Androgen Deprivation Therapy For Prostate Cancer Research Articles

Abstract 3316: Characterizing mechanisms of resistance to androgen deprivation in prostate cancer

Abstract Despite significant advances in the treatment of prostate cancer (PCa), this malignancy remains a leading cause of cancer death among men. PCa cells require androgen receptor (AR) signaling for their growth and survival. Androgen deprivation therapy (ADT) constitutes the main therapeutic option for patients with advanced PCa. However, the major cause of death in men with metastatic prostate cancer involves progression to castration-resistant prostate cancer (CRPC). Characterizing mechanisms of resistance to ADT could enable the development of more effective therapeutic strategies. To identify genes whose silencing drives resistance to ADT in androgen-sensitive PCa cells, we performed a systematic genome-wide suppressor RNAi screen in the androgen-sensitive LNCaP cells, using a 98,000-shRNA library, targeting approximately 16,000 human genes. After infection, cells were cultured in absence of androgens for several weeks. Cells showing the ability to proliferate upon androgen deprivation were harvested at different time points and shRNA sequences were identified and quantitated through nextgen sequencing. Hit genes were those with at least 2 shRNAs enriched >4 fold, and whose silencing exerted the most robust effects on cell proliferation. To validate the identified top-tier genes in vitro, we infected LNCaP cells with lentiviruses carrying shRNAs (2 shRNAs/candidate gene) targeting the top ∼30 candidate genes, in parallel with 15 negative control shRNAs. We monitored the ability of each shRNA to increase proliferation under androgen-deprived conditions, using cell viability assays. To determine whether any shRNAs drive castration resistance by reactivating the AR-signaling pathway, we analyzed the expression of known AR effector genes in the presence of candidate shRNAs and also tested their effect on cell proliferation in the presence of the direct AR antagonist MDV3100. In future, we will also validate candidate genes in vivo, using a LNCaP xenograft model. This study has identified several genes whose silencing may modulate resistance to ADT in prostate cancer. Additional functional studies should determine whether a subset of these may promote new therapeutic strategies for men with CRPC. Citation Format: Ginevra Botta, Judit Jane-Valbuena, Terence Wong, John Doench, Levi A. Garraway. Characterizing mechanisms of resistance to androgen deprivation in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3316. doi:10.1158/1538-7445.AM2014-3316

Measuring the effectiveness of androgen-deprivation therapy for prostate cancer in the medicare population: adequate data are neither the same as nor the enemy of perfect data.

In the late 1970s, investigators learned that androgendeprivation therapy (ADT) decreased serum testosterone levels and,more importantly, reducedbonepainamongmenwith prostate cancer. Whereas ADT demonstrated benefit in patients with metastatic disease and as an adjunct to radiation therapy in patients with locally advanced disease, its use at the organ-confined stage has never been supported by evidence or expert guidelines. Most importantly, randomized data have shown that immediate ADT for nonmetastatic prostate cancernotonly lacks a survival benefit but maycauseharm, suchasanexcess riskofbone fractures.1Nevertheless, the use of ADT for localized prostate cancer increased greatly between the 1990s and early 2000swith compelling evidence that favorable reimbursement contributed to this trend.2 In this issue of JAMA InternalMedicine, Lu-Yao et al3 have confirmed and extended their previous observational cohort studies of prostate cancer treatment outcomes in the Medicare population residing in a region encompassed by the National Cancer Institute’s Surveillance, Epidemiology, andEnd Results (SEER) registries. InaMedicare cohort spanningnearly 2 decades of 66 717 men aged 65 years and older with localized prostate cancerwho receivednodefinitive local therapy, they found that primary ADT confers neither overall nor disease-specific advantage. Moreover, Potosky et al4 have recently reported a similar observational cohort study of more than 15 000 men receiving non–curative intent treatment within integrated health care systems. This study leveraged longitudinalmedical recorddatawith richer clinicaldetail than is available in SEER-Medicare and, like the study of Lu-Yao et al,3 demonstrated neither a survival advantage nor disadvantage from ADT. The analysis of Lu-Yao et al3 highlights both the strengths andpitfalls of usingobservational cohorts, suchas those identified from SEER-Medicare linked data, tomeasure effectiveness. Inferences from observational studies aremost reliable when the groups being compared are similar in all respects other than the intervention under scrutiny. Of course in practice, this is often not the case. Indeed, in the study of Lu-Yao et al,3 baseline disease characteristics differ substantially between men who did and did not receive ADT with regard to clinical stage and grade, among other attributes. As it became clear that there is little or no role for primaryADT in the treatment of nonmetastatic prostate cancer, contemporary clinicians have becomemore selective in recommending primary ADT, for example, reserving it for patients with poor prognosis or the inability to tolerate radiation therapy. Conversely, “conservative management” of prostate cancer as a concept has shifted fromwatchfulwaiting, apassiveapproach forolder menwith limited life expectancy focused on palliation rather than treatment, to active surveillance, in which healthy patients are intensively monitored with repeated prostatespecific antigen tests, digital rectal examinations, and prostate biopsies at systematic intervals and in which definitive treatment is advocated at any signof disease progression.5 Finally, prostate-specific antigen testing at diagnosis, an important prognostic and predictive marker, is imperfectly captured by SEER and is only available for themost recent years. Both the missing data and the imbalance from this registrybased study impede the ability to make definitive comparisonsbetween these treatment strategies.The limitationsofobservational cohort studies using SEER-Medicare datamust be balanced against the recognition that there will not be additional randomized trials and that the assessment of effectiveness fromSEER-Medicare data canbedone expeditiously and at nominal cost. One strategy to circumvent the classic selection bias that plagues the ability to make valid inferences from treatment comparisons using observational data is to use an instrumental variable to account for confounding by unmeasured differences between treatment groups. To be considered valid, an instrumental variable must satisfy 2 quintessential conditions: thevariablemustbecorrelatedwith the treatmentwhile not being associated with the outcome of interest except through the effect of the treatment itself. This statistical method therefore reduces treatment selectionbias and“pseudorandomizes” patients. Lu-Yao et al3 used the proportion of patientswho receivedADTwithinahealth service areaas their instrument. Knowinghowwell an instrument performs is the key to interpreting how successfully it accomplished the goal of pseudorandomization. TheF-statistic is commonlyused to assess the strength of the instrument and thereby the ability tomitigate potential selection bias. A robust instrument typically has an F-statistic greater than 10. The attempt to identify an instrumental variable is a strength of the study of LuYao et al3; nonetheless, inclusion of an assessment of the instrument’s performance would have helped readers gain a better understanding of howwell it addressed potential confounding. Indeed, physicians needmore guidance on how to interpret the results of instrumental variable analyses as they Related article page 1460 Research Original Investigation Androgen-Deprivation Therapy for Prostate Cancer

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12Years of Follow-up

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12Years of Follow-up

Effects of Exercise on Treatment-Related Adverse Effects for Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Systematic Review

Androgen-deprivation therapy is a commonly used treatment for men with prostate cancer; however, the adverse effects can be detrimental to patient health and quality of life. Exercise has been proposed as a strategy for ameliorating a range of these treatment-related adverse effects. We conducted a systematic review of the literature regarding the effects of exercise on treatment-related adverse effects in men receiving androgen-deprivation therapy for prostate cancer. An online electronic search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, SPORTDiscus, and Health Source databases was performed to identify relevant peer-reviewed articles published between January 1980 and June 2013. Eligible study designs included randomized controlled trials as well as uncontrolled trials with pre- and postintervention data. Information was extracted regarding participant and exercise intervention characteristics as well as the effects of exercise on bone health, body composition, physical performance, cardiometabolic risk, fatigue, and quality of life. Ten studies were included, with exercise interventions involving aerobic and/or resistance training. Exercise training demonstrated benefits in muscular strength, cardiorespiratory fitness, functional task performance, lean body mass, and fatigue, with inconsistent effects observed for adiposity. The impact of exercise on bone health, cardiometabolic risk markers, and quality of life are currently unclear. Among patients with prostate cancer treated with androgen-deprivation therapy, appropriately prescribed exercise is safe and may ameliorate a range of treatment-induced adverse effects. Ongoing research of high methodologic quality is required to consolidate and expand on current knowledge and to allow the development of specific evidence-based exercise prescription recommendations.

Exercise effects on adipokines and the IGF axis in men with prostate cancer treated with androgen deprivation: A randomized study

Androgen deprivation therapy (ADT) has significant deleterious effects on body composition that may be accompanied by unfavourable changes in adipokine levels. While exercise has been shown to improve a number of side effects associated with ADT for prostate cancer, no studies have assessed the effect of exercise on adiponectin and leptin levels, which have been shown to alter the mitogenic environment. Twenty-six men with prostate cancer treated with ADT were randomized to home-based aerobic exercise training or resistance exercise training for 24 weeks. Adiponectin, leptin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) were analyzed by ELISA (enzyme-linked immunosorbent assay), in addition to physical activity volume, peak aerobic capacity, and anthropometric measurements, at baseline, 3 months and 6 months. Resistance exercise significantly reduced IGF-1 after 3 months (p = 0.019); however, this change was not maintained at 6 months. At 6 months, IGFBP-3 was significantly increased compared to baseline for the resistance training group (p = 0.044). In an exploratory analysis of all exercisers, favourable changes in body composition and aerobic fitness were correlated with favourable levels of leptin, and favourable leptin:adiponectin and IGF-1:IGFBP-3 ratios at 3 and 6 months. Home-based exercise is correlated with positive changes in adipokine levels and the IGF-axis that may be related to healthy changes in physical fitness and body composition. While the improvements of adipokine markers appear to be more apparent with resistance training compared to aerobic exercise, these findings must be considered cautiously and require replication from larger randomized controlled trials to clarify the role of exercise on adipokines and IGF-axis proteins for men with prostate cancer.

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to tumor regression. HIF1α expression is probably not a useful hypoxia biomarker during ADT in prostate cancer.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BackgroundTrials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. ObjectiveBased on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. Design, setting, and participantsEORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0–4 N0–2 M0 PCa patients. Outcome measurements and statistical analysisTime to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. Results and limitationsAfter a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3–5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05–1.39; p [noninferiority]=0.72, p [difference] = 0.0085). ConclusionsThis study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

Objective. The aim of this study was to assess patient preference regarding the length of treatment intervals of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists for prostate cancer. Material and methods. The study was conducted as a questionnaire-based, cross-sectional study at a large university hospital. A specific questionnaire was developed based on current literature, clinical experience and a pilot phase of the study. The primary endpoint was preferred treatment frequency. Secondary outcome measures included reasons for preferred treatment frequency, treatment satisfaction and side-effects. Overall, 238 men receiving ADT for prostate cancer were presented with the questionnaire between September 2011 and May 2012. Descriptive statistics, the chi-squared test and multiple regression were used for analyses. Results. In total, 176 questionnaires (74%) were available for analysis. A total of 38.1% of participants preferred frequent treatment (“Every month”, “Every third month”), 32.4% preferred infrequent treatment (“Every sixth month”, “Every twelfth month”) and 29.6% stated that length of the treatment intervals made no difference (p = 0.37). Patients with disease progression were most likely to prefer frequent treatment (odds ratio 4.4, 95% confidence interval 1.9–10.4). Overall, 84.1% were satisfied with treatment while one patient (0.6%) was dissatisfied. Nine per cent indicated severe side-effects. Conclusions. Less frequent ADT treatment may help to lower the pressure on healthcare systems and may be of benefit for a large group of patients. However, it cannot be prescribed blindly without possibly affecting patient satisfaction. The choice of treatment intervals should be made in collaboration between the physician and the patient.

Complementary and alternative medicine (CAM) in prostate and bladder cancer

To provide an overview of the scientific and clinical studies underlying the most common vitamin and herbal preparations used in prostate and bladder cancer and evaluate the evidence behind them. A literature search was undertaken on PubMed using various keywords relating to the use of complementary and alternative medicine (CAM) in prostate and bladder cancer.Vitamin E and selenium supplementation can potentially have adverse effects by increasing the risk of prostate cancer. Initial clinical studies of pomegranate and green tea, investigating their chemotherapeutic properties in prostate and bladder cancer have yielded encouraging results. Curcumin, resveratrol, and silibinin have potential anticancer properties through multiple molecular targets; their clinical effectiveness in prostate and bladder cancer is yet to be evaluated. Zyflamend, like PC-SPES, is a combined CAM therapy used in prostate cancer. Acupuncture is popular among patients experiencing hot flushes who are receiving androgen-deprivation therapy for prostate cancer. Conclusive evidence for the use of CAM in prostate and bladder cancer is lacking and not without risk.

Surgical castration for androgen-deprivation therapy of prostate cancer – relevance in current practice

Objective: Rapid control of the disease is essential in the management of patients with critical and symptomatic metastatic prostate cancer. Pharmacological castration has become the main form of androgen-deprivation therapy (ADT) for prostate cancer, with luteinising hormone-releasing hormone (LHRH) agonists being used in more than 90% of cases. Surgical castration has become the less preferred modality. This article aims to explore the clinical and economic advantages of bilateral sub-capsular orchidectomy (BSCO). Method: Pre- and post-operative serial testosterone levels were taken from patients who had BSCO for adenocarcinoma of the prostate. The half-life of testosterone was calculated. The cost of surgical castration on the National Health Service (NHS) was compared to the cost of LHRH agonists. Results: Ten patients with a median prostate-specific antigen (PSA) level of 93 ng/ml (range 26 to 4557 ng/ml) were included. Their mean random pre-operative testosterone level was 13.8 ng/ml (range 6.8 to 21.8 ng/ml). The mean half-life of testosterone was 61.7 minutes when calculated from the first two hours, and 67 minutes when calculated from the total drop with no significant variation ( p = 0.464). Four patients reached castrate levels of testosterone within four to six hours. The total cost of an inpatient BSCO in the NHS was £850 to £1154. This was more or less equivalent to one year’s worth of the commonly used LHRH agonists without including the cost of medical services. Conclusions: Testosterone has a short half-life and reaches castrate levels within hours of the BSCO procedure. Rapid castration by BSCO would benefit patients with critical metastatic disease. BSCO on the NHS in patients with more than one year of life expectancy is also economically beneficial.

857 Relationship between PSA level and impairment of proteinase-inhibitory balance of key proteolytic systems during androgen-deprivation therapy for prostate cancer

857 Relationship between PSA level and impairment of proteinase-inhibitory balance of key proteolytic systems during androgen-deprivation therapy for prostate cancer

Molecular Markers in Sex Hormone Pathway Genes Associated with the Efficacy of Androgen-Deprivation Therapy for Prostate Cancer

Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host genetic variations in sex hormone pathway genes are associated with the efficacy of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM) after ADT (P≤0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P<0.001). Our results identify two candidate molecular markers in key genes of androgen and estrogen pathways associated with PCSM after ADT, establishing the role of pharmacogenomics in this therapy.

Optimal bone health management strategies in patients with prostate cancer

Bone health is affected in patients with prostate cancer, both by the disease and its treatment. Metastases to bone leads to pain, fractures, and spinal cord compression; bone loss due to androgen deprivation therapy (ADT) leads to osteoporosis and its complications. Both these scenarios are a major cause of morbidity and adversely affect the quality of life of these patients. Maintaining an optimum bone health throughout the natural course of prostate cancer is an important aspect in the management of this disease. An understanding of the complex interplay between osteoclasts, osteoblasts, receptor activator of nuclear factor κB (RANK), and various other tyrosine kinases involved in the pathophysiology of bone metastases is essential. Zoledronic acid (ZA), an intravenously administered bisphosphonate, and Denosumab, a subcutaneously administered inhibitor of nuclear factor B ligand (RANKL), have already been approved by Food and Drug Administration (FDA) for their use in treatment of bone metastases. This article discusses the pathophysiology of bone metastases and bone loss due to ADT in prostate cancer, role of biomarkers, newer modalities of imaging, World Health Organization (WHO)/FRAX nomogram in evaluation of these patients, utility of currently available drugs and evidence supporting their use, and newer therapeutic agents like alpha-emitting Radium-223, endothelin-A receptor antagonists (Atrasentan and Zibotentan) and the proto-oncogene tyrosine-protein kinase (SRC) inhibitor, Dasatinib.

PCN8 The Association Between Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk in Taiwan: A Population-Based Cohort Study

PCN8 The Association Between Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk in Taiwan: A Population-Based Cohort Study

Preliminary Results of a Randomized Trial of Optimal Timing of Dose Escalated (76 Gy) Radiation and 6 months ADT in Prostate Cancer

A pooled analysis of trials using conventional dose radiation (XRT) indicates 6 months androgen deprivation therapy (ADT) improves prostate cancer survival in Gleason 7 Prostate Cancer. The benefits of ADT when used in combination with dose escalated XRT remains to be determined. The purpose of the report is to evaluate the compliance, toxicity and efficacy of Dose Escalated XRT in combination with 6 months goserelin + bicalutamide (ADT) in the context of a Phase 3 Trial.

Sarcopenia During Androgen-Deprivation Therapy for Prostate Cancer

To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT). We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months). Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645). In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.

Osteoporosis screening among prostate cancer survivors treated with androgen deprivation therapy.

6045 Background: Androgen deprivation therapy (ADT), the standard systemic treatment for prostate cancer, has adverse effects including bone loss and fractures. Current national guidelines suggest that men receiving ADT undergo dual energy x-ray absorptiometry (DXA) before and during ADT to better characterize fracture risk. We assessed receipt of DXA testing in a population-based cohort of men treated continuously with ADT for at least 1 year and identified factors associated with testing. Methods: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified men aged &gt;65 with local or regional prostate cancer diagnosed during 2001-2007 and followed through 2009 who received at least 1 year of continuous ADT. We identified receipt of DXA testing in the 18-month period beginning 6 months before the first dose of ADT. We used logistic regression to identify factors associated with DXA testing, including patient and tumor characteristics and the physicians with whom they had outpatient visits. Results: Among 28,960 men treated with ADT for ≥1 year, 6.5% had at least one DXA scan from 6 months before the first dose of ADT through 1 year after. DXA testing increased over time, with men initiating ADT in 2007-2009 more likely to be tested than those treated in 2001-2002 (10.0% vs. 3.4%, OR 2.29, 95% CI 1.83-2.85). Men aged ≥85 were less likely than men aged 66-69 to undergo testing (OR 0.76, 95% CI 0.65-0.89). Black men were less likely than white men to undergo testing (OR 0.92, 95% CI 0.61-0.86), as were men living in areas with lower educational attainment (P&lt;.001). Compared with men seeing a urologist but no medical oncologist or primary care provider (PCP), men seeing a medical oncologist and a urologist (OR 2.11, 95% CI 1.39-3.21) and those seeing a medical oncologist, urologist and PCP (OR 2.59, 95% CI 2.01-3.34) had higher odds of testing. Conclusions: Few men receiving ADT for prostate cancer undergo DXA testing, with particularly low rates of testing among older men, black men, and those living in areas with low educational attainment. Visits with a medical oncologist were associated with increased odds of testing. Interventions are needed to increase bone density testing among men receiving long-term ADT.

Does Comorbidity Influence the Risk of Myocardial Infarction or Diabetes During Androgen-Deprivation Therapy for Prostate Cancer?

BackgroundAndrogen-deprivation therapy (ADT) for prostate cancer (PCa) may be associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others. ObjectiveTo assess whether the risk of myocardial infarction (MI) or diabetes during ADT is modified by specific baseline comorbidities. Design, setting, and participantsWe conducted a population-based observational study of 185 106 US men ≥66 yr of age diagnosed with local/regional PCa from 1992 to 2007. We assessed comorbidities monthly over the follow-up period. Outcome measurements and statistical analysisCox proportional hazards models with time-varying variables assessing incident diabetes or MI. Results and limitationsA total of 49.9% of the men received ADT during follow-up. Among men with no comorbidities, ADT was associated with an increase in the adjusted hazard of MI (adjusted hazard ratio [AHR]: 1.09; 95% confidence interval [CI], 1.02–1.16) and diabetes (AHR: 1.33; 95% CI, 1.27–1.39). Risks of MI and diabetes were similarly increased among men with and without specific comorbid illnesses (p>0.10 for all interactions, with one exception). Previous MI, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new MI and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history. ConclusionsTraditional risk factors for MI and diabetes were also associated with developing these conditions during ADT but did not significantly modify the risk attributable to ADT. Strategies to screen and prevent diabetes and cardiovascular disease in men with PCa should be similar to the strategies recommended for the general population.

762 FRAX® ASSESSMENT OF MEN TREATED WITH ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced II1 Apr 2012762 FRAX® ASSESSMENT OF MEN TREATED WITH ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER Rafal Turo and William Cross Rafal TuroRafal Turo Leeds, United Kingdom More articles by this author and William CrossWilliam Cross Leeds, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.849AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) for prostate cancer is associated with loss of bone mineral density (BMD) and increased risk of fracture. At present, there is limited information on which men are suitable for preventative therapy to maintain bone health. In men treated with ADT for prostate cancer, we have evaluated fracture risk by application of the WHO/FRAX® tool. METHODS Patient and treatment parameters were prospectively collected from a practice cohort of men with prostate cancer treated with ADT. Fracture risk was calculated using the online WHO/FRAX® algorithm. RESULTS A total of 121 men with a median age of 76 years were evaluated. Bone metastases were present in 43.8% of subjects and 7.4% had a history of fracture. By the FRAX® algorithm the 3% hip fracture risk threshold for preventative treatment was exceeded by 66.9% of men (median 10-year hip fracture risk was 4.7%)Figure 1. When subjects were grouped by age the treatment threshold was exceeded by 18.5% of those younger than 70 years, 64.6% of those 70 to 79 years old and by 97.8 % of those 80 years old or older. Fracture risk was recalculated based on a normal dual-energy X-ray absorptiometry result and the median 10-year hip fracture risk was 1.7% and 9.9% of subjects exceeded the 3% threshold for pharmacotherapy Figure 2. CONCLUSIONS In this cohort of men the FRAX® calculated risk of fracture was clinically significant. The results have highlighted the need to address bone health and have guided our service development. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e311-e312 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rafal Turo Leeds, United Kingdom More articles by this author William Cross Leeds, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Gonadotropin‐releasing hormone: An update review of the antagonists versus agonists

Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future.