostate cancer cells. In conclusion, HR prostate cancer cells appeared to be more aggressive in tumor growth and in resistance to radiation treatment. Regulation of the expressions of p53 and MDM2 should be the promising treatment strategies for relative radioresistant prostate cancer.

POS-03.58: Prevalence and distress due to hot flushes in patients receiving endocrine therapy for prostate cancer and therapeutic efficacy of Japanese herbal medicine

POS-03.58: Prevalence and distress due to hot flushes in patients receiving endocrine therapy for prostate cancer and therapeutic efficacy of Japanese herbal medicine

Immunohistochemical Differentiation of High-grade Prostate Carcinoma From Urothelial Carcinoma

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial markers were relatively specific with only a few prostate cancers showing scattered (<or=2%) weak-moderate positive cells. In summary, PSA can be used as the first screening marker for differentiating high-grade prostate adenocarcinoma from high-grade urothelial carcinoma. Immunohistochemistry for P501S, PSMA, NKX3.1, and pPSA are useful when high-grade prostate cancer is suspected based on the morphology or clinical findings, yet shows negative or equivocal PSA staining. HMWCK and p63 are superior to the novel markers thrombomodulin and S100P.

Changes on endorectal MRI during neoadjuvant hormonal therapy for prostate cancer and biochemical outcome in men managed using radiation therapy: A prospective phase II Cancer and Leukemia Group B study

5072 Background: We prospectively determined whether changes in tumor volume (TV) on 1.5 Tesla endorectal magnetic resonance imaging (eMRI) during neoadjuvant androgen suppression therapy (AST) were associated with biochemical outcome after radiation and 6 months of AST. Methods: Between May, 1996 and April, 2001,180 men with T1c-T3c non-metastatic adenocarcinoma of the prostate cancer were registered. Fifteen were found to be ineligible leaving 165 men who had a eMRI TV measurement at baseline and following 2 months of neoadjuvant AST. An eMRI response was defined as &gt; 10% reduction in the volume of all lesions consistent with prostate cancer. In 32 men, the institutional MR radiologist could not completely assess the TV leaving 133 for analysis. A proportional hazards model was used to assess whether a significant association existed between eMRI response and time to prostate-specific antigen (PSA) failure following registration adjusting for PSA level (continuous), Gleason score (8 to 10 or 7 versus 6 or less) and stage (T3 versus T1, 2). PSA failure was defined as 2 consecutive rises of 0.2 above 1.0 ng/ml (PSA fail) and according to the 1997 and the 2006 American Society of Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Results: The median age and PSA level of the study cohort were 70 years and 10.7 ng/ml respectively. An eMRI response was noted in 112 (84%) men and 85, 47, and 47 men experienced PSA failure based on the 1997, 2006 ASTRO consensus and PSA fail definitions respectively. After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a statistically significant association between eMRI defined tumor response and time to PSA failure using the 1997 (p = 0.04) and 2006 (p = 0.009) ASTRO consensus definitions and a near significant association (p = 0.08) using PSA fail. Conclusion: Men lacking a &gt; 10% reduction in the eMRI defined TV during neoadjuvant AST are at increased risk for recurrence following radiation and AST. Therefore, eMRI enables the early documentation of androgen insensitive disease and identifies men for trials evaluating outcome when non-AST based approaches are combined with radiation and AST. No significant financial relationships to disclose.

Editorial Comment

No AccessJournal of UrologyAdult urology1 Jun 2007Editorial Comment Mark Garzotto Mark GarzottoMark Garzotto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2007.01.261AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 177(6), p. 2135 References 1 : Osteoporosis and obesity in men receiving hormone therapy for prostate cancer. J Urol2004; 172: S52. Link, Google Scholar 2 : Phase III intermittent MAB vs continuous MAB. J Clin Oncol2006; 24: 220s. abstract 4513. Google Scholar Department of Urology, Oregon Health & Science University, Portland VA Medical Center, Portland, Oregon© 2007 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 6June 2007Page: 2135 Advertisement Copyright & Permissions© 2007 by American Urological AssociationMetricsAuthor Information Mark Garzotto More articles by this author Expand All Advertisement PDF downloadLoading ...

Glucose intolerance during hormonal therapy for prostate cancer

The aim of this study was to examine the influence of hormonal therapy (HT) on glucose metabolism in prostate cancer (PCa) patients. Fifty-two PCa patients receiving HT with gonadotropin-releasing hormone (GnRH) analogues and/or antiandrogen drugs were enrolled in this study. Both blood and urine samples were taken a few hours after breakfast before and after HT, and glucose levels in the blood and urine were measured. Elevations of blood glucose levels of 30-50, 50-100 and over 100 mg/dl after HT as compared with the levels before HT were observed in two, eight and five patients, respectively. Urine examination revealed deterioration of glucosuria in seven patients. The mean blood glucose level after HT was significantly higher than that measured before HT. The elevation of blood glucose level significantly correlated with concurrence of diabetes mellitus (DM) and higher body mass index (BMI) before HT. Deterioration of glucosuria significantly correlated with the concurrence of DM. HT for PCa patients, especially with concurrent DM or obesity, induces elevation of the blood glucose level and deterioration of glucosuria. Therefore, glucose intolerance should be considered during HT for PCa.

Predictors of Overall and Cancer-Free Survival of Patients With Localized Prostate Cancer Treated With Primary Androgen Suppression Therapy: Results From the Prostate Cancer Outcomes Study

Primary androgen suppression therapy for clinically localized prostate cancer is increasingly common in the United States despite a lack of supportive evidence for its use. We determined which demographic and clinical factors predict overall and cancer specific survival with this treatment strategy in patients enrolled in the Prostate Cancer Outcomes Study. In 1994 to 1995 the Prostate Cancer Outcomes Study recruited 3,533 men diagnosed with prostate cancer. Clinical and treatment information was abstracted from medical records and demographic characteristics were obtained from patient surveys 6, 12, 24 and 60 months after diagnosis. Overall and cancer specific mortality was analyzed through December 2002 using the Kaplan-Meier method and Cox regression. A total of 276 patients had organ confined (cT1-2) prostatic adenocarcinoma and received primary androgen suppression therapy within 1 year of diagnosis. Median followup for censored patients was 7.6 years (range 1.1 to 8.1). Five-year overall and cancer specific survival was 66% (95% CI 59-72) and 91% (95% CI 86-94), respectively. Independent predictors of shorter overall survival were patient age 75 years or older, prostate specific antigen 20 ng/ml or greater, Gleason score 7 or greater and abnormal digital rectal examination. Gleason score 7 or greater, prostate specific antigen 20 ng/ml or greater and a low comorbidity index were independent predictors of shorter cancer specific survival. The use of primary androgen suppression therapy in the Prostate Cancer Outcomes Study data set resulted in 91% 5-year cancer specific survival. Advanced age, and factors that reflect tumor burden and biology were predictive of overall survival, while cancer specific survival was predicted by tumor factors and the burden of comorbid conditions. A nomogram for predicting overall survival at 5 years was constructed.

Early versus delayed endocrine therapy for prostate cancer

Endocrine treatment (ET) has in the past been shown to be beneficial in delaying clinical progression in all stages of prostate cancer, leading to an improvement of progression free survival in virtually all trials ever conducted. The first observations on this issue date back to the studies of the Veterans Administration Cooperative Urological Research Group in the 1960s. The period of time during which ET and the resulting side effects can be avoided is strongly dependent on the clinical stage of the disease. This treatment period is long in men who have minimal disease, such as a rising prostate-specific antigen after potentially curative management; however, it is considerably shorter in men who initially present with metastatic disease. In these situations, the potential benefit in quality of life, and avoidance of adverse events must be matched against the benefit in terms of gaining progression free time for the individual patient. This difficult task is supported by information supplied in this review. Locally advanced and regional (lymph node positive; stage T3N0-1M0Gx) disease is the domain of adjuvant ET. In this field, important progress has recently been made due to trials, which combine aggressive treatment of the primary tumor with adjuvant ET initiated at the same time. Therefore, in locally advanced and regional disease, radiotherapy or surgery combined with adjuvant ET must be considered state-of-the-art.

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Hormonal therapy of prostate cancer, by inhibiting androgen production and/or androgen function, is the treatment of choice for advanced prostate cancer. Although most patients respond initially, the effect is only temporary, and the tumor cells will resume proliferation in an androgen-deprived environment. The mechanism for androgen-independent proliferation of cancer cells is unclear. Hormonal therapy induces neuroendocrine differentiation of prostate cancer cells, which is hypothesized to contribute to tumor recurrence by a paracrine mechanism. We studied signal transduction pathways of neuroendocrine differentiation in LNCaP cells after androgen withdrawal, and we showed that both the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway and ERK are activated, but only the former is required for neuroendocrine differentiation. A constitutively active AKT promotes neuroendocrine differentiation and a dominant negative AKT inhibits it. Activation of AKT by IGF-1 leads to neuroendocrine differentiation, and neuroendocrine differentiation induced by epinephrine requires AKT activation. We also show that the AKT pathway is likely responsible for neuroendocrine differentiation in DU145, an androgen-independent prostate cancer cell line. Therefore, our study demonstrated a novel function of the AKT pathway in prostate cancer progression and identified potential targets that may be explored for the treatment of androgen-independent cancer.

The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight

Intermittent androgen deprivation (IAD) is one approach to hormonal therapy for prostate cancer that has been developed with the aim of minimizing the negative effects of therapy while maximizing the clinical benefits and the patient's quality of life (QoL). It can be used in any clinical situation where continuous AD (CAD) treatment could be applied. IAD is a cyclic therapy consisting of on-treatment periods followed by observation periods, known as off-treatment periods or intervals (OTIs), and the response to therapy, or occurrence of disease progression, is monitored by measuring the patient's prostate-specific antigen (PSA) levels. The on-treatment period is generally fixed, normally lasting for 6-9 months or in some protocols until a PSA nadir of <4 ng/mL is reached. By contrast, the OTI is variable and treatment is re-instituted depending on the patient's PSA level; however, the exact trigger point is chosen empirically. The potential advantages of IAD over CAD therapy are an improved QoL, a prolonged period of androgen dependence, a reduced incidence of the side-effects normally associated with AD therapy, and a decrease in the cost of care. Results from phase II clinical studies of IAD have shown that it has good acceptance and feasibility. QoL improves during the OTIs, there is reduced toxicity, and a positive affect on bone density compared with CAD therapy. In these studies IAD appeared to have no negative effects on time to progression or survival. Further investigations of IAD are ongoing in randomized, controlled, phase III trials in the USA, Canada and Europe. Most of these studies are not yet mature and final results are awaited; however, interim analyses from some studies suggest IAD and CAD therapy are equally effective in terms of progression-free survival.