Androgen Deprivation In Prostate Cancer Research Articles

Clinical Results after High-Dose Intensity-Modulated Radiotherapy for High-Risk Prostate Cancer

Purpose. Patients with high-risk prostate cancer (PC) can be treated with high-dose intensity-modulated radiotherapy (IMRT) and long-term androgen deprivation (AD). In this paper we report on (i) late toxicity and (ii) biochemical (bRFS) and clinical relapse-free survival (cRFS) of this combined treatment. Methods. 126 patients with high-risk PC (T3-4 or PSA >20 ng/mL or Gleason 8–10) and ≥24 months of followup were treated with high-dose IMRT and AD. Late toxicity was recorded. Biochemical relapse was defined as PSA nadir +2 ng/mL. Clinical relapse was defined as local failure or metastases. Results. The incidence of late grade 3 gastrointestinal and genitourinary toxicity was 2 and 6%, respectively. Five-year bRFS and cRFS were 73% and 86% respectively. AD was a significant predictor of bRFS (P = 0.001) and cRFS (P = 0.01). Conclusion. High-dose IMRT and AD for high-risk PC offers excellent biochemical and clinical control with low toxicity.

Androgen deprivation for prostate cancer

The list of adverse consequences of androgen deprivation therapy for prostate cancer continues to grow, with the latest addition being an increased risk of thromboembolism. Accordingly, use of androgen deprivation therapy should be restricted to settings where clear evidence of benefit exists.

Radiotherapy and androgen deprivation for prostate cancer.

Radiotherapy and androgen deprivation for prostate cancer.

Radiotherapy and Androgen Deprivation for Prostate Cancer

Radiotherapy and Androgen Deprivation for Prostate Cancer

Factors Associated With Vertebral Fractures in Men Treated With Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy for prostate cancer causes accelerated loss of bone mineral density and is associated with increased fracture risk. We evaluated risk factors associated with vertebral fractures among men enrolled in a fracture prevention trial. Analysis included men receiving androgen deprivation therapy for prostate cancer and enrolled in a phase III fracture prevention trial. All men were 70 years old or older or had a low bone mineral density (T-score less than -1.5 for the lumbar spine or total hip). We analyzed demographic and laboratory characteristics of men with and those without vertebral fractures at study entry. Of the 1,244 subjects 162 (13.0%) had a vertebral fracture at baseline. The 2 factors significantly associated with vertebral fractures were white race (p=0.028 compared with nonwhite race) and osteoporosis (p=0.002 for osteoporosis at any site, p=0.053 for osteoporosis at the spine, p=0.002 for osteoporosis at the hip). Lower bone mineral density was also significantly associated with vertebral fractures when analyzed as a continuous variable. Factors not associated with vertebral fractures included age, country of residence, androgen deprivation therapy duration at baseline, androgen deprivation therapy mode, body mass index, testosterone, estradiol, C-telopeptide, bone specific alkaline phosphatase and osteocalcin. Results were similar in analyses limited to men 70 years old or older. White race and low bone mineral density were significantly associated with vertebral fractures in this study of men treated with androgen deprivation for prostate cancer. These observations should inform the assessment and management of fracture risk among such men.

Androgen deprivation for prostate cancer and the development of cardiovascular disease, its risk factors, and all-cause mortality.

e15178 Background: The overall benefit of androgen deprivation (AD) therapy may involve a trade off between improved prostate cancer control and increased cardiovascular (CV) mortality. Our study examines the risk of development of CV disease and risk factors, as well as all-cause mortality (ACM), for patients on AD for prostate cancer. Methods: Patients with localized biopsy-proven prostate cancer between 2001 and 2008 were identified using a medical records database. CV risk factors (diabetes, hypertension, hypercholesterolemia and obesity) and systolic heart failure were identified by medical record and lab findings while remaining CV endpoints (myocardial infarction, coronary artery disease and sudden cardiac death) were found by outpatient and inpatient billing data. Correlation with chi-squared or t-statistic and proportional hazard models were calculated with CV endpoints and CV risk factors. Results: Cohort consisted of 1660 patients with prostate cancer observed for a mean of 68.3 ± 28.6 months. AD was used in 287 patients as primary (31%) or adjuvant (69%) therapy with radiation or prostatectomy. Age at diagnosis was 65.1 ± 9.0 years for patients without AD and 71.7 ± 8.5 years for AD (p<0.001). Higher incidence of diabetes (22% versus 15%), hypertension (69% versus 54%), coronary artery disease (32% versus 16%) and systolic heart failure (7.1% versus 2.4%) occurred with AD (p<0.01). When adjusted for age at diagnosis, only the development of systolic heart failure (adjusted HR, 1.92; p=0.033) and diabetes (adjusted HR,1.39; p=0.043) were associated with use of AD. ACM was associated with prevalent and incident diabetes, hypertension and systolic heart failure, but not AD. Analysis of a high-risk subgroup of patients with prior systolic heart failure or myocardial infarction revealed no association between AD and ACM. Conclusions: AD is associated with a higher risk of diabetes and systolic heart failure, but not with other CV risk factors, CV endpoints or ACM in this cohort. Additional work is needed to further characterize the relationship between AD and systolic heart failure, as well as diabetes, and its role in ACM.

Steroidogenic Enzymes and Stem Cell Markers Are Upregulated during Androgen Deprivation in Prostate Cancer

Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent tumors. To study this hypothesis, we assessed the expression of several steroidogenic enzymes and stem cell markers in clinical PCa samples and cell cultures during androgen depletion. Gene expression profiles were determined by microarray or qRT-PCR. In addition, we measured cell viability and analyzed stem cell marker expression in DuCaP cells by immunocytochemistry. Seventy patient samples from different stages of PCa, and the PCa cell line DuCaP were included in this study. The androgen receptor (AR) and enzymes (AKR1C3, HSD17B2, HSD17B3, UGT2B15 and UGT2B17 ) that are involved in the metabolism of adrenal steroids were upregulated in castration resistant prostate cancer (CRPC). In vitro, some DuCaP cells survived androgen depletion, and eventually gave rise to a culture adapted to these conditions. During and after this transition, most of the steroidogenic enzymes were upregulated. These cells also are enriched with stem/progenitor cell markers cytokeratin 5 (CK5) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, putative stem/progenitor cell markers CK5, c-Kit, nestin, CD44, c-met, ALDH1A1, α2-integrin, CD133, ABCG2, CXCR4 and POU5F1 were upregulated in clinical CRPC. The upregulation of steroidogenic enzymes and stem cell markers in recurrent tumors suggests that cancer initiating cells can expand by adaptation to their T/DHT deprived environment. Therapies targeting the metabolism of adrenal steroids by the tumor may prove effective in preventing tumor regrowth.

Triptorelin embonate: a 6-month formulation for prostate cancer

Importance of the field: Luteinizing hormone releasing hormone (LH RH) agonists are the major agent for androgen deprivation therapy in advanced and metastatic prostate cancer. They also have a role in endometriosis, uterine fibroids and central precocious puberty.Areas covered in the review: Triptorelin embonate 22.5 mg is a new, sustained-release, 6-month formulation of an LH RH agonist. It possesses longer duration of action than the current standard 3-month preparation and appears to have similar efficacy and side effects.What the reader will gain: The use of LH RH agonists for androgen deprivation in prostate cancer has increased considerably in the last 20 years. Recent work has shown that some of this usage has constituted overtreatment and it is within these newer paradigms of therapy that the new 6-month preparation is situated.Take home message: The new 6-month LH RH preparation – triptorelin embonate – will be of help in several key areas of therapy for prostate cancer, notably as an adjunct to radiation therapy and chemotherapy. It possesses a similar effect, but with fewer side effects, than those that are now commonly available.

Characteristics and management of erectile dysfunction after various treatments for prostate cancer

Preface Currently, there are many wellestablished therapeutic options for early prostate cancer, and therefore, it is difficult for both urologists and patients to choose the optimal treatment. It is essential for urologists to counsel their patients according to reliable information about the advantages and disadvantages of each therapeutic option. We picked the topic for this issue, “Characteristics and management of erectile dysfunction after various treatments for prostate cancer,” because erectile dysfunction (ED) is one of the most frequent adverse events encountered in the management of prostate cancer. We invited six specialists to review each therapeutic option: radical prostatectomy, laparoscopic radical prostatectomy, robot-assisted laparoscopic radical prostatectomy, external beam radiotherapy, brachytherapy, and androgen deprivation therapy (ADT). Among these modalities, surgical interventions tend to induce a quick drop in erectile function with slow postoperative recovery. Early postoperative rehabilitation has been introduced, aiming at the early recovery of ED. On the contrary, radiation therapy tends to maintain the patient’s erectile function for a while after treatment but it gradually decreases. ADT may compromise not only the erectile function but also the libido level, and may result in significant deterioration of the patient’s quality of life. We hope these reviews will help urologists to counsel their patients with regards to decision-making in the management of early prostate cancer.

1289 A MECHANISM FOR ANDROGEN-INDEPENDENT PROSTATE CANCER THROUGH MODULATION OF ANDROGEN RECEPTOR SIGNALING BY THE P21-ACTIVATED KINASE 6 (PAK6)

You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101289 A MECHANISM FOR ANDROGEN-INDEPENDENT PROSTATE CANCER THROUGH MODULATION OF ANDROGEN RECEPTOR SIGNALING BY THE P21-ACTIVATED KINASE 6 (PAK6) Min Zhang, Michael Siedow, Gregory Saia, and Arnab Chakravarti Min ZhangMin Zhang More articles by this author , Michael SiedowMichael Siedow More articles by this author , Gregory SaiaGregory Saia More articles by this author , and Arnab ChakravartiArnab Chakravarti More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.873AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES p21-activated kinase 6 (PAK6) is a serine/threonine kinase belonging to the p21-activated kinase (PAK) family. PAK6 was first identified in a yeast two-hybrid screen for novel androgen receptor (AR) interactors, but its functions have not been established. In this study, we explored the role of PAK6 in mediation hormone resistance in prostate cancer cells. METHODS PAK6 expression was detected in androgen deprived prostate cancer cell line LNCaP. Short hairpin RNA (shRNA) was used to attenuate PAK6 expression in LNCaP cells, and apoptosis and cell cycle distribution were assessed in these cells. Given that AR can be phosphorylated by either the AKT or the mitogen-activated protein kinase (MAPK) pathway and becomes a ligand-independent AR, we investigated the effect of PAK6 on the cross-talks between AR signaling and AKT/MAPK pathways. RESULTS We found that PAK6 expression in LNCaP PCa cells was markedly increased when the cells were cultured for 8 weeks in steroid hormone depleted medium. Antagonism of PAK6 using short hairpin RNA (shRNA) significantly increased antiangogen bicalutamide-induced apoptosis and G1 arrest. These finds implied that PAK6 may play a role in the development of androgen independent prostate cancer. Knockdown of PAK6 in LNCaP cells diminished AKT phosporylation at Ser473 and Thr308 as well as p44/42 MAPK phophorylation at Thr202 and Tyr204, indicating that overexpression of PAK6 during androgen deprivation may activate AR signaling by phosporylation of both AKT and MAPK. CONCLUSIONS These findings extended the current vision of PAK6 functions, and indicated that PAK6 may be involved in androgen-independent prostate cancer development through modulation of AR signaling. Columbus, OH© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e499 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Zhang More articles by this author Michael Siedow More articles by this author Gregory Saia More articles by this author Arnab Chakravarti More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Letters: Andrew Seidman, Clifford Hudis, and Eric Winer on the Point-Counterpoint on Dosing for Paclitaxel for Ovarian Cancer (11/25/09 issue); Letters: Simone's OncOpinion: 'Professional Professional Careers for ‘Old’ Guys (12/10/09 issue), by Leonard Zwelling MD; Letters: “Advances in Bone Biology Research Setting Stage for New Cancer Therapies” (11/25/09 issue), by W. Reid Pitts, Jr., MD

Letters: Andrew Seidman, Clifford Hudis, and Eric Winer on the Point-Counterpoint on Dosing for Paclitaxel for Ovarian Cancer (11/25/09 issue); Letters: Simone's OncOpinion: 'Professional Professional Careers for ‘Old’ Guys (12/10/09 issue), by Leonard Zwelling MD; Letters: “Advances in Bone Biology Research Setting Stage for New Cancer Therapies” (11/25/09 issue), by W. Reid Pitts, Jr., MD

Induction of neuronal apoptosis inhibitory protein expression in response to androgen deprivation in prostate cancer

A mechanism for survival of prostate cancer cells in an androgen-deprived environment remains elusive. Here, we find that expression of neuronal apoptosis inhibitory protein (NAIP) was significantly increased in vivo and in vitro in response to androgen deprivation therapy (ADT). Increased expression of NAIP corresponded to increased DNA-binding activity of NF-κB that physically associated to previously uncharacterized κB-like sites in the NAIP locus. Importantly, expression of NAIP was significantly increased ( p = 0.04) in clinical samples of prostate cancer from patients receiving ADT. Expression of NAIP may be associated with enhanced survival of prostate cancer in response to castration.

Effects of Denosumab on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

In a recently completed 3-year, randomized, double-blind study, denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappaB ligand, significantly increased bone mineral density and decreased new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. We conducted subgroup analyses to evaluate the relationships between subject characteristics and the effects of denosumab on bone mineral density at multiple skeletal sites. A total of 1,468 subjects were randomized 1:1 to receive 60 mg subcutaneous denosumab every 6 months or placebo for 36 months. In these analyses we evaluated the effects of denosumab on bone mineral density at the lumbar spine, total hip and distal 1/3 radius (substudy of 309 subjects) during 36 months in specific subgroups according to age, duration and type of prior androgen deprivation therapy, bone mineral density T score, weight, body mass index, bone turnover marker levels and prevalent vertebral fractures. After 36 months denosumab significantly increased bone mineral density of the lumbar spine, total hip and distal 1/3 radius by 7.9%, 5.7% and 6.9%, respectively, compared with placebo (p <0.0001 for each comparison). Denosumab significantly increased bone mineral density to a degree similar to that observed in the overall analysis for every subgroup including older men as well as those with prevalent fractures, lower baseline bone mineral density, and higher serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b. Mean increases in bone mineral density at each skeletal site were greatest for men with the highest levels of serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b. Denosumab significantly and consistently increased bone mineral density at all skeletal sites and in every subgroup, including men at greatest risk for bone loss and fractures.

Ten Years Results with High-dose Radiotherapy and Risk-adapted Androgen Deprivation in Prostate Cancer: How Curable is T3 Disease?

Ten Years Results with High-dose Radiotherapy and Risk-adapted Androgen Deprivation in Prostate Cancer: How Curable is T3 Disease?

Androgen Deprivation in Prostate Cancer — Step by Step

Androgen Deprivation in Prostate Cancer — Step by Step

Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients

Introduction Our goal was to study the hormonal regulation of immune cell infiltration in prostate cancer patients treated by androgen deprivation therapy (ADT) using an optimized computer-assistance quantification approach. Methods The relative density of immune cell subtypes (CD3 +, CD8 +, CD20 +, CD56 +, CD68 + and Foxp3 +) was analyzed by immunohistochemistry in archived prostate specimens from control patients (radical prostatectomy only, n = 40) and ADT-treated patients (ADT prior to radical prostatectomy, n = 35) using an image analysis software and a whole-slide scanner. Results ADT-treated patients had significantly increased relative density of CD3 + ( p < 0.001) and CD8 + T lymphocytes ( p < 0.001) as well as CD68 + macrophages ( p < 0.001). Elevated abundance of CD56 + Natural Killer (NK) cells was associated with a lower risk of prostate cancer progression ( p = 0.044), while a high density of CD68 + macrophages was related to an increased risk of biochemical recurrence ( p = 0.011). Conclusions Our results demonstrate that the infiltration of specific immune cell subtypes is modulated by ADT. Furthermore our data confirm that NK cells have a protective role against tumor progression while macrophages seem to favor the development of advanced prostate cancer.

Androgen Deprivation in Prostate Cancer — Step by Step

Clinicians and researchers have debated the relative efficacy and timing of androgen deprivation since 1941, when Charles B. Huggins and Clarence V. Hodges reported that androgen deprivation reduced testosterone levels and produced dramatic positive therapeutic responses in patients with advanced prostate cancer.1 By 1966, when Huggins won the Nobel Prize in Physiology or Medicine for this work, many clinicians assumed that castration or treatment with diethylstilbestrol prolonged life and in some instances was curative. The Veterans Administration Cooperative Urological Research Group (VACURG) trials conducted in the 1960s tested this hypothesis.2 The group found that androgen deprivation dramatically relieved the obstructive . . .

MDM2 and Ki-67 Predict for Distant Metastasis and Mortality in Men Treated With Radiotherapy and Androgen Deprivation for Prostate Cancer: RTOG 92-02

PURPOSE MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. PATIENTS AND METHODS Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). CONCLUSION Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

A 16-year clinical experience with intermittent androgen deprivation for prostate cancer: oncological results

To present oncological results with intermittent androgen deprivation (IAD) in a single center. Between 1992 and 2008, 566 patients with prostate cancer (PC) were selected for a non-randomized study of IAD. Two hundred and eighteen patients had biochemical recurrence (BCR) after local treatment for PC and 348 patients had micro- or macro-metastatic disease. On-treatment period (ONTP) consisted of three-monthly injections of gonadatropin-releasing hormone (GnRH) agonist combined with daily oral androgen receptor antagonist. Off-treatment period (OFTP) was indicated when prostate-specific antigen (PSA) was <4 ng/ml. Criteria for resumption of hormonal therapy were PSA >20 ng/ml or clinical symptoms. Cancer specific survival curves were computed according to the Kaplan-Meier method. Median follow-up was 81 months (12-230). Median age was 74.7 years (52-92). Median Gleason score at diagnosis was 7 (3-9). Median initial PSA was 17 ng/ml (0.4-433). Cycle duration decreased progressively from 23 months for the 1st cycle to 10 months at 12th cycle. The number of patients who became hormone resistant was 182 (32%). Median cancer specific survival probability for the series is 12 (10.8-infinity) years. No previous treatment group showed a higher cancer specific survival probability (log rank test, CI 95%, P = 0.003) versus BCR group. Multivariate analysis of cancer specific survival demonstrates age, initial Gleason score and initial PSA level as significant factors affecting mortality (P < 0.05). Intermittent androgen deprivation is an acceptable treatment in different stages of PC. Duration of cycle decreased progressively during therapy. Age, Gleason score and PSA are factors predicting mortality.

Recognizing False Biochemical Failure Calls After Radiation With or Without Neo-Adjuvant Androgen Deprivation for Prostate Cancer

We studied prostate-specific antigen (PSA) changes after radiation with or without neoadjuvant androgen deprivation to determine posttreatment PSA scenarios in which false-positive biochemical failures (FPBF) are most likely to occur. In the Trans-Tasman Radiation Oncology 96.01 Group trial, patients with T2b, 2c, 3, 4 N0 prostate cancer were randomized to 3 or 6 months goserelin and flutamide (STAD) before and during 66 Gy to the prostate and seminal vesicles (XRT) or to XRT alone. Piecewise longitudinal changes in PSA before relapse were characterized and quantified to determine which might cause FPBF calls. Between 1996 and 2000, 802 eligible patients were randomized. Of these, 492 met the criteria for American Society for Therapeutic Radiology and Oncology (ASTRO) failure and 467 for Phoenix failure. Seventy-seven ASTRO fails and 39 Phoenix fails were deemed false positives (FPs). The majority of FPBFs were associated with the "plateauing" in PSA values that follow posttreatment nadir. FPBFs were particularly common in men treated with STAD, in whom small, consecutive PSA rises before or during this phenomenon triggered 56 FP ASTRO fail calls. In these men, the Phoenix fail criteria triggered only 15 FPBF calls. However, the Phoenix criteria were more vulnerable than ASTRO to short-term isolated PSA rises during plateau, which resulted in 15 Phoenix fail calls but only 3 FP ASTRO fails. The Phoenix definition avoided 50% of FPBF calls that occurred with the ASTRO definition. Failures should be confirmed by further PSA rises before investigation and treatment is considered.